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Chapter 235

Zygomycosis (Mucormycosis)Jane M. Gould and Stephen C. Aronoff

ETIOLOGY

Zygomycosis refers to a group of opportunistic fungal infections

caused by dimorphic fungi of the class Zygomycetes, which areprimitive, fast-growing fungi that are largely saprophytic andubiquitous. These organisms are found commonly in soil, indecaying plant and animal matter, and on moldy cheese, fruit,and bread.

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This class is subdivided into 2 orders, Mucorales and Ento-mophthorales, each containing human pathogens. The termmucormycosis refers only to infections caused by Mucorales,which includes the genera Absidia, Apophysomyceae, Mucor,Rhizomucor, and Rhizopus and represents the more-commoncause of zygomycosis in humans. Infections caused by organismsof the genera Cunninghamella, Saksenaea, and Cokeromyces areseen less often. Mucorales disease in humans is characterized bya rapidly evolving course, tissue necrosis, and blood vessel inva-

sion in addition to subcutaneous infection. These infections aremost acute and fulminant in debilitated patients. Genera of theorder Entomophthorales causing infection in humans includeConidiobolus and Basidiobolus. These agents typically causeindolent sinus or subcutaneous infections in immunocompetentpersons.

EPIDEMIOLOGY

Zygomycosis is primarily a disease of persons with underlyingconditions that impair host immunity. Predisposing factorsinclude diabetes, hematologic malignancies, persistent acidosis,corticosteroid or deferoxamine therapy, organ transplantation,prematurity, and, less commonly, AIDS. Fungi that are patho-genic in humans grow on almost any carbohydrate substrate andare able to grow at temperatures >37C. Acidosis diminishes the

phagocytic and chemotactic ability of neutrophils while increas-ing the availability of unbound iron. Deferoxamine-bound ironcan also be used by the fungus to enhance its growth.

PATHOGENESIS

Macrophages and neutrophils are the main host defense againstZygomycetes and other lamentous fungi and provide almostcomplete immunity against Zygomycetes by phagocytosis andoxidative killing of spores, perhaps explaining the predilectionfor zygomycosis in patients with neutropenia or neutrophil dys-function. The primary route of infection from Zygomycetes isinhalation of spores from the environment. In immunocompro-mised persons, if spores are not cleared by macrophages theygerminate into hyphae, resulting in local invasion and tissue

destruction. Cutaneous or percutaneous routes of infection canlead to cutaneous and subcutaneous zygomycosis. Ingestion ofcontaminated food or drinks has been linked to gastrointestinaldisease.

CLINICAL MANIFESTATIONS

There are no unique signs or symptoms of zygomycosis. It canoccur as any of several clinical syndromes, including sinus/rhino-cerebral, pulmonary, gastrointestinal, disseminated, or cutaneousor subcutaneous disease.

Sinus and rhinocerebral infection is the most common formof zygomycosis and occurs primarily in persons with diabetesmellitus or who are immunocompromised. Infection typicallyoriginates in the paranasal sinuses. Initial symptoms are consis-

tent with sinusitis and include headache, retro-orbital pain,fever, and nasal discharge. Infection can evolve rapidly or beslowly progressive. Orbital involvement manifesting as perior-bital edema, proptosis, ptosis, and ophthalmoplegia can occurearly in the disease. The nasal discharge is often dark andbloody; examination of the nasal mucosa reveals black, necroticareas. Extension beyond the nasal cavity into the mouth iscommon. Involved tissues become red, then violaceous, and thenblack as vessel thrombosis and tissue necrosis occur. Direct bonyinvolvement is common as a result of contiguous pressure effectsor because of direct invasion and infarction. Destructive parana-sal sinusitis with intracranial extension can be demonstrated byCT or MRI. Cases complicated by cavernous sinus thrombosisand thrombosis of the internal carotid artery have been reported.

Brain abscesses can occur in patients with rhinocerebral infetion that extends directly from the nasal cavity and sinuseusually to the frontal or frontotemporal lobes. In patients widisseminated disease, abscesses can involve the occipital lobe brainstem.

Pulmonary zygomycosis infection usually occurs in severeneutropenic patients and is characterized by fever, tachypnea, anproductive cough with pleuritic chest pain and hemoptysis. wide range of pulmonary radiologic ndings, including solita

pulmonary nodule, segmental or lobar consolidation, and cavtary and bronchopneumonic changes, are recognized.Gastrointestinal zygomycosis is uncommon. It can occur as

complication of disseminated disease or as an isolated intestininfection in diabetics, immunosuppressed or malnourished chdren, or preterm infants. Abdominal pain and distention wihematemesis, hematochezia, or melena can occur. Stomach bowel wall perforation is not uncommon.

Disseminated zygomycosis is associated with a very high motality rate, especially among immunocompromised persons. Pumonary involvement is most common, but infection can originafrom any of the primary sites of infection.

Cutaneous and soft tissue zygomycosis can complicate buror surgical wounds. An outbreak occurred among preterm infanfollowing the use of contaminated wooden tongue depressors immobilize the extremities. Primary cutaneous disease may

invasive locally, progressing through all tissue layers, includinmuscle, fascia, and bone. Necrotizing fasciitis may occur. Infetion manifests as an erythematous papule that ulcerates, leavina black necrotic center. The skin lesions are painful, and affectpatients may be febrile. Cutaneous lesions from hematogenoseeding tend to be nodular, with minimal destruction of tepidermis.

DIAGNOSIS

The diagnosis relies on direct morphologic identication mycotic elements and recovery of Zygomycetes in culture or bbiopsy identication in specimens obtained at the site of prsumed involvement. To identify the fungus from scrapingsputum, and exudates under direct microscopy, the use

Calcouor white or 10% potassium hydroxide and Parker inkrecommended. In lung and other tissue biopsy specimens, demonstration of fungal elements with fungal specic stains is recommended. Mucorales appear as broad (5-25 m in diameteinfrequently septate, thin-walled hyphae, branching irregularly right angles when stained with Gomori methenamine silver hematoxylin and eosin. Secondary to their thin-walled structuand lack of regular septation, they often appear twisted, colapsed, or folded. Angiotrophism is a hallmark of zygomycosThe fungi can be cultured on standard laboratory media frosputum, bronchoalveolar lavage uid, skin lesions, or biopmaterial. Mucorales are common culture contaminants. Serologtests for detecting zygomycosis are not clinically useful. Real-timquantitative polymerase chain reaction assay targeting the 28rRNA gene has been tested in a rabbit model of experiment

pulmonary zygomycosis and shows great promise as a rapisensitive, and specic diagnostic test.

TREATMENT

All forms of the disease can be aggressive and difcult to treawith high fatality rates. The optimal therapy for zygomycosis children requires early diagnosis and prompt institution medical therapy combined with extensive surgical debridemeof all devitalized tissue. Correction of the underlying disease, possible, is an essential component of management. Use of granlocyte colony stimulating factor or granulocyte-macrophacolony stimulating factor to reverse immunosuppression is reommended in conjunction with antifungal agents.

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Amphotericin B deoxycholate (1-1.5 mg/kg/day to a total doseof 70 mg/kg or 3-4 g over several wk) or amphotericin B lipidcomplex (3-5 mg/kg/day) has been successful in treating infec-tion. Anecdotal reports suggest that higher total doses of ampho-tericin B lipid complex (15-20 mg/kg/day) are associated withbetter outcomes in invasive infection. Pulmonary and cutaneousdisease has been successfully treated with intermediate dosagesof amphotericin B (30 mg/kg total dose).

Surveillance in the USA suggests an association between use

of voriconazole prophylaxis and the emergence of zygomycosisin transplant patients, which might represent increased patientsurvival or selection of resistant organisms. Voriconazole is inac-tive against the Zygomycetes. Posaconazole appears to be activeagainst most of the Zygomycetes both in vitro and in vivo andtogether with surgery has been associated with dramatic clinicalresponses and holds promise as a therapeutic agent for mucor-mycosis. Caspofungin has limited or no in vitro activity againstZygomycetes; however, when combined with amphotericin lipidcomplex, caspofungin has been found to be more active than lipidcomplex alone or caspofungin alone for the treatment of experi-mental zygomycosis in diabetic mice. Caspofungin has beenshown to uncover -glucan in the cell wall ofRhizopus, whichresults in an increase in neutrophil activity. Hyperbaric oxygenhas been used anecdotally as an adjunctive therapy, and ironchelation with deferasirox has been tried as salvage therapy in

refractory mucormycosis.

BIBLIOGRAPHY

Diekema DJ, Messer SA, Hollis RJ, et al: Activities of caspofungin, itracon-azole, posaconazole, ravuconazole, voriconazole and amphotericin Bagainst 448 recent clinical isolates of lamentous fungi, J Clin Microbiol41:36233626, 2003.

Garcia-Diaz JB, Palau L, Pankey GA: Resolution of rhinocerebral zygomycosisassociated with adjuvant administration of granulocyte-macrophage col-ony-stimulating factor, Clin Infect Dis 32:145150, 2001.

Gonzalez CE, Rinaldi MG, Sugar AM: Zygomycosis, Infect Dis Clin NorthAm 16(4):895914, 2002.

Greenberg RN, Mullane K, van Burik JA, et al: Posaconazole as salvagetherapy for zygomycosis, Antimicrob Agents Chemother 50:126133,2006.

John BV, Chamilos G, Kontoyiannis DP: Hyperbaric oxygen as an adjunctivetreatment for zygomycosis, Clin Microbiol Infect11:515517, 2005.

Kasai M, Harrington SM, Francesconi A, et al: Detection of a molecularbiomarker for zygomycetes by quantitative PCR assays of plasma, bron-choalveolar lavage, and lung tissue in a rabbit model of experimentalpulmonary zygomycosis,J Clin Microbiol46(11):36903702, 2008.

Lamaris GA, Lewis RE, Chamilos G, et al: Caspofungin-mediated -glucanunmasking and enhancement of human polymorphonuclear neutrophilactivity against Aspergillus and non-Aspergillus molds, J Infect Dis198(2):186192, 2008.

Marty FM, Cosimi LA, Baden LR: Breakthrough zygomycosis after voricon-azole treatment in recipients of hematopoietic stem-cell transplants, N Engl

J Med350:950952, 2004.Reed C, Bryant R, Ibrahim AS, et al: Combination polyene-caspofungin treat-

ment of rhino-orbital-cerebral mucormycosis, Clin Infect Dis 47(3):364371, 2008.

Reed C, Ibrahim A, Edwards JE, et al: Deferasirox, an iron chelating agent assalvage therapy for rhinocerebral mucormycosis, Antimicrob Agents Che-mother 50(11):39683969, 2006.

Ribes JA, Vanover-Sams CL, Baker DJ: Zygomycetes in human disease, ClinMicrobiol Rev 13:236301, 2000.

Spellberg B, Fu Y, Edwards JE, et al: Combination therapy with amphotericinB lipid complex and caspofungin acetate of disseminated zygomycosis indiabetic ketoacidotic mice, Antimicrob Agents Chemother 49:830832,

2005.Tobin AM, Arango M, Fernandez D, Restrepo A: Mucormycosis (zygomyco-sis) in a heartkidney transplant recipient: recovery after posaconazoletherapy, Clin Infect Dis 36:14881491, 2003.

Walsh TJ, Antachopoulos C: New agents for invasive mycoses in children,Curr Opin Pediatr 17:7887, 2005.

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