Chapter 304. Zygomycosis (Mucormycosis)

Zygomycosis is an umbrella term for all diseases caused by fungi of the class Zygomycetes. The more common term mucormycosis refers to a group of invasive mycoses caused by members of the order Mucorales within the class Zygomycetes.1Rhizopus species are the most commonly isolated agents of mucormycosis.2 The Mucorales are distributed worldwide and commonly grow in decaying organic matter.3 Although exposure to the airborne spores of these thermotolerant, rapidly growing fungi is universal, human disease is infrequent and is indicative of a serious underlying predisposing condition.4 Diabetes mellitus, particularly diabetic ketoacidosis, is the most common predisposing condition in patients with mucormycosis.2,5 Underlying disease accompanied by acidosis, such as uremia, malnutrition,6 and congenital metabolic aciduria,7 may also predispose to mucormycosis. Additional risk factors include neutropenia,8 hematological malignancies,9 burns,10 prematurity,11 corticosteroid therapy,12 solid-organ transplantation,13 bone marrow transplantation,14 and deferoxamine/desferrioxamine therapy for management of iron and aluminum overload states.15

Infection in humans most commonly occurs following inhalation of the spores of Mucorales into the respiratory tract.4 Spores may also be ingested or introduced directly into abraded skin.16 Germination of spores occurs with hyphal proliferation and invasion of tissue. Infection may spread by direct extension and hematogenous dissemination. Regardless of the tissue involved, the pathologic hallmark of mucormycosis is hyphal invasion of blood vessels with resultant hemorrhage, thrombosis, infarction, and production of black, necrotic debris.6,17 The reasons these fungi target the vasculature are unknown.

The mechanisms that account for the increased susceptibility to mucormycosis in different patient groups remain incompletely understood. Neutrophils and macrophages are important components of the host response to Mucorales.18,19 Thus, defects in their function likely contribute to the pathogenesis of mucormycosis. Iron is an important growth factor for these fungi; hence, interactions between iron molecules and transferrin have been postulated to play a role in predisposing deferoxamine-treated patients to the development of mucormycosis.20 Because these fungi metabolize ketones and grow optimally at an acid pH,21 the metabolic conditions encountered in ketoacidotic hosts may enhance their growth.

Clinical Manifestations

The clinical manifestations of mucormycosis are classified by site of involvement into rhinocerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous infections.1 Rhinocerebral infection occurs most frequently and typically presents as facial pain, nasal congestion, and headache in a poorly controlled diabetic patient.22,23 From the nasal mucosa and paranasal sinuses, Infection may spread to the orbit, resulting in orbital cellulitis, paresis of extraocular muscles, and proptosis. Further extension into the cerebral vasculature and brain can lead to cavernous sinus thrombosis, brain infarcts, and focal neurologic deficits.24

Most cases of pulmonary mucormycosis have occurred in neutropenic hosts, especially those receiving chemotherapy for leukemia and lymphoma.25 Clinically, These patients present with unremitting fever and dyspnea. The chest roentgenogram may show patchy consolidation and cavity formation. Infection progresses rapidly, and hemoptysis may be a fatal complication.26

Cutaneous mucormycosis usually occurs at sites of burns, trauma, and invasive procedures in immunosuppressed hosts, including premature infants.11,16,27 The skin lesion may begin as an area of erythema and induration that subsequently develops central necrosis. Skin lesions may also be a manifestation of disseminated infection.28,29

Risk factors for gastrointestinal mucormycosis include malnutrition, prematurity,30,31 kidney transplantation,32 and underlying gastrointestinal disease. The stomach, ileum, and colon are involved most frequently.33 Presenting findings may include nonspecific abdominal pain, hematochezia, or melena. Premature infants may experience necrotizing enterocolitis.28

Disseminated infection most often follows pulmonary invasion and may spread to the brain, liver, spleen, and other tissues.25,34 Clinically, these patients have rapidly progressive multiple organ failure with a high mortality rate. Miscellaneous forms of mucormycosis include endocarditis, osteomyelitis, and pyelonephritis.1

Diagnosis

Mucormycosis must be differentiated from other opportunistic infections in immunosuppressed hosts. Cutaneous mucormycosis may mimic ecthyma gangrenosum, which is commonly due to Pseudomonas aeruginosa.35 Invasion of blood vessels is a major pathologic finding with Aspergillus infection.36 Not surprisingly, the pulmonary, cerebral, and cutaneous manifestations of aspergillosis are clinically indistinguishable from those of mucormycosis. The definitive diagnosis of mucormycosis requires demonstration of hyphal elements invading tissue in a biopsy specimen.1,4 Because the Mucorales may colonize body surfaces, swabs of drainage or abnormal tissue are inappropriate. Tissue biopsies, especially of black necrotic lesions, should be sent for histologic examination and for culture. Grinding of tissue should be avoided because it may disrupt the hyphal elements. Demonstration of irregularly shaped, broad, nonseptate hyphae with right-angle branching by either hematoxylin and eosin or Grocott-Gomori methenamine-silver nitrate staining is the gold standard for diagnosis of mucormycosis. The agents of mucormycosis may be difficult to isolate in culture from infected tissues. Cultures of blood, urine, and cerebrospinal fluid are rarely positive.

Treatment

Successful treatment of mucormycosis requires a coordinated medical and surgical approach.22 If possible, the underlying predisposing condition should be reversed. Metabolic acidosis should be corrected, and the doses of corticosteroids and other immunosuppressive drugs should be lowered if at all possible. All devitalized tissue should be surgically removed. Often, debridement must be repeated daily for several days. Intravenous administration of amphotericin B is the standard therapy.37 Posaconazole, an orally available triazole, has been used as salvage therapy in mucormycosis.37 Duration of therapy for antifungals is often hard to define and should be individualized for the specific location of infection in a particular patient.