REVIEW URRENT C OPINION
Fungal skin and soft tissue infections Sarah Gue´gan a,b,c, Fanny Lanternier d,e,f,g, Claire Rouzaud f, Nicolas Dupin g,h, and Olivier Lortholary d,e,f,g
Purpose of review Cutaneous and subcutaneous mycoses are a source of significant morbidity both in immunocompetent and immunocompromised patients. We here review the latest findings in terms of genetic predisposition, epidemiology, clinical manifestations, and therapeutic strategies in these diseases. Recent findings A growing number of fungal skin and soft tissue infections are reported worldwide. In immunocompromised patients, these infections are often associated with disseminated disease. Skin and soft tissue biopsies usually allow mycological identification. Although tissue culture remains the gold standard, molecular biology is increasingly used and sometimes mandatory for accurate diagnosis. Advances in therapeutics have improved outcome and lowered dissemination risk in patients. Summary Cutaneous and subcutaneous mycoses are an evolving field. Clinicians all over the world should be aware of the common manifestations of these diseases – infectious diseases – as they are increasingly reported and may lead to or be associated with dissemination. Keywords eumycetoma, fungus, fusariosis, phaeohyphomycosis, skin
INTRODUCTION Cutaneous and subcutaneous mycoses develop following either traumatic inoculation (phaeohyphomycosis, eumycetoma, sporotrichosis, chromoblastomycosis) or hematogenous seeding (cryptococcosis, aspergillosis, histoplasmosis). Both cosmopolitan and tropical fungi are implicated, but because of worldwide travel, tropical mycoses are now reported outside their endemic areas. Moreover, the increasing number of severely immunocompromised patients has led to the emergence of rare and even new pathogens, such as Trichosporon spp., Fusarium spp., mucormycoses, and Emmonsia spp. [1,2]. We here review recent and novel findings concerning genetic predisposition, clinical features, mycological identification, and therapeutic options in these skin and soft tissue infections (Table 1).
COSMOPOLITAN FUNGAL SKIN AND SOFT TISSUE INFECTIONS Cryptococcosis Cryptococcosis is mainly caused by Cryptococcus neoformans (subdivided into two variants, grubii and www.co-infectiousdiseases.com
neoformans) and Cryptococcus gattii [3]. In a study of 320 fungal isolates from 303 HIV patients, Cryptococcus was the most frequently isolated fungus (50.0% of isolates). The main sites of infection were central nervous system, blood, and lung [4]. On the other hand, cryptococcosis is the third fungal infection after aspergillosis and candidiasis in solid organ transplant (SOT) recipients among whom cutaneous lesions are described in 18% of cases. Maculopapules, pustules, ulcers, or abscesses usually affecting the lower extremities are described in disseminated infections [5] whereas isolated distal skin lesions a
Assistance Publique-Hoˆpitaux de Paris, Service de Dermatologie, Hoˆpital Tenon, bUniversite´ Pierre et Marie Curie-Paris VI, cINSERM U938, Saint Antoine Research Center, dInstitut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, eCNRS URA3012, fAssistance Publique-Hoˆpitaux de Paris, Centre d’Infectiologie Necker Pasteur, Hoˆpital Necker-Enfants malades, g Universite´ Rene´ Descartes-Paris and hAssistance Publique-Hoˆpitaux de Paris, Service de Dermatologie, Hoˆpital Cochin, Paris, France Correspondence to Professor Olivier Lortholary, MD, PhD, Institut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Paris, France. Tel: +33 1 40 61 33 41; fax: +33 1 45 68 84 20; e-mail: [email protected] Curr Opin Infect Dis 2016, 29:124–130 DOI:10.1097/QCO.0000000000000252 Volume 29 Number 2 April 2016
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Fungal skin and soft tissue infections Gue´gan et al.
KEY POINTS Cutaneous and subcutaneous mycoses are a significant source of morbidity both in immunocompetent and immunocompromised patients. Both cosmopolitan and imported skin mycoses are increasingly reported in immunocompromised patients; dissemination should be investigated in these patients. In most cases, a polyphasic approach combining morphological and molecular analysis is useful for mycological identification. Expansion of the therapeutic arsenal has significantly improved management of these diseases.
develop deep dermatophytosis with dermis invasion [8]. Autosomal recessive CARD9 deficiency was evidenced to be the main cause of deep dermatophytosis in patients without any known immunosuppression. Patients displayed recurrent superficial dermatophytosis in childhood. In young adulthood, invasive, extensive, and treatment resistant infection developed with frequent lymph node involvement [9 ]. &&
Phaeohyphomycosis Phaeohyphomycoses affect both immunocompetent and immunocompromised patients worldwide and are caused by multiple genera of melanized fungi [10 ]. Exophiala spp., common agents of phaeohyphomycosis, are usually responsible for skin infections whereas invasive disease is extremely rare. Autosomal recessive CARD9 deficiency has recently been reported in two otherwise healthy patients presenting a disseminated form of Exophiala infection [11 ]. Alternaria spp., mostly Alternaria alternata, are increasingly described as emerging opportunistic infections in SOT recipients. These patients represent 50% of cutaneous alternariosis cases [12 ,13]. A rural environment is usually reported as local trauma induces fungus penetration. Lesions (plaques, nodules, or ulcers) are mainly solitary [13], but multiple lesions are also described [12 ]. Schieffelin and colleagues [14] reviewed 27 cases of phaeohyphomycosis occurring in SOT recipients. The majority of patients (89%, 24/27) developed an infection limited to the skin. The most frequently isolated fungus was Exophiala spp. (44%, 12/27). McCarty et al. [15 ] reported 56 cases of phaeohyphomycosis in 26 stem cell transplant and 30 SOT recipients. The most common pathogens were Alternaria spp. (32%), Exophiala spp. (11%), Cladophialophora spp. (8.9%), and Scopulariopsis spp. (8.9%). The two most frequent sites of infection and providers of positive cultures were skin and respiratory tract. Cutaneous disease affected more SOT than stem cell transplant patients: 53.3 vs 23.1% respectively. In total, 50% of patients presented disseminated disease [15 ]. Current treatment recommendations identify itraconazole, voriconazole, and posaconazole as first-line therapy in cutaneous and subcutaneous phaeohyphomycoses. Amphotericin B may be useful in refractory cases. Surgical debridement should be performed when possible [10 ]. In Schieffelin study, out of the 24 patients with cutaneous infections, 22 were treated by excision, either alone (three patients) or in association with itraconazole (19 patients) or voriconazole (two patients). Two &
correspond to primary cutaneous cryptococcosis. Cryptococcus skin manifestations such as cellulitis, necrotizing soft tissue infection, have been increasingly reported in SOT patients, and can also be a manifestation of immune reconstitution syndrome [5]. As multiple skin lesions correspond to hematogenous dissemination, they should be treated with amphotericin B (deoxycholate or a lipid formulation) and flucytosine (induction) followed by fluconazole (consolidation) [3,6 ]. Primary cutaneous cryptococcosis should be treated with fluconazole [3,6 ]. &
&
&
&
&
Trichosporonosis Trichosporonosis most commonly affects immunocompetent patients in the form of white piedra, a superficial infection of the hair shaft, whereas primary invasive cutaneous trichosporonosis is a very rare manifestation [7]. Nevertheless, invasive infections because of Trichosporon spp. are increasingly reported in immunocompromised patients: fungemia is the most frequent manifestation (75%), with associated metastatic skin lesions in 50% of cases [3]. Most cases are caused by Trichosporon asahii (74%), followed by Trichosporon dermatis (12%). Triazoles are the most effective antifungals in prophylaxis and treatment: voriconazole is the preferred agent with good in-vivo outcome in most animal and clinical studies, both for primitive cutaneous and disseminated infections [3,7].
Deep dermatophytosis Dermatophytes are cosmopolitan fungi responsible for benign and very frequent infections limited to stratum corneum. However, a few immunocompromised patients (HIV, solid organ transplant, and patients receiving immunosuppressive therapy)
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&
&
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Cosmopolitan
Cosmopolitan
Tropical
Tropical
Aspergillosis
Fusariosis
Mucormycosis
Histoplasmosis
Penicilliosis
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Tropical
Tropical
Sporotrichosis
Chromoblastomycosis
Fonsecaea pedrosoi, Cladiophialophora carrionii
Sporothrix schenckii species complex
Madurella mycetomatis, Scedosporium boydii
Emmonsia spp.
Talaromyces marneffei (Penicillium marneffei)
Histoplasma capsulatum
Apophysomyces variabilis, Apophysomyces elegans, Rhizopus arrhizus, Lichtheimia corymbifera, Saksanea vasiformis
Fusarium spp.
Aspergillus flavus, Aspergillus fumigatus
Exophiala spp., Alternaria spp., (mostly Alternaria alternata), Cladophialophora spp., Scopulariopsis spp.
Trichosporon asahii, Trichosporon dermatis
Cryptococcus neoformans (two variants grubii and neoformans) Cryptococcus gattii
Causative agent
Primary cutaneous and subcutaneous lesions
Primary fixed cutaneous lesions or lymphocutaneous disease
Primary cutaneous and subcutaneous lesions
Secondary cutaneous
Secondary cutaneous
Secondary cutaneous (blood culture þ)
Surgery and antifungal: itraconazole or posaconazole
Itraconazole
Surgery and antifungal: itraconazole, voriconazole or posaconazole
Amphotericin B (deoxycholate or liposomal formulation) followed by itraconazole
Itraconazole (mild) or amphotericin B deoxycholate (severe) followed by itraconazole
Itraconazole (mild) or liposomal amphotericin B (severe and/or immunocompromised) followed by itraconazole
Surgery and liposomal amphotericin B or isavuconazole followed by posaconazole
Secondary cutaneous
Voriconazole Surgery and liposomal amphotericin B or isavuconazole followed by posaconazole
Voriconazole; combination therapy
Secondary cutaneous Primary cutaneous
Voriconazole
Secondary cutaneous (blood culture þ)
Voriconazole
Primary cutaneous
Surgery and voriconazole
Secondary cutaneous
Surgery and antifungal (itraconazole, voriconazole, posaconazole, amphotericin B deoxycholate, or lipid formulation)
Multiple lesions
Primary cutaneous
Surgery
Single lesion
Voriconazole
Amphotericin B (deoxycholate or lipid formulation) þ flucytosine followed by fluconazole
Secondary cutaneous (blood culture þ) Primary cutaneous
Fluconazole
Treatment
Primary cutaneous
Clinical characteristics
a Mycoses covered in the present review. As there were no major recommendations in the past year concerning blastomycosis, coccidioidomycosis, and paracoccidioidomycosis, these three diseases are not detailed in the table.
Tropical
Eumycetoma
Subcutaneous mycoses
South Africa, India
Cosmopolitan
Phaeohyphomycosis
Emmonsiosis
Cosmopolitan
Cosmopolitan
Trichosporonosis
Cosmopolitan
Geographical distribution
Cryptococcosis
Invasive fungal diseases
Name
Table 1. Main cutaneous and subcutaneous mycosesa
Skin and soft tissue infections
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Fungal skin and soft tissue infections Gue´gan et al.
patients received itraconazole only [14]. In McCarty et al.’s study [15 ], voriconazole and lipid formulations of amphotericin B were the two most frequent antifungals used either alone or in combination. In transplanted patients, immunosuppressant reduction is mandatory to improve immune status. &
Aspergillosis Cutaneous aspergillosis represented 1% of invasive aspergillosis in a national retrospective French study from 2005 to 2010 [16 ]. Most cases corresponded to secondary cutaneous aspergillosis (10 cases), whereas primary cutaneous aspergillosis was less frequent (five cases). Primary aspergillosis was characterized by infiltrative and/or suppurative lesions; in secondary aspergillosis, both disseminated nodules or papules and isolated cellulitis or nodule were described. Aspergillus flavus was responsible for all primary cases, whereas Aspergillus fumigatus was most frequently isolated from secondary cases. Pathology evidenced an isolated dermal infiltrate in secondary aspergillosis that contrasted with the dermo-epidermal infiltrate characteristic of primary forms. Prognosis was very different with 100% and 30% survival rates in primary and secondary forms respectively [16 ]. Mold infections are also a severe complication in burned patients. A retrospective single-center French study from 2000 to 2011 reported a filamentous fungal infection incidence of 1.7%. The most frequent fungal infection was aspergillosis followed by mucormycosis and fusariosis. Risk factors were total body surface area burned, full-thickness burn surface area, unit burn standard, and severity scores such as Tobiasen score and SAPS2 [17]. &
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Fusariosis
from 2001 to 2011 (period 2) 233 cases of invasive fusariosis. Most patients (92%) had hematological malignancies [19]. Outcome changed between the two periods with 22% survival at 90 days in period 1 and 43% in period 2. Primary treatment was also modified with more voriconazole and combination prescription in the second period. Death was associated with corticosteroids, receipt of deoxycholate amphotericin B and neutropenia. Fusarium associated skin and nail lesions are associated with development of invasive fusariosis in high-risk hematology patients [20] whereas skin colonization with Fusarium sp. is not associated with invasive fusariosis. First-line recommended treatment for fusariosis is voriconazole [2].
Mucormycosis Mucormycosis affects patients with hematological malignancies and diabetes mellitus. In India, skin is the second site (29%) involved in mucormycosis after rhino-orbitocerebral infections; 38% of patients had diabetes mellitus, 31% a history of intramuscular injection, 31% underwent abscess incision or drainage, and 7% were involved in a road accident. Apophysomyces variabilis and Apophysomyces elegans were more frequently associated with cutaneous location [21]. In a Mexican study of 22 cases of mucormycosis in children, skin was also the second site involved (18%) after rhinocerebral manifestations. Predisposing factors were diabetes mellitus (68%) and hematological malignancy (27%). The main agents were Rhizopus arrhizus and Lichtheimia corymbifera [22]. In France, skin is the third location of mucormycosis after sinus and lung. Posttraumatic mucormycosis was associated with underlying disease in 31% of cases. A. elegans and Saksanea vasiformis were associated with skin location. Most patients (93%) had surgery and survival rate was higher than in other mucormycoses (87% survival rate) [23 ]. Recommended treatment is high dose liposomal amphotericin B or isavuconazole associated with surgery and control of underlying conditions including diabetes mellitus [1,24–25]. &
Invasive fusariosis mainly affects patients with hematological malignancies. Cutaneous dissemination is frequent. However, portal of entry is usually airways. An increasing incidence was reported in hematology patients in Brazil after 2005 with an incidence rise from 0.86 to 10.23 cases/1000 admissions in this particular setting [18 ]. Portal of entry was cutaneous in most patients (67%) with onychomycosis, periungueal cellulitis, or interdigital intertrigo sometimes associated with lymphangitis. An increase was demonstrated on the same period for superficial infections. Main clinical strains were Fusarium solani, whereas those from environment were mostly Fusarium oxysporum [18 ]. An international retrospective study with 11 participating countries studied from 1985 to 2000 (period 1) and &&
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TROPICAL FUNGAL SKIN AND SOFT TISSUE INFECTIONS Histoplasmosis Histoplasma capsulatum is endemic to various areas of North and South America, Africa, Asia and Australia. Presentation and incidence of cutaneous histoplamosis depends on patients’ immune status. Indeed, cutaneous lesions rarely affect immunocompetent hosts. Sun et al. [26] reviewed 22 cases
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Skin and soft tissue infections
of cutaneous histoplamosis in renal transplant recipients. In 77% of patients (17/22), a disseminated form of the disease was reported. Cutaneous lesions (nodules, papules or plaques, ulcerations) were often asymptomatic and nonspecific. Prognosis differed between patients with isolated cutaneous histoplasmosis (100% survival) and those with disseminated disease (71% survival) [26]. Marukutira et al. [4] analyzed fungemias in 303 HIV patients: Histoplasma was the third isolated fungus (9.1% of isolates) with an 84% survival rate. Amphotericin B or its lipid formulations followed by itraconazole or itraconazole alone are the mainstay of treatment. Liposomal Amphotericin B followed by itraconazole is the first-line therapy of severe disseminated histoplasmosis in immunocompromised patients. In this setting, itraconazole represents the maintenance therapy of choice.
Penicilliosis Penicilliosis, third opportunistic infection in HIV patients in South-East Asia and AIDS-defining illness, is caused by Penicillium marneffei (renamed Talaromyces marneffei). Its incidence is increasing both within and outside its endemic areas. Cutaneous lesions (skin-colored umbilicated papules or nodules with or without central necrosis) can be isolated, but in 70% of cases are associated with disseminated infection [27]. In a study of 100 disseminated penicillioses, bone involvement was described exclusively in the HIV-negative group (one-third of patients). Osteolytic lesions affected 40% of HIV-negative patients and were associated with cutaneous lesions in 85% of cases [28]. Itraconazole is effective both for prophylaxis and treatment of cutaneous forms of penicilliosis. Amphotericin B deoxycholate followed by itraconazole is recommended in severe infections. Voriconazole is an alternative for both mild and severe forms of the disease [27].
Emmonsiosis Emmonsiosis is a new emerging infectious disease very recently reported in South Africa and India and caused by dimorphic fungi, Emmonsia spp. [29 ,30]. This fungal infection has been described mostly in HIV patients with a CD4þ T-cell count under 50 cells/cubic millimeter (94% of patients) [29 ,31 ] and very rarely in immunocompetent and SOT patients [30,31 ,32]. Patients had disseminated disease with secondary widespread skin (96% of cases) or mucous membrane lesions. They displayed erythematous papules, plaques, nodules, or ulcers, possibly crusted or necrotic, healing with residual &&
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hyperpigmentation and marked scarring [29 ,31 ]. Culture of skin biopsy usually allows fungus identification [31 ]. First-line therapy should be amphotericin B (deoxycholate or liposomal formulation) followed by itraconazole, as the mortality rate is very high (48%) [31 ]. &&
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Eumycotic mycetoma &&
Van de Sande [33 ] conducted a meta-analysis including 50 studies and analyzing 8763 mycetoma cases, most of which were reported from Mexico, Sudan, and India. Mycetoma was caused by fungi in 41.7% of cases, Madurella mycetomatis being the most prevalent causative agent worldwide (24.3% of cases). Mycetoma affected most commonly the foot (68.7%) in men between 11 and 40 years of age (sex ratio 3.5/1). Fahal et al. [34] report similar data in their Sudanese study of 6792 mycetomas affecting predominantly male patients (76%) and the foot (76%). Madurella mycetomatis (70%) was the most frequently isolated organism. On the other hand, Bonifaz et al. [35 ] reported only 7.88% of eumycetomas among 482 Mexican mycetoma cases, with M. mycetomatis and Scedosporium boydii as fungal agents. The importance of molecular biology and internal transcribed spacer sequencing for mycological identification has been underlined [33 ], and a new molecular-based method using rollingcircle amplification has proven efficient, reproducible, and highly specific [36]. Current therapeutic recommendations advocate extensive surgical debridement combined with prolonged antifungal therapy. Itraconazole is now the drug of choice in this disease as ketoconazole was recently banned because of its high toxicity [34]. Rates of relapse as high as 31% are nevertheless reported in this disease [34]. Voriconazole and posaconazole were also recently reported to be active in vitro against 19 mycetoma strains [37], and in a retrospective study of 11 imported eumycetoma cases, voriconazole or posaconazole treatment was assessed: complete response was observed in 5/11 patients, partial response in five, and failure in one. Relapse occurred in two patients following treatment discontinuation [38]. Triazole treatment is, therefore, a relevant therapeutic alternative in this disease. &
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Sporotrichosis Sporotrichosis is a subcutaneous mycosis caused by traumatic inoculation of a dimorphic fungus, usually Sporothrix schenkii. Lesions most commonly affect face and extremities in immunocompetent patients, and the two most frequent forms of the disease are Volume 29 Number 2 April 2016
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Fungal skin and soft tissue infections Gue´gan et al.
lymphocutaneous and fixed cutaneous. Oral itraconazole, terbinafine, or potassium iodide are advocated in these cases. Amphotericin B or triazoles are recommended in extracutaneous and disseminated infections that occur in immunocompromised patients [27]. Therapeutic challenges concern the more aggressive and resistant infections caused by S. brasiliensis [39]. Sporothrix Gp70 protein is involved in the host immune response, and an anti-Gp70 monoclonal antibody already tested in a murine model could be of use for vaccine development [39].
Chromoblastomycosis Chromobastomycosis (CBM), the third endemic mycosis in tropical and subtropical areas after eumycetoma and sporotrichosis, is mainly caused by Fonsecaea pedrosoi or Cladophialophora carrionii. Cutaneous papular nodules and vegetating cauliflower-like or ulcerated plaques develop at the site of fungal entry following skin trauma. The most severe complication is malignant transformation with a total of 19 reported cases of squamous cell carcinomas developing on chronic CBM [40]. Followup biopsies should therefore be performed if new ulcers appear during the healing phase. Antifungals (itraconazole, terbinafine, flucytosine, and amphotericin B), surgical excision, and physical treatments have been used with variable success and high rates of relapse. Topical imiquimod stimulates immune pathways through Toll-like receptor activation, and has potent antiviral and antitumor properties. Both with and without a concurrent antifungal, it allowed marked lesion improvement in four patients [41]. Further studies are required to confirm the relevance of imiquimod as adjuvant treatment in CBM.
CONCLUSION Cutaneous and subcutaneous mycoses arise following either traumatic inoculation or hematogenous seeding. They are reported with an ever-growing frequency as a consequence of increasing numbers of immunocompromised patients. In parallel, rare and even new pathogens are regularly implicated in human infections. In most cases, skin or soft tissue biopsies allow mycological identification; the relevance of a polyphasic approach combining culture and the use of molecular biology is underlined in many publications. Finally, expansion of the therapeutic arsenal has significantly improved management of these diseases. Acknowledgements None.
Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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29. Kenyon C, Bonorchis K, Corcoran C, et al. A dimorphic fungus causing disseminated infection in South Africa. N Engl J Med 2013; 369:1416–1424. The article describes 13 South African cases of disseminated emmonsiosis, a new emerging fungal disease caused by a dimorphic fungus Emmonsia sp. 30. Malik R, Capoor MR, Vanidassane I, et al. Disseminated Emmonsia pasteuriana infection in India: a case report and a review. Mycoses 2016; 59:127–132. 31. Schwartz IS, Govender NP, Corcoran C, et al. Clinical characteristics, && diagnosis, management, and outcomes of disseminated emmonsiosis: a retrospective case series. Clin Infect Dis 2015; 61:1004–1012. The multicenter retrospective study describes clinical characteristics, treatment, and outcome of 54 South African cases of disseminated emmonsiosis. This new emerging fungal disease mostly affects HIV patients (94% of patients) and has a very low survival rate (52%). 32. van Hougenhouck-Tulleken WG, Papavarnavas NS, Nel JS, et al. HIV-associated disseminated emmonsiosis, Johannesburg, South Africa. Emerg Infect Dis 2014; 20:2164–2166. 33. van de Sande WW. Global burden of human mycetoma: a systematic review && and meta-analysis. PLoS Negl Trop Dis 2013; 7:e2550. This meta-analysis estimates the global burden of mycetoma worldwide analyzing 8763 mycetoma cases. Prevalence, clinical characteristics, causative agents, and their distribution per country are described. 34. Fahal A, Mahgoub el S, El Hassan AM, Abdel-Rahman ME. Mycetoma in the Sudan: an update from the Mycetoma Research Centre, University of Khartoum, Sudan. PLoS Negl Trop Dis 2015; 9:e0003679. 35. Bonifaz A, Tirado-Sa´nchez A, Caldero´n L, et al. Mycetoma: experience of 482 & cases in a single center in Mexico. PLoS Negl Trop Dis 2014; 8:e3102. The single-center study with long follow-up reports 482 cases of mycetoma over a 33-year period and determines the clinical and microbiological characteristics of mycetoma in different regions of Mexico. 36. Ahmed SA, van den Ende BH, Fahal AH, et al. Rapid identification of black grain eumycetoma causative agents using rolling circle amplification. PLoS Negl Trop Dis 2014; 8:e3368. 37. Ahmed SA, de Hoog GS, Stevens DA, et al. In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals. Med Mycol 2015; 53:295–301. 38. Crabol Y, Poiree S, Bougnoux ME, et al., French Mycosis Study Group. Last generation triazoles for imported eumycetoma in eleven consecutive adults. PLoS Negl Trop Dis 2014; 8:e3232. 39. Lopes-Bezerra LM, Mora-Montes HM. Sporothrix and sporotrichosis: contributions from the first international meeting sponsored by the Working Group on Sporothrix and sporotrichosis of the International Society for Human and Animal Mycology, Rio de Janeiro, Brazil, October, 2013. Med Mycol 2015; 53:1–2. 40. Azevedo CM, Marques SG, Santos DW, et al. Squamous cell carcinoma derived from chronic chromoblastomycosis in Brazil. Clin Infect Dis 2015; 60:1500–1504. 41. de Sousa Mda G, Belda W Jr, Spina R, et al. Topical application of imiquimod as a treatment for chromoblastomycosis. Clin Infect Dis 2014; 58:1734– 1737. &&
Volume 29 Number 2 April 2016
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Fungal skin and soft tissue infections Sarah Gue´gan a,b,c, Fanny Lanternier d,e,f,g, Claire Rouzaud f, Nicolas Dupin g,h, and Olivier Lortholary d,e,f,g
Purpose of review Cutaneous and subcutaneous mycoses are a source of significant morbidity both in immunocompetent and immunocompromised patients. We here review the latest findings in terms of genetic predisposition, epidemiology, clinical manifestations, and therapeutic strategies in these diseases. Recent findings A growing number of fungal skin and soft tissue infections are reported worldwide. In immunocompromised patients, these infections are often associated with disseminated disease. Skin and soft tissue biopsies usually allow mycological identification. Although tissue culture remains the gold standard, molecular biology is increasingly used and sometimes mandatory for accurate diagnosis. Advances in therapeutics have improved outcome and lowered dissemination risk in patients. Summary Cutaneous and subcutaneous mycoses are an evolving field. Clinicians all over the world should be aware of the common manifestations of these diseases – infectious diseases – as they are increasingly reported and may lead to or be associated with dissemination. Keywords eumycetoma, fungus, fusariosis, phaeohyphomycosis, skin
INTRODUCTION Cutaneous and subcutaneous mycoses develop following either traumatic inoculation (phaeohyphomycosis, eumycetoma, sporotrichosis, chromoblastomycosis) or hematogenous seeding (cryptococcosis, aspergillosis, histoplasmosis). Both cosmopolitan and tropical fungi are implicated, but because of worldwide travel, tropical mycoses are now reported outside their endemic areas. Moreover, the increasing number of severely immunocompromised patients has led to the emergence of rare and even new pathogens, such as Trichosporon spp., Fusarium spp., mucormycoses, and Emmonsia spp. [1,2]. We here review recent and novel findings concerning genetic predisposition, clinical features, mycological identification, and therapeutic options in these skin and soft tissue infections (Table 1).
COSMOPOLITAN FUNGAL SKIN AND SOFT TISSUE INFECTIONS Cryptococcosis Cryptococcosis is mainly caused by Cryptococcus neoformans (subdivided into two variants, grubii and www.co-infectiousdiseases.com
neoformans) and Cryptococcus gattii [3]. In a study of 320 fungal isolates from 303 HIV patients, Cryptococcus was the most frequently isolated fungus (50.0% of isolates). The main sites of infection were central nervous system, blood, and lung [4]. On the other hand, cryptococcosis is the third fungal infection after aspergillosis and candidiasis in solid organ transplant (SOT) recipients among whom cutaneous lesions are described in 18% of cases. Maculopapules, pustules, ulcers, or abscesses usually affecting the lower extremities are described in disseminated infections [5] whereas isolated distal skin lesions a
Assistance Publique-Hoˆpitaux de Paris, Service de Dermatologie, Hoˆpital Tenon, bUniversite´ Pierre et Marie Curie-Paris VI, cINSERM U938, Saint Antoine Research Center, dInstitut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, eCNRS URA3012, fAssistance Publique-Hoˆpitaux de Paris, Centre d’Infectiologie Necker Pasteur, Hoˆpital Necker-Enfants malades, g Universite´ Rene´ Descartes-Paris and hAssistance Publique-Hoˆpitaux de Paris, Service de Dermatologie, Hoˆpital Cochin, Paris, France Correspondence to Professor Olivier Lortholary, MD, PhD, Institut Pasteur, Unite´ de Mycologie Mole´culaire, Centre National de Re´fe´rence Mycoses Invasives et Antifongiques, Paris, France. Tel: +33 1 40 61 33 41; fax: +33 1 45 68 84 20; e-mail: [email protected] Curr Opin Infect Dis 2016, 29:124–130 DOI:10.1097/QCO.0000000000000252 Volume 29 Number 2 April 2016
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Fungal skin and soft tissue infections Gue´gan et al.
KEY POINTS Cutaneous and subcutaneous mycoses are a significant source of morbidity both in immunocompetent and immunocompromised patients. Both cosmopolitan and imported skin mycoses are increasingly reported in immunocompromised patients; dissemination should be investigated in these patients. In most cases, a polyphasic approach combining morphological and molecular analysis is useful for mycological identification. Expansion of the therapeutic arsenal has significantly improved management of these diseases.
develop deep dermatophytosis with dermis invasion [8]. Autosomal recessive CARD9 deficiency was evidenced to be the main cause of deep dermatophytosis in patients without any known immunosuppression. Patients displayed recurrent superficial dermatophytosis in childhood. In young adulthood, invasive, extensive, and treatment resistant infection developed with frequent lymph node involvement [9 ]. &&
Phaeohyphomycosis Phaeohyphomycoses affect both immunocompetent and immunocompromised patients worldwide and are caused by multiple genera of melanized fungi [10 ]. Exophiala spp., common agents of phaeohyphomycosis, are usually responsible for skin infections whereas invasive disease is extremely rare. Autosomal recessive CARD9 deficiency has recently been reported in two otherwise healthy patients presenting a disseminated form of Exophiala infection [11 ]. Alternaria spp., mostly Alternaria alternata, are increasingly described as emerging opportunistic infections in SOT recipients. These patients represent 50% of cutaneous alternariosis cases [12 ,13]. A rural environment is usually reported as local trauma induces fungus penetration. Lesions (plaques, nodules, or ulcers) are mainly solitary [13], but multiple lesions are also described [12 ]. Schieffelin and colleagues [14] reviewed 27 cases of phaeohyphomycosis occurring in SOT recipients. The majority of patients (89%, 24/27) developed an infection limited to the skin. The most frequently isolated fungus was Exophiala spp. (44%, 12/27). McCarty et al. [15 ] reported 56 cases of phaeohyphomycosis in 26 stem cell transplant and 30 SOT recipients. The most common pathogens were Alternaria spp. (32%), Exophiala spp. (11%), Cladophialophora spp. (8.9%), and Scopulariopsis spp. (8.9%). The two most frequent sites of infection and providers of positive cultures were skin and respiratory tract. Cutaneous disease affected more SOT than stem cell transplant patients: 53.3 vs 23.1% respectively. In total, 50% of patients presented disseminated disease [15 ]. Current treatment recommendations identify itraconazole, voriconazole, and posaconazole as first-line therapy in cutaneous and subcutaneous phaeohyphomycoses. Amphotericin B may be useful in refractory cases. Surgical debridement should be performed when possible [10 ]. In Schieffelin study, out of the 24 patients with cutaneous infections, 22 were treated by excision, either alone (three patients) or in association with itraconazole (19 patients) or voriconazole (two patients). Two &
correspond to primary cutaneous cryptococcosis. Cryptococcus skin manifestations such as cellulitis, necrotizing soft tissue infection, have been increasingly reported in SOT patients, and can also be a manifestation of immune reconstitution syndrome [5]. As multiple skin lesions correspond to hematogenous dissemination, they should be treated with amphotericin B (deoxycholate or a lipid formulation) and flucytosine (induction) followed by fluconazole (consolidation) [3,6 ]. Primary cutaneous cryptococcosis should be treated with fluconazole [3,6 ]. &
&
&
&
&
Trichosporonosis Trichosporonosis most commonly affects immunocompetent patients in the form of white piedra, a superficial infection of the hair shaft, whereas primary invasive cutaneous trichosporonosis is a very rare manifestation [7]. Nevertheless, invasive infections because of Trichosporon spp. are increasingly reported in immunocompromised patients: fungemia is the most frequent manifestation (75%), with associated metastatic skin lesions in 50% of cases [3]. Most cases are caused by Trichosporon asahii (74%), followed by Trichosporon dermatis (12%). Triazoles are the most effective antifungals in prophylaxis and treatment: voriconazole is the preferred agent with good in-vivo outcome in most animal and clinical studies, both for primitive cutaneous and disseminated infections [3,7].
Deep dermatophytosis Dermatophytes are cosmopolitan fungi responsible for benign and very frequent infections limited to stratum corneum. However, a few immunocompromised patients (HIV, solid organ transplant, and patients receiving immunosuppressive therapy)
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&
&
&
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Cosmopolitan
Cosmopolitan
Tropical
Tropical
Aspergillosis
Fusariosis
Mucormycosis
Histoplasmosis
Penicilliosis
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Tropical
Tropical
Sporotrichosis
Chromoblastomycosis
Fonsecaea pedrosoi, Cladiophialophora carrionii
Sporothrix schenckii species complex
Madurella mycetomatis, Scedosporium boydii
Emmonsia spp.
Talaromyces marneffei (Penicillium marneffei)
Histoplasma capsulatum
Apophysomyces variabilis, Apophysomyces elegans, Rhizopus arrhizus, Lichtheimia corymbifera, Saksanea vasiformis
Fusarium spp.
Aspergillus flavus, Aspergillus fumigatus
Exophiala spp., Alternaria spp., (mostly Alternaria alternata), Cladophialophora spp., Scopulariopsis spp.
Trichosporon asahii, Trichosporon dermatis
Cryptococcus neoformans (two variants grubii and neoformans) Cryptococcus gattii
Causative agent
Primary cutaneous and subcutaneous lesions
Primary fixed cutaneous lesions or lymphocutaneous disease
Primary cutaneous and subcutaneous lesions
Secondary cutaneous
Secondary cutaneous
Secondary cutaneous (blood culture þ)
Surgery and antifungal: itraconazole or posaconazole
Itraconazole
Surgery and antifungal: itraconazole, voriconazole or posaconazole
Amphotericin B (deoxycholate or liposomal formulation) followed by itraconazole
Itraconazole (mild) or amphotericin B deoxycholate (severe) followed by itraconazole
Itraconazole (mild) or liposomal amphotericin B (severe and/or immunocompromised) followed by itraconazole
Surgery and liposomal amphotericin B or isavuconazole followed by posaconazole
Secondary cutaneous
Voriconazole Surgery and liposomal amphotericin B or isavuconazole followed by posaconazole
Voriconazole; combination therapy
Secondary cutaneous Primary cutaneous
Voriconazole
Secondary cutaneous (blood culture þ)
Voriconazole
Primary cutaneous
Surgery and voriconazole
Secondary cutaneous
Surgery and antifungal (itraconazole, voriconazole, posaconazole, amphotericin B deoxycholate, or lipid formulation)
Multiple lesions
Primary cutaneous
Surgery
Single lesion
Voriconazole
Amphotericin B (deoxycholate or lipid formulation) þ flucytosine followed by fluconazole
Secondary cutaneous (blood culture þ) Primary cutaneous
Fluconazole
Treatment
Primary cutaneous
Clinical characteristics
a Mycoses covered in the present review. As there were no major recommendations in the past year concerning blastomycosis, coccidioidomycosis, and paracoccidioidomycosis, these three diseases are not detailed in the table.
Tropical
Eumycetoma
Subcutaneous mycoses
South Africa, India
Cosmopolitan
Phaeohyphomycosis
Emmonsiosis
Cosmopolitan
Cosmopolitan
Trichosporonosis
Cosmopolitan
Geographical distribution
Cryptococcosis
Invasive fungal diseases
Name
Table 1. Main cutaneous and subcutaneous mycosesa
Skin and soft tissue infections
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Fungal skin and soft tissue infections Gue´gan et al.
patients received itraconazole only [14]. In McCarty et al.’s study [15 ], voriconazole and lipid formulations of amphotericin B were the two most frequent antifungals used either alone or in combination. In transplanted patients, immunosuppressant reduction is mandatory to improve immune status. &
Aspergillosis Cutaneous aspergillosis represented 1% of invasive aspergillosis in a national retrospective French study from 2005 to 2010 [16 ]. Most cases corresponded to secondary cutaneous aspergillosis (10 cases), whereas primary cutaneous aspergillosis was less frequent (five cases). Primary aspergillosis was characterized by infiltrative and/or suppurative lesions; in secondary aspergillosis, both disseminated nodules or papules and isolated cellulitis or nodule were described. Aspergillus flavus was responsible for all primary cases, whereas Aspergillus fumigatus was most frequently isolated from secondary cases. Pathology evidenced an isolated dermal infiltrate in secondary aspergillosis that contrasted with the dermo-epidermal infiltrate characteristic of primary forms. Prognosis was very different with 100% and 30% survival rates in primary and secondary forms respectively [16 ]. Mold infections are also a severe complication in burned patients. A retrospective single-center French study from 2000 to 2011 reported a filamentous fungal infection incidence of 1.7%. The most frequent fungal infection was aspergillosis followed by mucormycosis and fusariosis. Risk factors were total body surface area burned, full-thickness burn surface area, unit burn standard, and severity scores such as Tobiasen score and SAPS2 [17]. &
&
Fusariosis
from 2001 to 2011 (period 2) 233 cases of invasive fusariosis. Most patients (92%) had hematological malignancies [19]. Outcome changed between the two periods with 22% survival at 90 days in period 1 and 43% in period 2. Primary treatment was also modified with more voriconazole and combination prescription in the second period. Death was associated with corticosteroids, receipt of deoxycholate amphotericin B and neutropenia. Fusarium associated skin and nail lesions are associated with development of invasive fusariosis in high-risk hematology patients [20] whereas skin colonization with Fusarium sp. is not associated with invasive fusariosis. First-line recommended treatment for fusariosis is voriconazole [2].
Mucormycosis Mucormycosis affects patients with hematological malignancies and diabetes mellitus. In India, skin is the second site (29%) involved in mucormycosis after rhino-orbitocerebral infections; 38% of patients had diabetes mellitus, 31% a history of intramuscular injection, 31% underwent abscess incision or drainage, and 7% were involved in a road accident. Apophysomyces variabilis and Apophysomyces elegans were more frequently associated with cutaneous location [21]. In a Mexican study of 22 cases of mucormycosis in children, skin was also the second site involved (18%) after rhinocerebral manifestations. Predisposing factors were diabetes mellitus (68%) and hematological malignancy (27%). The main agents were Rhizopus arrhizus and Lichtheimia corymbifera [22]. In France, skin is the third location of mucormycosis after sinus and lung. Posttraumatic mucormycosis was associated with underlying disease in 31% of cases. A. elegans and Saksanea vasiformis were associated with skin location. Most patients (93%) had surgery and survival rate was higher than in other mucormycoses (87% survival rate) [23 ]. Recommended treatment is high dose liposomal amphotericin B or isavuconazole associated with surgery and control of underlying conditions including diabetes mellitus [1,24–25]. &
Invasive fusariosis mainly affects patients with hematological malignancies. Cutaneous dissemination is frequent. However, portal of entry is usually airways. An increasing incidence was reported in hematology patients in Brazil after 2005 with an incidence rise from 0.86 to 10.23 cases/1000 admissions in this particular setting [18 ]. Portal of entry was cutaneous in most patients (67%) with onychomycosis, periungueal cellulitis, or interdigital intertrigo sometimes associated with lymphangitis. An increase was demonstrated on the same period for superficial infections. Main clinical strains were Fusarium solani, whereas those from environment were mostly Fusarium oxysporum [18 ]. An international retrospective study with 11 participating countries studied from 1985 to 2000 (period 1) and &&
&&
TROPICAL FUNGAL SKIN AND SOFT TISSUE INFECTIONS Histoplasmosis Histoplasma capsulatum is endemic to various areas of North and South America, Africa, Asia and Australia. Presentation and incidence of cutaneous histoplamosis depends on patients’ immune status. Indeed, cutaneous lesions rarely affect immunocompetent hosts. Sun et al. [26] reviewed 22 cases
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Skin and soft tissue infections
of cutaneous histoplamosis in renal transplant recipients. In 77% of patients (17/22), a disseminated form of the disease was reported. Cutaneous lesions (nodules, papules or plaques, ulcerations) were often asymptomatic and nonspecific. Prognosis differed between patients with isolated cutaneous histoplasmosis (100% survival) and those with disseminated disease (71% survival) [26]. Marukutira et al. [4] analyzed fungemias in 303 HIV patients: Histoplasma was the third isolated fungus (9.1% of isolates) with an 84% survival rate. Amphotericin B or its lipid formulations followed by itraconazole or itraconazole alone are the mainstay of treatment. Liposomal Amphotericin B followed by itraconazole is the first-line therapy of severe disseminated histoplasmosis in immunocompromised patients. In this setting, itraconazole represents the maintenance therapy of choice.
Penicilliosis Penicilliosis, third opportunistic infection in HIV patients in South-East Asia and AIDS-defining illness, is caused by Penicillium marneffei (renamed Talaromyces marneffei). Its incidence is increasing both within and outside its endemic areas. Cutaneous lesions (skin-colored umbilicated papules or nodules with or without central necrosis) can be isolated, but in 70% of cases are associated with disseminated infection [27]. In a study of 100 disseminated penicillioses, bone involvement was described exclusively in the HIV-negative group (one-third of patients). Osteolytic lesions affected 40% of HIV-negative patients and were associated with cutaneous lesions in 85% of cases [28]. Itraconazole is effective both for prophylaxis and treatment of cutaneous forms of penicilliosis. Amphotericin B deoxycholate followed by itraconazole is recommended in severe infections. Voriconazole is an alternative for both mild and severe forms of the disease [27].
Emmonsiosis Emmonsiosis is a new emerging infectious disease very recently reported in South Africa and India and caused by dimorphic fungi, Emmonsia spp. [29 ,30]. This fungal infection has been described mostly in HIV patients with a CD4þ T-cell count under 50 cells/cubic millimeter (94% of patients) [29 ,31 ] and very rarely in immunocompetent and SOT patients [30,31 ,32]. Patients had disseminated disease with secondary widespread skin (96% of cases) or mucous membrane lesions. They displayed erythematous papules, plaques, nodules, or ulcers, possibly crusted or necrotic, healing with residual &&
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hyperpigmentation and marked scarring [29 ,31 ]. Culture of skin biopsy usually allows fungus identification [31 ]. First-line therapy should be amphotericin B (deoxycholate or liposomal formulation) followed by itraconazole, as the mortality rate is very high (48%) [31 ]. &&
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Eumycotic mycetoma &&
Van de Sande [33 ] conducted a meta-analysis including 50 studies and analyzing 8763 mycetoma cases, most of which were reported from Mexico, Sudan, and India. Mycetoma was caused by fungi in 41.7% of cases, Madurella mycetomatis being the most prevalent causative agent worldwide (24.3% of cases). Mycetoma affected most commonly the foot (68.7%) in men between 11 and 40 years of age (sex ratio 3.5/1). Fahal et al. [34] report similar data in their Sudanese study of 6792 mycetomas affecting predominantly male patients (76%) and the foot (76%). Madurella mycetomatis (70%) was the most frequently isolated organism. On the other hand, Bonifaz et al. [35 ] reported only 7.88% of eumycetomas among 482 Mexican mycetoma cases, with M. mycetomatis and Scedosporium boydii as fungal agents. The importance of molecular biology and internal transcribed spacer sequencing for mycological identification has been underlined [33 ], and a new molecular-based method using rollingcircle amplification has proven efficient, reproducible, and highly specific [36]. Current therapeutic recommendations advocate extensive surgical debridement combined with prolonged antifungal therapy. Itraconazole is now the drug of choice in this disease as ketoconazole was recently banned because of its high toxicity [34]. Rates of relapse as high as 31% are nevertheless reported in this disease [34]. Voriconazole and posaconazole were also recently reported to be active in vitro against 19 mycetoma strains [37], and in a retrospective study of 11 imported eumycetoma cases, voriconazole or posaconazole treatment was assessed: complete response was observed in 5/11 patients, partial response in five, and failure in one. Relapse occurred in two patients following treatment discontinuation [38]. Triazole treatment is, therefore, a relevant therapeutic alternative in this disease. &
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Sporotrichosis Sporotrichosis is a subcutaneous mycosis caused by traumatic inoculation of a dimorphic fungus, usually Sporothrix schenkii. Lesions most commonly affect face and extremities in immunocompetent patients, and the two most frequent forms of the disease are Volume 29 Number 2 April 2016
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Fungal skin and soft tissue infections Gue´gan et al.
lymphocutaneous and fixed cutaneous. Oral itraconazole, terbinafine, or potassium iodide are advocated in these cases. Amphotericin B or triazoles are recommended in extracutaneous and disseminated infections that occur in immunocompromised patients [27]. Therapeutic challenges concern the more aggressive and resistant infections caused by S. brasiliensis [39]. Sporothrix Gp70 protein is involved in the host immune response, and an anti-Gp70 monoclonal antibody already tested in a murine model could be of use for vaccine development [39].
Chromoblastomycosis Chromobastomycosis (CBM), the third endemic mycosis in tropical and subtropical areas after eumycetoma and sporotrichosis, is mainly caused by Fonsecaea pedrosoi or Cladophialophora carrionii. Cutaneous papular nodules and vegetating cauliflower-like or ulcerated plaques develop at the site of fungal entry following skin trauma. The most severe complication is malignant transformation with a total of 19 reported cases of squamous cell carcinomas developing on chronic CBM [40]. Followup biopsies should therefore be performed if new ulcers appear during the healing phase. Antifungals (itraconazole, terbinafine, flucytosine, and amphotericin B), surgical excision, and physical treatments have been used with variable success and high rates of relapse. Topical imiquimod stimulates immune pathways through Toll-like receptor activation, and has potent antiviral and antitumor properties. Both with and without a concurrent antifungal, it allowed marked lesion improvement in four patients [41]. Further studies are required to confirm the relevance of imiquimod as adjuvant treatment in CBM.
CONCLUSION Cutaneous and subcutaneous mycoses arise following either traumatic inoculation or hematogenous seeding. They are reported with an ever-growing frequency as a consequence of increasing numbers of immunocompromised patients. In parallel, rare and even new pathogens are regularly implicated in human infections. In most cases, skin or soft tissue biopsies allow mycological identification; the relevance of a polyphasic approach combining culture and the use of molecular biology is underlined in many publications. Finally, expansion of the therapeutic arsenal has significantly improved management of these diseases. Acknowledgements None.
Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al., European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group. European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis. Clin Microbiol Infect 2014; 20(Suppl 3):5–26. 2. Tortorano AM1, Richardson M, Roilides E, et al., European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group. European Confederation of Medical Mycology. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect 2014; 20(Suppl 3): 27–46. 3. Arendrup MC, Boekhout T, Akova M, et al., European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group. European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of rare invasive yeast infections. Clin Microbiol Infect 2014; 20(Suppl 3):76–98. 4. Marukutira T, Huprikar S, Azie N, et al. Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the Prospective Antifungal Therapy Alliance registry, a multicenter, observational study. HIV AIDS (Auckl) 2014; 6:39–47. 5. Henao-Martı´nez AF, Beckham JD. Cryptococcosis in solid organ transplant recipients. Curr Opin Infect Dis 2015; 28:300–307. 6. Gavalda` J, Meije Y, Fortu´n J, et al., ESCMID Study Group for Infections in & Compromised Hosts. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect 2014; 20(Suppl 7):27–48. The article issues guidelines for diagnosis, treatment, and prevention of invasive fungal diseases in solid organ transplant recipients. 7. Bhari N, Xess I, Pandey M, et al. Primary cutaneous trichosporonosis responsive to voriconazole. JAMA Dermatol 2015; 151:1139–1141. 8. Rouzaud C, Hay R, Chosidow O, et al. Severe dermatophytosis and acquired or innate immunodeficiency: a review. J Fungi 2016; in press. 9. Lanternier F, Pathan S, Vincent QB, et al. Deep dermatophytosis and inherited && CARD9 deficiency. N Engl J Med 2013; 369:1704–1714. The study reports autosomal recessive CARD9 deficiency in 17 patients from eight unrelated families with unexplained invasive deep dermatophytosis. 10. Chowdhary A, Meis JF, Guarro J, et al. ESCMID and ECMM joint clinical & guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Infect 2014; 20(Suppl 3):47–75. The article issues guidelines for diagnosis, accurate mycological identification, and treatment of invasive phaeohyphomycosis. 11. Lanternier F, Barbati E, Meinzer U, et al. Inherited CARD9 deficiency in 2 & unrelated patients with invasive exophiala infection. J Infect Dis 2015; 211:1241–1250. The article reports autosomal recessive CARD9 deficiency in two unrelated patients with unexplained invasive exophiala infection. 12. Coutinho I, Teixeira V, Gameiro A, et al. Cutaneous alternariosis: a case series & of an increasing phaeohyphomycosis. J Eur Acad Dermatol Venereol 2015; 29:2053–2054. The article reports eight cases of cutaneous alternariosis, emerging opportunistic infection in transplant recipients. 13. Hsu CC, Chang SS, Lee PC, Chao SC. Cutaneous alternariosis in a renal transplant recipient: a case report and literature review. Asian J Surg 2015; 38:47–57. 14. Schieffelin JS, Garcia-Diaz JB, Loss GE Jr, et al. Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment. Transpl Infect Dis 2014; 16:270–278. 15. McCarty TP, Baddley JW, Walsh TJ, et al., TRANSNET Investigators. Phaeo& hyphomycosis in transplant recipients: results from the Transplant Associated Infection Surveillance Network (TRANSNET). Med Mycol 2015; 53:440– 446. The study describes the epidemiology and clinical characteristics of phaeohyphomycosis in transplant recipients throughout the USA over a 5-year period.
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Skin and soft tissue infections 16. Bernardeschi C, Foulet F, Ingen-Housz-Oro S, et al., French Mycosis Study Group. Cutaneous invasive aspergillosis: retrospective multicenter study of the French invasive-aspergillosis registry and literature review. Medicine (Baltimore) 2015; 94:e1018. The unique clinical series describes prevalence and clinical characteristics of skin manifestations in 1410 patients with invasive aspergillosis. The study reports differences in terms of mycological features, management, and prognosis between primary cutaneous and secondary cutaneous invasive aspergillosis. 17. Schaal JV, Leclerc T, Soler C, et al. Epidemiology of filamentous fungal infections in burned patients: a French retrospective study. Burns 2015; 41:853–863. 18. Nucci M, Varon AG, Garnica M, et al. Increased incidence of invasive && fusariosis with cutaneous portal of entry, Brazil. Emerg Infect Dis 2013; 19:1567–1572. The single-center retrospective Brazilian study describes clinical characteristics of 21 hematology patients with invasive fusariosis and reports a high incidence of a cutaneous portal of entry in these patients. It reports an increase in both invasive fusariosis in hematology patients and superficial fusariosis in patients from the dermatology outpatient clinic. 19. Nucci M, Marr KA, Vehreschild MJ, et al. Improvement in the outcome of invasive fusariosis in the last decade. Clin Microbiol Infect 2014; 20:580– 585. 20. Varon AG, Nouer SA, Barreiros G, et al. Superficial skin lesions positive for Fusarium are associated with subsequent development of invasive fusariosis. J Infect 2014; 68:85–89. 21. Bala K, Chander J, Handa U, et al. A prospective study of mucormycosis in north India: experience from a tertiary care hospital. Med Mycol 2015; 53:248–257. 22. Bonifaz A, Tirado-Sa´nchez A, Caldero´n L, et al. Mucormycosis in children: a study of 22 cases in a Mexican hospital. Mycoses 2014; 57 (Suppl 3):79–84. 23. Lelievre L, Garcia-Hermoso D, Abdoul H, et al., French Mycosis Study Group. & Posttraumatic mucormycosis: a nationwide study in France and review of the literature. Medicine (Baltimore) 2014; 93:395–404. Clinical and mycological characteristics of posttraumatic mucormycosis as well as outcome are described in this nationwide retrospective French study with literature review. 24. Skiada A, Lanternier F, Groll AH, et al., European Conference on Infections in Leukemia. Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3). Haematologica 2013; 98:492–504. 25. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis 2015; 61:1558–1565. 26. Sun NZ, Augustine JJ, Gerstenblith MR. Cutaneous histoplasmosis in renal transplant recipients. Clin Transplant 2014; 28:1069–1074. 27. Nor NM, Baseri MM. Skin and subcutaneous infections in south-east Asia. Curr Opin Infect Dis 2015; 28:133–138. 28. Qiu Y, Zhang J, Liu G, et al. Retrospective analysis of 14 cases of disseminated Penicillium marneffei infection with osteolytic lesions. BMC Infect Dis 2015; 15:47. &
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29. Kenyon C, Bonorchis K, Corcoran C, et al. A dimorphic fungus causing disseminated infection in South Africa. N Engl J Med 2013; 369:1416–1424. The article describes 13 South African cases of disseminated emmonsiosis, a new emerging fungal disease caused by a dimorphic fungus Emmonsia sp. 30. Malik R, Capoor MR, Vanidassane I, et al. Disseminated Emmonsia pasteuriana infection in India: a case report and a review. Mycoses 2016; 59:127–132. 31. Schwartz IS, Govender NP, Corcoran C, et al. Clinical characteristics, && diagnosis, management, and outcomes of disseminated emmonsiosis: a retrospective case series. Clin Infect Dis 2015; 61:1004–1012. The multicenter retrospective study describes clinical characteristics, treatment, and outcome of 54 South African cases of disseminated emmonsiosis. This new emerging fungal disease mostly affects HIV patients (94% of patients) and has a very low survival rate (52%). 32. van Hougenhouck-Tulleken WG, Papavarnavas NS, Nel JS, et al. HIV-associated disseminated emmonsiosis, Johannesburg, South Africa. Emerg Infect Dis 2014; 20:2164–2166. 33. van de Sande WW. Global burden of human mycetoma: a systematic review && and meta-analysis. PLoS Negl Trop Dis 2013; 7:e2550. This meta-analysis estimates the global burden of mycetoma worldwide analyzing 8763 mycetoma cases. Prevalence, clinical characteristics, causative agents, and their distribution per country are described. 34. Fahal A, Mahgoub el S, El Hassan AM, Abdel-Rahman ME. Mycetoma in the Sudan: an update from the Mycetoma Research Centre, University of Khartoum, Sudan. PLoS Negl Trop Dis 2015; 9:e0003679. 35. Bonifaz A, Tirado-Sa´nchez A, Caldero´n L, et al. Mycetoma: experience of 482 & cases in a single center in Mexico. PLoS Negl Trop Dis 2014; 8:e3102. The single-center study with long follow-up reports 482 cases of mycetoma over a 33-year period and determines the clinical and microbiological characteristics of mycetoma in different regions of Mexico. 36. Ahmed SA, van den Ende BH, Fahal AH, et al. Rapid identification of black grain eumycetoma causative agents using rolling circle amplification. PLoS Negl Trop Dis 2014; 8:e3368. 37. Ahmed SA, de Hoog GS, Stevens DA, et al. In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals. Med Mycol 2015; 53:295–301. 38. Crabol Y, Poiree S, Bougnoux ME, et al., French Mycosis Study Group. Last generation triazoles for imported eumycetoma in eleven consecutive adults. PLoS Negl Trop Dis 2014; 8:e3232. 39. Lopes-Bezerra LM, Mora-Montes HM. Sporothrix and sporotrichosis: contributions from the first international meeting sponsored by the Working Group on Sporothrix and sporotrichosis of the International Society for Human and Animal Mycology, Rio de Janeiro, Brazil, October, 2013. Med Mycol 2015; 53:1–2. 40. Azevedo CM, Marques SG, Santos DW, et al. Squamous cell carcinoma derived from chronic chromoblastomycosis in Brazil. Clin Infect Dis 2015; 60:1500–1504. 41. de Sousa Mda G, Belda W Jr, Spina R, et al. Topical application of imiquimod as a treatment for chromoblastomycosis. Clin Infect Dis 2014; 58:1734– 1737. &&
Volume 29 Number 2 April 2016
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
