Cutaneous zygomycosis

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1 Clinics in Dermatology (2012) 30, Cutaneous zygomycosis Alexandro Bonifaz, MSc a,, Denisse Vázquez-González, MD b, Andrés Tirado-Sánchez, MD, MSc b, Rosa María Ponce-Olivera, MD b a Department of Mycology, General Hospital of Mexico, DO, Dr. Balmis 148, Colonia Doctores, Mexico City, Mexico b Dermatology Service, General Hospital of Mexico, DO, Mexico City, Mexico Abstract Cutaneous zygomycosis is a fungal infection caused by zygomycetes that affects the skin. It occurs in uncontrolled diabetic patients and immunosuppressed individuals. It has 2 clinical forms: primary cutaneous zygomycosis and secondary cutaneous zygomycosis. The first is characterized by necrotic lesions and the fungus is usually inoculated by trauma. If diagnosed early, it generally has a good prognosis. Secondary zygomycosis is usually a complication and extension of the rhinocerebral variety that starts as a palpebral fistula and progresses to a necrotic lesion with a poor prognosis. The diagnosis is made by identification of the fungus by direct KOH examination, culture, and biopsy. Treatment for the primary disease is surgical debridement plus amphotericin B. The secondary type is treated with amphotericin B and/or posaconazole Elsevier Inc. All rights reserved. Introduction The term zygomycosis can be applied to 2 conditions: one caused by opportunistic fungi of the order of Mucorales and another caused by primary pathogenic fungi of the order of Entomophtorales. 1-3 This contribution addresses only the former. Zygomycosis, also known as mucormycosis (because of its taxonomy), is caused by a group of opportunistic fungi of the class of Zygomycetes, characterized by acute rhinocerebral and pulmonary episodes with vascular involvement, thrombosis, and infarctions. 3,4-6 It occurs mainly in uncontrolled diabetic patients and in immunosuppressed individuals. Its clinical varieties are rhinocerebral (the most frequent), pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous. 2,5 Corresponding author. Tel.: address: a_bonifaz@yahoo.com.mx (A. Bonifaz). Cutaneous zygomycosis has 2 forms: primary cutaneous and secondary cutaneous. Primary cutaneous, which starts with various types of trauma, is frequent in immunosuppressed patients and has a good prognosis when diagnosed early. Secondary cutaneous zygomycosis, which is usually a dissemination to the skin from a rhinocerebral location, occurs more frequently in uncontrolled diabetic patients and immunocompromised individuals, being a severe invasive entity with a poor prognosis. 3,7,8 Etiology The disease is caused by various Zygomycetes of the order of Mucorales, including several families, among which Mucoraceae is predominant. The most frequently isolated genera are Rhizopus, Mucor, and Lichtheimia (previously Absidia), and to a lesser extent Rhizomucor, Mortierella, Saksenaea, Syncephalastrum, Cunninghamella, and Apophysomyces. 3,9,10 The most frequently reported genus X/$ see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.clindermatol

2 414 A. Bonifaz et al. Fig. 3 Deep primary cutaneous zygomycosis after a motorcycle accident (immunocompetent patient). Fig. 1 Primary cutaneous zygomycosis, necrotic ulcer in an immunosuppressed patient (leukopenia and thrombocytopenia). Lesion in site of venipuncture. is Rhizopus. At the cutaneous level, the most frequently reported species is Rhizopus oryzae in 47% to 85% of cases, followed by Lichtheimia corymbifera, Rhizomucor pusillus, and Saksenaea vasiformis Mucorales are a group of fungi with teleomorph (sexual) and anamorph (asexual) reproductive stages. The former occurs through zygospores, thus their name. They are heterothallic and require physiologically distinct hyphae. In anamorphs, it occurs by sporangiospores or endospores. In general, zygomycetes have thick and coenocytic hyphae (macrosiphoned, 10 to 20 μm) that are characteristic of this order. The fungus sustains its asexual reproduction by means of structures called sporangiophores, which terminate in a widening structure known as the columella, the starting point of the membrane covering the spores (sporangium). 3 Epidemiology Zygomycosis is a cosmopolitan disease. It is a rare entity that has experienced a significant increase in the past 2 decades. Some authors consider it the third most frequent opportunistic mycosis, after candidiosis and aspergillosis. There are 1.7 cases per million per year in the United States with an estimate of 500 new cases per year. 15 In a pathologic analysis, 5 1 to 5 cases per 100,000 autopsies were reported. There are no precise data from Latin American Fig. 2 Primary cutaneous zygomycosis, necrotic ulcer on the nasal ala (caused by an adhesive band for a nasogastric tube) in a patient with acute leukemia. Fig. 4 Secondary cutaneous zygomycosis, palpebral lesion from a rhinocerebral form.

3 Cutaneous zygomycosis 415 Fig. 5 Secondary cutaneous zygomycosis, palatine lesion from a rhinocerebral form. countries, but some tertiary-care Mexican hospitals report more cases of this disease than for aspergillosis. 3,16 Most opportunistic Zygomycete fungi are ubiquitous but usually grow in warm, humid climates. Fungi are frequently isolated from soil, decaying organic matter, animal excreta, decaying fruits, and wheat and rye bread. 3,17 Zygomycosis is also considered a nosocomial infection, and fungi have been isolated from ventilation systems, adhesive tape, wooden tongue depressors, ostomy bags, and bathrooms in hospitals. 18,19 The main route of entry in rhinocerebral cases is through the respiratory tract and the nasal mucosa. Primary cutaneous cases resulting from trauma have been reported after injections, in areas surrounding intravenous lines, after mosquito bites, and in burn patients. Zygomycosis is slightly more frequent among men with a male:female ratio of approximately 6:4. The disease has been reported in all ages; however, it varies according to age. The cutaneous and gastrointestinal forms are more frequent in preterm and full-term neonates, whereas the rhinocerebral and pulmonary forms are more often found in children, adults, and the elderly. There is no definite incubation period. Fig. 7 Rhizopus oryzae. Left: culture on Sabouraud agar media. Right: multiple sporangia that arise from the rhizoid (Cotton blue, 10). Development of the disease depends on the patient's health status and the degree of fungal inoculum. 1,3,11 The major predisposing factors are uncontrolled diabetes and metabolic acidosis. Both are related to the rhinocerebral form. In our experience, these factors are associated in up to 80% of cases, unlike developed countries (United States and the European Union), where the association rate is 30% to 40%. 3,5,11 Hematologic conditions rank second, especially neutropenia owing to leukemia and, to a lesser extent, lymphoma. 5,11,20,21 Other associated factors are solid organ transplantation, treatment with deferoxamine and steroids, kidney failure, prematurity, malnutrition, and AIDS. 3,4,22-25 Additional factors for cutaneous cases are trauma, catheters, injection sites, burns, and macerated skin. 8,11,12,26 Zygomycosis is also considered a nosocomial infection that may be seen in immunosuppressed patients with long hospital stays. 1,3,11,18,27 The disease also occurs in immunocompetent patients with no apparent risk factors. 11,26,28-30 Fig. 6 Direct examination showing nonseptate thick coenocytic hyphae with a wide angle and bifurcations (KOH 10%, 40). Fig. 8 Biopsy. Nonseptate thick hyphae (hematoxylin and eosin, 40). (Courtesy of Dr Liliana Salgado.)

4 416 A. Bonifaz et al. Fig. 9 Biopsy. Nonseptate and thick hyphae (Grocott, 40). In an extensive review of 929 cases, the 3 major predisposing factors found were diabetes (36%), malignancy, (17%), and solid organ transplantation (7%). 11 Primary cutaneous cases represent 7% to 16%, depending on the associated factors; however, no underlying condition is seen in up to 50%. Pathogenesis The onset of this disease is becoming increasingly clear. The disruption of defense mechanisms is extremely important, particularly neutrophil and macrophage activity. The presence of serum iron ions (Fe 2+ ) is of vital importance, as, under normal conditions, they are taken up by serum proteins, but due to the acidity of the medium, particularly in cases of diabetic ketoacidosis or metabolic acidosis, iron ions are dissociated and are a clear stimulus for the development of mucorales. 3,5 In certain cases, deferoxamine (iron binder) acts as a siderophore (iron transporter), stimulating fungal growth and adhesion. 5,25 In primary cutaneous zygomycosis, fungi enter through skin trauma (because of rupture of the skin barrier), especially at venipuncture sites, particularly in severely immunosuppressed hosts. It is important to emphasize that when the skin barrier is intact, infection does not occur. 7,8,12 Clinical aspects Primary cutaneous zygomycosis Primary cutaneous zygomycosis is a relatively rare cutaneous and subcutaneous disease that accounts for 7% to 15% of all reported cases of zygomycoses. 11 It starts after fungal inoculation caused by contaminated elastic or adhesive tape at catheter or venipuncture sites in severely immunosuppressed patients. Most cases are in patients with acute and chronic leukemia with acute lymphoblastic leukemia being the most frequent. It has no specific location, but has been observed on the arms, legs, trunk, and face. The morphology is variable. Lesions are usually limited, indurated, and initially reddish purple. They later become necrotic with an erythematous halo. The fungus produces cutaneous vasculature infarction causing a brown or black discoloration with lesions that tend to ulcerate and drain a blackish fetid exudate. 3,8,12 If the disease progresses, it may affect the fascia (necrotizing fasciitis), muscles, tendons, and bones. In this last location, it can produce sinuses that reflect an osteolytic process. Most cases involve rapid-growing necrotic lesions that produce a blood-borne infection that results in disseminated zygomycosis. 8,12,31 Cases affecting deep structures can occur after motor vehicle accidents; excoriations with soil containing the fungus; and extensive, deep burns with a subacute (7 to 25 days) evolution. 26 These cases initially occurred with edema and gave rise to important cellulitis and necrosis with involvement of the fascia and muscles. They are clinically undistinguishable from cases of cutaneous aspergillosis. 3 Other differential diagnoses include multiple autoimmune diseases, drug reactions, infiltrative diseases, pyoderma gangrenosum, and various bacterial infections, such as gangrene (Figures 1 and 2). 5,12 As with Aspergillus spp, zygomycetes may extensively invade the lesions in burn patients. Other clinical forms of primary cutaneous zygomycosis may occur as papular, vesicular lesions, 32 and erythema nodosumlike 33 disease. There is alonereportofmycetomacausedbyrhizopus sp (Figure 3). 34 Secondary cutaneous zygomycosis This clinical form of secondary cutaneous zygomycosis is more frequent than the primary infection. It usually occurs as a result of rhinocerebral and disseminated zygomycosis. 2-4 Rhinocerebral zygomycosis occurs mainly in decompensated diabetic patients with ketoacidosis (85%) and, to a lesser extent, in patients with neutropenia, after transplantation, and in those undergoing steroid treatment. It has an acute course (2 to 15 days) and a mortality rate that may be as high as 85% to 90%. 3,5,12 Sporangiospores enter the nasal mucosa and paranasal sinuses and invade the carotid and ophthalmic arteries. They may also enter through the palate or pharynx, entering the palatine and sphenopalatine arteries. 1,3 The initial picture is a torpid sinusitis. The patient initially presents with unilateral and periorbital edema. Upon exploration of the nasal septum, an erythematous mucosa is observed, initially with discrete necrotic areas and bloody discharge. 1-4 Approximately 20% of cases have involvement of the palate. 16 At this stage, patients complain of a strong headache and impaired vision. As the picture progresses, unilateral edema is more pronounced. It is seldom bilateral. Another cutaneous manifestation that occurs is the appearance of a single fistula located in the eyelid, which drains a

5 Cutaneous zygomycosis seropurulent and fetid material. With progression of the disease (8 to 15 days), the edema persists and the fistula becomes a necrotic area, at times very large, both located at the nasal septum and the adjacent skin. In cases of palate involvement, it extends and forms a large ulcer; the fungus has considerable osteolytic activity and virtually all the facial bones may undergo lysis (ethmoid, sphenoid, and so forth). 3,5,20 Fungal progression occurs with thrombosis and infarctions, which lead to an impaired function of the cranial nerves (II, III, IV, VI) that causes proptosis, mydriasis, and decreased visual acuity that may end up in blindness. Patients complain of strong pain, loss of wakefulness, and even seizures. At this stage, the infection is virtually lethal. From the rhinocerebral focus, the disease may spread to the lungs, bowel, heart, or skin. This will depend on the control of diabetes and immunosuppression status (Figures 4 and 5). 11,35-38 The cases of secondary cutaneous zygomycosis should be differentiated from centrofacial lymphomas, rhinoscleromas, sinusitis, anaerobe infections, and necrotic ulcers caused by Aspergillus. 1,4,6 Table 1 shows the differences between primary and secondary cutaneous zygomycosis. Laboratory diagnosis One of the first studies performed is direct potassium hydroxide (KOH) examination of the exudates, nasal discharge, and macerated biopsies. The specimen should be cleared with 10% to 20% KOH. Under the microscope, one can see numerous coenocytic (nonseptated), hyaline, bifurcated hyphae, 5 μm wide by 20 to 50 μm long. The etiologic agent is confirmed by means of (repeated) cultures in Sabouraud dextrose agar and potato dextrose agar. Specimens should not be seeded in Sabouraud media with antibiotics that inhibit fungus growth. The culture incubation period is 3 to 5 days at a temperature of 25 to 28 C. In our experience, approximately 90% of cultures are positive. Zygomycete fungi produce similar colonies: villous, whitish to grayish cottonlike colonies that fill the Petri dishes. Their identification is based on micromorphologic and biochemical criteria. 3,5 With real-time polymerase chain reaction techniques, it is possible to identify the main zygomycetes with virtually a 100% specificity and sensitivity from both isolated cultures and paraffin biopsies (Figures 6 and 7). 10,39,40 Biopsies are important, more in the primary cutaneous cases than in the secondary ones. The histopathology shows an inflammatory reaction with thick, hyaline, nonseptated and bifurcated hyphae, which are better highlighted with periodic acid-schiff and Grocott stains. Histologically, there is edema and necrosis, with polymorphonuclear clusters, plasma cells, and a few eosinophils. Phenomena such as thrombosis and infarctions are also seen. Hyphae tend to invade the blood vessels at the level of the walls (veins and arteries), owing to their angiotrophic properties, which explains why the disease has a tendency to disseminate (Figures 8 and 9). 1,3,26 Treatment In general, treatment success depends on a prompt diagnosis, resolution of associated factors, the patient's condition, and the promptness in starting therapy. 5,41 Treatment of primary cutaneous zygomycosis 417 The best management strategy is extensive surgical debridement or cleansing, removing all necrotic tissue. This Table 1 Differences between primary cutaneous and secondary cutaneous zygomycosis Variables Primary cutaneous Secondary cutaneous Route of entry Trauma, injections, catheter, burns, softened skin Respiratory: through the nasal and palatine mucosa Principal predisposing factors Principal etiologic agents Hematologic malignancy (leukemia) Solid organ transplantation Uncontrolled diabetes Uncontrolled diabetes Metabolic acidosis Hematologic malignancy (leukemia) Solid organ transplantation Deferoxamine therapy Rhizopus oryzae Apophysomyces elegans Lichtheimia corymbifera Saksenaea vasiformis R oryzae Mucor circinelloides Mucor spp L corymbifera Location Upper and lower limbs Face, eyelids, palate Morphology Treatment Necrotic lesions, limited and indurated; exceptionally necrotizing fasciitis Surgical debridement + amphotericin B and/or posaconazole Initially with unique palpebral fistula; later necrosis that affects the eyelid and adjacent areas Palatine ulcers Amphotericin B (+ posaconazole); surgical debridement of necrotic tissue

6 418 A. Bonifaz et al. should be combined with systemic treatment, preferably amphotericin B (deoxycholate suspension or lipid complex) 5,26,41,42 at the usual doses. Posaconazole is also effective at 800 mg per day given twice a day. 31,41,43-45 Good results have been reported with Mohs surgery. 46 Hyperbaric oxygen may be used as adjuvant therapy because it is extremely toxic to Mucorales. 3,41,47 The mortality rate of the primary cutaneous form depends on limitation of the process and prompt intervention. According to the literature, the mortality rate in localized cases is 4% to 10%, in deep lesions the rate is 26% to 29%, and in those with dissemination from a skin focus it may be as high as 83% to 94%. 12 Treatment of secondary cutaneous zygomycosis The treatment of choice consists of traditional or lipid amphotericin B, observing all the controls inherent to the administration of these drugs. Amphotericin B deoxycholate should be given at the standard dosage of 0.25 to 0.75 mg/kg per day; in severe cases at 1.0 to 1.5 mg/kg per day. Better results and fewer side effects are reported with the AB lipid complex. The recommended dosage is 5 mg/kg per day with a range of 3 to 6 mg/kg per day. The standard dosage of liposomal amphotericin B is 3 mg/kg per day, with a range of 3 to 5 mg/kg per day; for amphotericin B colloidal dispersion (cholesteryl-sulphate complex), the dosage is 3 to 4 mg/kg per day. 3,5,41,42 Regarding azole derivatives, variable results have been obtained with fluconazole and itraconazole; voriconazole is not recommended, as zygomycetes have not shown a good in vitro response. Some authors consider it a predisposing factor, particularly when used prophylactically in cases of immunosuppression (transplanted patients). 3,12,41 There are reports on the effectiveness of posaconazole. Because of rapid progression of infection, it is suggested to administer it concomitantly with amphotericin B or as a maintenance drug. 31,43,45 Surgical debridement or cleansing of the lesions is very helpful because it removes all necrotic tissue containing large amounts of fungal material. Hyperbaric oxygen has also been reported helpful. 3,47 The most recent series reports a mean success rate of 50%, which depends on early diagnosis and patient status. Our experience in patients with extensive palpebral lesions, and a Glasgow Coma Score lower than 6, is a mortality rate of approximately 85%. 3,5,12,41 Prophylaxis The most important aspect of treatment is the control of comorbidities, such as diabetes stabilization and control, the return to normal immune status, as well as immunosuppressive therapies (immunosuppressors, steroids, deferoxamine). The recommended prophylactic measures for diabetic and uncontrolled patients or those with hematologic conditions, such as leukemia and lymphoma, are those used in any immunocompromised patient: isolation in sterile areas, closely supervised clinical management, and an increase in cleansing measures. Low doses of systemic antifungals with few side effects, such as posaconazole, fluconazole, and itraconazole, can be used. 4,6,41 References 1. Gonzalez CE, Rinaldi MG, Sugar AM. Zygomycosis. Infect Dis Clin North Am 2002;16: Mantadakis E, Samonis G. Clinical presentation of zygomycosis. Clin Microbiol Infect 2009;15(Suppl 5): Bonifaz A. Zigomicosis. Micología médica básica, 3rd ed. Mexico City, Mexico: McGraw-Hill; p Eucker J, Sezer O, Graf B, Possinger K. Mucormycosis Mycoses 2001;44: Spellberg B, Edwards Jr J, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18: Brown J. Zygomycosis: an emerging fungal infection. 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