CHAPTER 117: MUCORMYCOSIS

Mucormycosis represents a group of life-threatening infections caused by fungi of the order Mucorales of the subphylum Mucoromycotina (formerly known as the class Zygomycetes). Infection caused by the Mucorales is most accurately referred to as mucormycosis, although the term zygomycosis may still be used by some sources. Mucormycosis is highly invasive and relentlessly progressive, resulting in higher rates of morbidity and mortality than many other infections. However, recent studies have suggested that mortality rates from mucormycosis have declined with newer therapies. A high index of suspicion is critical for diagnosis, and early initiation of therapy—often before confirmation of the diagnosis—is necessary to optimize outcomes.

Fungi of the order Mucorales belong to seven medically relevant families (Table 117-1), all of which can cause mucormycosis. Among the Mucorales, Rhizopus oryzae (in the family Mucoraceae) is by far the most common cause of infection in the Western Hemisphere. Less frequently isolated species of the Mucoraceae that cause a similar spectrum of infections include Rhizopus microsporus, Rhizomucor pusillus, Lichtheimia corymbifera (formerly Absidia corymbifera), Apophysomyces elegans, and Mucor species (which, despite its name, only rarely causes mucormycosis). Increasing numbers of cases of mucormycosis due to infection with Cunninghamella species (family Cunninghamellaceae) have also been reported, particularly in highly immunocompromised patients. Rare case reports have demonstrated the ability of fungi in the remaining families of the Mucorales to cause mucormycosis, although other Mucorales can be the major cause of disease in certain geographic areas (e.g., A. elegans in India and Mucor irregularis in China).

The Mucorales are ubiquitous environmental fungi to which humans are constantly exposed. These fungi cause infection primarily in patients with diabetes or defects in phagocytic function (e.g., those associated with neutropenia or glucocorticoid treatment). Patients with elevated levels of free iron, which supports fungal growth in serum and tissues, are likewise at increased risk for mucormycosis. In iron-overloaded patients with end-stage renal failure, treatment with deferoxamine predisposes to the development of rapidly fatal disseminated mucormycosis; this agent, an iron chelator for the human host, serves as a fungal siderophore, directly delivering iron to the Mucorales. Furthermore, patients with diabetic ketoacidosis (DKA) are at high risk of developing rhinocerebral mucormycosis. The acidosis causes dissociation of iron from sequestering proteins in serum, resulting in enhanced fungal survival and virulence. Nevertheless, the majority of diabetic patients who present with mucormycosis are not acidotic, and, even absent acidosis, hyperglycemia directly contributes to the risk of mucormycosis by at least three likely mechanisms: (1) hyperglycation of iron-sequestering proteins, disrupting normal iron sequestration; (2) upregulation of a mammalian cell receptor (GRP78) that binds to Mucorales, enabling tissue penetration (due to both a direct effect of hyperglycemia and increasing levels of free iron, which independently enhances GRP78 expression); and (3) induction of poorly characterized defects in phagocytic function.

Mucormycosis typically occurs in patients with diabetes mellitus, solid organ or hematopoietic stem cell transplantation (HSCT), prolonged neutropenia, or malignancy. The majority of diabetic patients are not acidotic on presentation with mucormycosis. Furthermore, patients often have no previously recognized history of diabetes mellitus when they present with mucormycosis. In these instances, presentation for mucormycosis may result in the first clinical recognition of hyperglycemia, which may have been unmasked by recent glucocorticoid use. Thus a high index of suspicion of mucormycosis must be maintained, even in the absence of a known history of diabetes, if hyperglycemia is present. In patients undergoing HSCT, mucormycosis develops at least as commonly during nonneutropenic as during neutropenic periods, probably because of glucocorticoid treatment of graft-versus-host disease. Mucormycosis can occur as isolated cutaneous or subcutaneous infection in immunologically normal individuals after traumatic implantation of soil or vegetation (e.g., due to natural disasters or motor vehicle accidents) or in nosocomial settings via direct access through IV catheters, SC injections, or maceration of the skin by a moist dressing.

Patients receiving antifungal prophylaxis with either itraconazole or voriconazole may be at increased risk of mucormycosis. These patients typically present with disseminated mucormycosis, the most lethal form of disease. Breakthrough mucormycosis also has been described in patients receiving posaconazole or echinocandin prophylaxis.

Mucormycosis can be divided into at least six clinical categories based on clinical presentation and the involvement of a particular anatomic site: rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous. These categories of invasive mucormycosis tend to affect patients with specific defects in host defense. For example, patients with DKA typically develop the rhino-orbital-cerebral form and much more rarely develop pulmonary or disseminated disease. In contrast, pulmonary mucormycosis occurs most commonly in leukemic patients who are receiving chemotherapy and in patients undergoing HSCT.

Rhino-orbital-cerebral disease

Rhino-orbital-cerebral mucormycosis continues to be the most common form of the disease. Most cases occur in patients with diabetes, although such cases (probably due to glucocorticoid use) are increasingly being described in the transplantation setting, often along with glucocorticoid-induced diabetes mellitus. The initial symptoms of rhino-orbital-cerebral mucormycosis are nonspecific and include eye or facial pain and facial numbness followed by the onset of conjunctival suffusion and blurry vision. Fever may be absent in up to half of cases. White blood cell counts are typically elevated as long as the patient has functioning bone marrow. If untreated, infection usually spreads from the ethmoid sinus to the orbit, resulting in compromise of extraocular muscle function and proptosis, typically with chemosis. Onset of signs and symptoms in the contralateral eye, with resulting bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is ominous, suggesting the development of cavernous sinus thrombosis.

Upon visual inspection, infected tissue may appear to be normal during the earliest stages of fungal spread, then progressing through an erythematous phase, with or without edema, before the onset of a violaceous appearance and finally the development of a black necrotic eschar. Infection can sometimes extend from the sinuses into the mouth and produce painful necrotic ulcerations of the hard palate, but this is a late finding that suggests extensive, well-established infection.

Pulmonary disease

Pulmonary mucormycosis is the second most common manifestation. Symptoms include dyspnea, cough, and chest pain; fever is often but not invariably present. Angioinvasion results in necrosis, cavitation, and/or hemoptysis. Lobar consolidation, isolated masses, nodular disease, cavities, or wedge-shaped infarcts may be seen on chest radiography. High-resolution chest CT is the best method for determining the extent of pulmonary mucormycosis and may demonstrate evidence of infection before it is seen on chest x-ray. In the setting of cancer, where mucormycosis may be difficult to differentiate from aspergillosis, the presence of ≥10 pulmonary nodules, pleural effusion, or concomitant sinusitis makes mucormycosis more likely. It is critical to distinguish mucormycosis from aspergillosis as rapidly as possible because treatments for these infections differ. Indeed, voriconazole—the first-line treatment for aspergillosis—exacerbates mucormycosis in mouse and fly models of infection.

Cutaneous disease

Cutaneous mucormycosis may result from external implantation of the fungus or conversely from hematogenous dissemination. External implantation–related infection has been described in the setting of soil exposure from trauma (e.g., in a motor vehicle accident or natural disaster), penetrating injury with plant material (e.g., a thorn), injections of medications (e.g., insulin), catheter insertion, contamination of surgical dressings, and use of tape to secure endotracheal tubes. Cutaneous disease can be highly invasive, penetrating into muscle, fascia, and even bone. In mucormycosis, necrotizing fasciitis carries a mortality rate approaching 80%. Necrotic cutaneous lesions in the setting of hematogenous dissemination also are associated with an extremely high mortality rate. However, with prompt, aggressive surgical debridement, isolated cutaneous mucormycosis has a favorable prognosis and a low mortality rate.

Gastrointestinal disease

In the past, gastrointestinal mucormycosis occurred primarily in premature neonates in association with disseminated disease and necrotizing enterocolitis. However, there has been a marked increase in case reports describing adults with neutropenia or other immunocompromising conditions. In addition, gastrointestinal disease has been reported as a nosocomial process following administration of medications mixed with contaminated wooden applicator sticks. Nonspecific abdominal pain and distention associated with nausea and vomiting are the most common symptoms. Gastrointestinal bleeding is common, and fungating masses may be seen in the stomach at endoscopy. The disease may progress to visceral perforation, with extremely high mortality rates.

Disseminated and miscellaneous forms of disease

Hematogenously disseminated mucormycosis may originate from any primary site of infection. The most common site of dissemination is the brain, but metastatic lesions may also be found in any other organ. The mortality rate associated with dissemination to the brain approaches 100%. Even without central nervous system (CNS) involvement, mortality rates for disseminated mucormycosis exceed 90%. Miscellaneous forms of mucormycosis may affect any body site, including bones, mediastinum, trachea, kidneys, and (in association with dialysis) peritoneum.

A high index of suspicion is required for diagnosis of mucormycosis. Unfortunately, autopsy series have shown that up to half of cases are diagnosed only post-mortem. Because the Mucorales are environmental isolates, definitive diagnosis requires a positive culture from a sterile site (e.g., a needle aspirate, a tissue biopsy specimen, or pleural fluid) or histopathologic evidence of invasive mucormycosis. A probable diagnosis of mucormycosis can be established by culture from a nonsterile site (e.g., sputum or bronchoalveolar lavage) when a patient has appropriate risk factors as well as clinical and radiographic evidence of disease. However, given the urgency of administering therapy early, the patient should be treated while confirmation of the diagnosis is awaited.

Biopsy with histopathologic examination remains the most sensitive and specific modality for definitive diagnosis (Fig. 117-1). Biopsy reveals characteristic wide (≥6- to 30-μm), thick-walled, ribbon-like, aseptate hyphal elements that branch at right angles. Other fungi, including Aspergillus, Fusarium, and Scedosporium species, have septa, are thinner, and branch at acute angles. Because artificial septa may result from folding of tissue during processing (which may also alter the appearance of the angle of branching), the width and the ribbon-like form of the fungus are the most reliable features distinguishing mucormycosis. The Mucorales are visualized most effectively with periodic acid–Schiff or methenamine silver stain or, if the organism burden is high, with hematoxylin and eosin. While histopathology can identify the Mucorales, specific species can be identified only by culture. Polymerase chain reaction (PCR) is being investigated as a diagnostic tool for mucormycosis but is not yet approved by the U.S. Food and Drug Administration (FDA) for this purpose and is not generally available.

Unfortunately, cultures are positive in fewer than half of cases of mucormycosis. Nevertheless, the Mucorales are not fastidious organisms and tend to grow quickly (i.e., within 48 h) on culture media. The likely explanation for the low sensitivity of culture is that the Mucorales form long filamentous structures that are killed by tissue homogenization—the standard method for preparing tissue cultures in the clinical microbiology laboratory. Thus the laboratory should be advised when a diagnosis of mucormycosis is suspected, and the tissue should be cut into sections and placed in the center of culture dishes rather than homogenized. There is also substantial variability among isolates in optimal growth temperature, so growth at both room temperature and 37°C is advisable.

Imaging techniques often yield subtle findings that underestimate the extent of disease. For example, the most common finding on CT or MRI of the head or sinuses of a patient with rhino-orbital mucormycosis is sinusitis that is indistinguishable from bacterial sinusitis. It is also common to detect no abnormalities in sinus bones despite clinical evidence of progressive disease. MRI is more sensitive (~80%) for detecting orbital and CNS disease than is CT. High-risk patients should always undergo endoscopy and/or surgical exploration, with biopsy of the areas of suspected infection. If mucormycosis is suspected, initial empirical therapy with a polyene antifungal agent should be initiated while the diagnosis is being confirmed.

Other mold infections, including aspergillosis, scedosporiosis, fusariosis, and infections caused by the dematiaceous fungi (brown-pigmented soil organisms), can cause clinical syndromes identical to mucormycosis. Histopathologic examination usually allows distinction of the Mucorales from these other organisms, and a positive culture permits definitive species identification. As stated above, it is important to distinguish the Mucorales from these other fungi, as the preferred antifungal treatments differ (i.e., polyenes for the Mucorales vs. expanded-spectrum triazoles for most septate molds). The entomophthoromycoses caused by Basidiobolus and Conidiobolus also can cause identical clinical syndromes. These fungi may appear similar to the Mucorales on histopathology and can be reliably distinguished from the latter only by culture.

In a patient with sinusitis and proptosis, orbital cellulitis and cavernous sinus thrombosis caused by bacterial pathogens (most commonly Staphylococcus aureus, but also streptococcal and gram-negative species) must be excluded. Klebsiella rhinoscleromatis is a rare cause of an indolent facial rhinoscleroma syndrome that may appear similar to mucormycosis. Finally, the Tolosa-Hunt syndrome causes painful ophthalmoplegia, ptosis, headache, and cavernous sinus inflammation; biopsies and clinical follow-up may be needed to distinguish the Tolosa-Hunt syndrome from mucormycosis by the lack of progression of the former entity.