Angioinvasive fungal infections impacting the skin

Angioinvasive fungal infections impacting the skin Diagnosis, management, and complications Anthony P. Berger, MD,a Bradley A. Ford, MD, PhD,b Zoe Brown-Joel, BS,c Bridget E. Shields, MD,d Misha Rosenbach, MD,e and Karolyn A. Wanat, MDf Iowa City, Iowa; Madison, Wisconsin; and Philadelphia, Pennsylvania

Learning Objectives After completing this learning activity, participants should be able to categorize and describe the diagnostic testing available for angioinvasive fungal infections; distinguish histopathologic features of angioinvasive fungal infections; and list treatments for angioinvasive fungal infections with cutaneous manifestations. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

As discussed in the first article in this continuing medical education series, angioinvasive fungal infections pose a significant risk to immunocompromised and immunocompetent patients alike, with a potential for severe morbidity and high mortality. The first article in this series focused on the epidemiology and clinical presentation of these infections; this article discusses the diagnosis, management, and potential complications of these infections. The mainstay diagnostic tests (positive tissue culture with histologic confirmation) are often supplemented with serum biomarker assays and molecular testing (eg, quantitative polymerase chain reaction analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry) to ensure proper speciation. When an angioinvasive fungal infection is suspected or diagnosed, further workup for visceral involvement also is essential and may partially depend on the organism. Different fungal organisms have varied susceptibilities to antifungal agents, and knowledge on optimal treatment regimens is important to avoid the potential complications associated with undertreated or untreated fungal infections. ( J Am Acad Dermatol 2019;80:883-98.) Key words: angioinvasive fungal infections; antifungal therapy; aspergillosis; candidiasis; fusariosis; mucormycetes.

From the Departments of Dermatologya and Pathology and Clinical Microbiologyb and the University of Iowa Carver College of Medicine,c University of Iowa Hospitals and Clinics, and the Department of Dermatology and Pathology,f University of Iowa, Iowa City; Department of Dermatology,d University of Wisconsin, Madison; and the Department of Dermatology,e University of Pennsylvania, Philadelphia. Dr Wanat is currently affiliated with the Medical College of Wisconsin, Department of Dermatology, Milwaukee, WI. Dr Wanat received a Dermatology Foundation Career Development Award.

Conflicts of interest: None disclosed. Accepted for publication April 25, 2018. Correspondence to: Karolyn A. Wanat, MD, Department of Dermatology and Pathology, University of Iowa, 200 Hawkins Dr, Iowa City, IA 52246. E-mail: [email protected]. 0190-9622/$36.00 Ó 2018 by the American Academy of Dermatology, Inc. https://doi.org/10.1016/j.jaad.2018.04.058 Date of release: April 2019 Expiration date: April 2022

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DIAGNOSIS AND WORKUP Key points d

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Obtaining a sterile punch biopsy specimen and a fungal culture are standard components of the diagnostic workup It is important to notify the microbiology laboratory if mucormycosis is suspected, because tissue samples should be handled gently (ie, no grinding or stomaching); this decreases the likelihood of a false negative Frozen sectioning or touch preparations of a punch biopsy specimen can be an effective method to quickly ascertain the presence of fungal organisms in tissue

Angioinvasive fungal infections pose a significant risk to immunocompromised and immunocompetent patients alike.1 The prompt diagnosis of angioinvasive fungal infections is of paramount importance to guide appropriate treatment and to avoid adverse outcomes. The numerous potential organisms implicated and their varied susceptibilities to antifungal agents make proper speciation and diagnostic accuracy an essential component of patient management. The diagnostic armamentarium is rapidly expanding, and multiple modalities may be used to obtain a proper diagnosis. If clinically suspected, treatment should be initiated immediately, before a histologic examination and culture in severely ill or immunocompromised patients.2 With cutaneous disease, obtaining a sterile punch biopsy specimen for histologic examination and fungal culture is standard in the diagnostic workup. Other approaches to laboratory diagnosis, such as aspergillus galactomannan, beta-D-glucan, and other antigen tests, are helpful adjuncts but are often nondiagnostic. Blood cultures, while an appealing approach for angioinvasive disease, are essentially always negative, except in the case of fusariosis, where positive blood cultures can be a helpful diagnostic feature.3 Obtaining a sterile punch biopsy specimen involves cleaning the affected area with chlorhexidine or other antimicrobial cleanser to eliminate surface organisms, followed by obtaining a biopsy specimen under sterile technique and with prompt submission to microbiology, where direct examination and culture is performed. If candida is clinically suspected, intact pustules also can be cleaned, unroofed, scraped, and submitted for Gram stain and culture.4 If mucormycosis is suspected, fragile hyphae can be killed by grinding or stomaching samples, as is typically done in clinical microbiology laboratories. Yield of culture is greatly increased if whole tissue samples are minimally processed and placed directly onto cycloheximide-free culture

Fig 1. Touch preparation from suspected angioinvasive fungus demonstrating broad, ribbon-like hyphae without septae. The culture grew Rhizopus. (Potassium hydroxide stain; original magnification: 340. Photograph courtesy of Mary Stone, MD.)

media5 (Supplemental Fig 1; available at http://www.jaad.org). Informing the microbiology laboratory of likely etiologies is therefore helpful because typical procedures can be modified according to likely etiology. If possible, stat frozen section biopsy specimens or touch preparations also can be used for initial diagnosis, providing more rapid tissue visualization and potentially near-immediate diagnosis, with resultant rapid initiation of therapy (Fig 1). For these techniques, a punch biopsy is still performed and initially processed under frozen section, with subsequent permanent staining. Histologic verification of tissue invasion with corresponding fungal culture is essential to diagnose cutaneous disease. Unfortunately, fungal cultures are historically nonsensitive and nonspecific because of sampling error or organism nonviability.6 In addition, the number of fungal colonies obtained in culture does not easily delineate disease versus contamination, a distinction that is complicated by the ubiquity of potentially pathogenic fungal organisms in the environment, so clinical and histologic correlation is important in all cases.

HISTOPATHOLOGY Key points d

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Histopathology can help identify fungi and their morphologic features regarding septated hyphae and pigmentation, but it is not possible to completely accurately speciate a fungal organism subtype via histology alone The presence of septated hyphae largely rules out Mucorales spp, which present as nonseptated and wide, ribbon-like organisms Septated and nonpigmented hyphae can represent several hyalohyphomycotic species, including Fusarium spp, Aspergillus spp, and Pseudallescheria spp

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Fig 2. Various stains can be used to visualize fungal infections. Aspergillus spp can be seen on hematoxylineeosin staining (A and C), and hyphae are highlighted with periodic acideSchiff (B) and Gomori methenamine silver (D) stain. (Original magnification: 360.) d

Candida spp will demonstrate a range of morphologies, most commonly budding yeast and pseudohyphae, although Candida glabrata does not form true hyphae or pseudohyphae and may mimic histoplasmosis

Histopathology can identify the etiologic organisms and help with the initial identification and classification of infection. Organisms can usually be seen on hematoxylineeosin staining, and Gomori methenamine silver (GMS) or periodic acideSchiff (PAS) stains can help highlight organisms (Fig 2, A-D). Mucormycetes can paradoxically stain GMSweak or -negative, which may both obscure their presence and assist with presumptive identification because this property is not shared with other fungi (Fig 3). The presence of nonspecific inflammation is dependent upon the host’s immune status. Features of infection often include intradermal or subcutaneous microabscesses with neutrophils, macrophages, multinucleated giant cells, and necrosis. Organisms are often present within or around blood vessel walls and within the dermis, along with blood vessel wall destruction and hemorrhage7 (Supplemental Fig 2, available at http://www.jaad.org). The presence of fungal forms on histology is an indication for rapid initiation of broad-spectrum antifungal agents (generally amphotericin).

Fig 3. Rarely, mucormycetes stains weakly or not at all with Gomori methenamine silver stain. (Original magnification: 3100.)

The differentiation of angioinvasive fungi on histopathology can be difficult, but certain features can help narrow or make the diagnosis (Table I). The presence of septation will rule out mucormycetous infections (save Lichtheimia corymbifera, which rarely exhibits septations), and the presence of brown-black pigment within hyphal cell walls will support phaeohyphomycotic infections (Fig 4, A-C ). Candida spp will demonstrate a range of morphologies, most commonly budding yeast and pseudohyphae (Fig 5). Many dematiaceous molds do not produce visible amounts of melanin, which can be

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Table I. Histopathologic features by etiology8,10,11 Genus/group

Features

Special stains

Exceptions

Weakly stains with GMS and Lichtheimia corymbifera Broad hyphae 3-25 m wide; PAS stains occasionally exhibits without septations; septations compression/distortion can create false appearance of septations; perineural invasion present in 90% of tissue samples containing nerves d FontanaeMasson for better Phaeohyphomycetes Brown-black pigment within visualization of melanin hyphal cell walls; septate within cells walls; silver stains hyphae; hyphae often unhelpful, because predominantly found in fungi become obscured dermis and subcutaneous tissue d Dead hyaline molds can swell to Hyalohyphomycetes 3-6 mewide septated, size of Mucorales spp nondematiaceous hyphae with dichotomous acute angle branching d d Scedosporium spp Brown pigmented hyphae can sometimes be seen; can appear histologically identical to hyalohyphomycetes Candida spp Budding yeast and d Candida glabrata does not form pseudohyphae true hyphae or pseudohyphae; Candida albicans can be predominantly true hyphae

Mucormycetes

GMS, Gomori methenamine silver; PAS, periodic acideSchiff.

Fig 4. Mucorales spp (A) do not have septated hyphae, with the exception of Lichtheimia corymbifera which can have septations. Most other angioinvasive fungi have septated hyphae, including Aspergillus spp (B), and dematiaceous fungal infections, including Alternaria (C), where pigmentation can be highlighted by Fontana-Masson stain (original magnification: B, 360; C, 3100.)

best demonstrated with a melanin stain such as FontanaeMasson (Fig 4, D). It is important to note that many nondematiaceous fungal species are capable of producing melanin. Thus, morphology should take precedence over the presence of pigment on FontanaeMasson staining. Mucorales spp will demonstrate broad (3-25 m wide), wide-angle

branching, aseptate hyphae (Fig 6, A and B).8 Occasionally, hyphae are compressed and distorted, resulting in the appearance of false septae, which may lead to diagnostic confusion (Fig 6, C ).9 Compared with other filamentous pathogens, Mucorales spp stain more lightly or even negative with specialized fungal stains like GMS and PAS (Fig 6, D). Calcofluor white,

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TISSUE CULTURE Key points d

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Fig 5. Candida can demonstrate spores or pseudohyphae. (Hematoxylineeosin stain; original magnification: 360.)

Blankofluor, and Uvitrex may improve visualization of hyphae and help discriminate between septate and aseptate hyphal forms (Fig 6, E ).8 Histologically, the causes of hyalohyphomycosis, which include Fusarium spp, Aspergillus spp, Pseudallescheria/Scedosporium spp, and others may be indistinguishable.10 Hyalohyphomycotic fungi will demonstrate 3- to 6-m wide, septated, nondematiaceous (nonpigmented) hyphae with dichotomous acute angle (ie, approximately 458) branching (Fig 7). The hyphae of dead hyaline molds may swell to the size of the Mucorales spp; however, they can be differentiated from mucormycosis by the pale-staining, thin cell wall.10 Scedosporium, a cause of hyalohyphomycosis, can occasionally demonstrate brown-pigmented structures in hematoxylineeosin-stained sections, confusing the diagnosis if this is not appreciated (Fig 8). In phaeohyphomycosis, histology will demonstrate dematiaceous (brown pigmented), septate hyphae in the dermis or subcutaneous tissue with abundant acute and chronic inflammatory cells (Fig 9). While hematoxylineeosin stain may be sufficient to appreciate melanized hyphae, better visibility may be achieved with PAS and, preferably, FontanaeMasson melanin stains.11 Silver-based stains are often unhelpful as the fungi will be obscured, making it difficult to appreciate the melanin pigment. Curvularia spp may show curved conidia.12 In situ hybridization performed on a positive tissue biopsy specimen is a method that exists to differentiate Aspergillus, Fusarium, and Pseudallescheria. In situ hybridization is 85% sensitive, 100% specific, and has a 100% positive predictive value.11 Broad-range polymerase chain reaction studies and sequencing of 18S ribosomal DNA from formalin-fixed blocks or fresh tissue is best interpreted in the context of culture and histopathology but may be a useful adjunct in making a species-level identification.12

Tissue culture provides pathogen speciation and treatment susceptibilities Aspergillus spp should be considered a true pathogen if isolated in an immunocompromised patient Growth rates vary widely by species, and adequate time for growth is important

Tissue culture is often an essential component of the diagnostic workup, both to determine the etiologic organism and to perform susceptibility testing. Historically, fungal culture has been practically challenging because of highly specific growth requirements, delays in the initiation of treatment, or contamination caused by organism ubiquity in the environment.13 Cultures that are positive for Aspergillus spp should be considered a true pathogen in patients with neutropenia or patients who are otherwise immunocompromised. In conjunction with histopathologic confirmation, tissue culture can help solidify the diagnosis. When positive, specific fungal species may require handling or exhibit unique behavior in tissue culture.14-17 Table II highlights these differences.

BLOOD CULTURE Key points d

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For disseminated candidiasis, positive blood culture is the gold standard Infection by Fusarium spp has a high frequency of positive blood cultures, as Fusarium spp sporulate in vivo

Fungal blood cultures may be necessary to confirm or establish a diagnosis. With some angioinvasive fungal infections, blood cultures are often the main mode for diagnosis (Candida spp), where for others, they are rarely positive (Aspergillus spp). For disseminated candidiasis, a positive blood culture is the diagnostic gold standard. Candida albicans is the most common cause of candidiasis, but Candida glabrata and Candida krusei have been increasing in incidence.18,19 Candida spp are aerobes and grow in routine ‘‘bacterial’’ blood cultures; therefore, the yield of routine blood culture for Candida spp correlates with the volume of blood placed in aerobic blood culture bottles. Patients who are undergoing prophylactic antifungal therapy are at increased risk of false negative cultures.20 Because of the likelihood of a persistent focus of infection in patients with Candida fungemia, this condition is one of the few in which follow-up blood cultures are recommended after an initial positive culture.

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Fig 6. Histopathology of Mucorales. A and B, Mucorales demonstrates broad, ribbon-like hyphae without septations. C, Distorted and compressed fungi can be misinterpreted as septation D, A diagnostic pitfall includes lack of staining with Gomori methenamine silver stain (Lichtheimia). E, Calcofluor white can be a useful tool to highlight Rhizopus. (A and B, Hematoxylineeosin stain; C and D, Gomori methenamine silver stain; original magnification: A, B, and D, 360; C, 350; D, 340.)

Fig 7. Hyalohyphomycotic fungi will have septated, nonpigmented hyphae with dichotomous acute angle as demonstrated by Fusarium. Fusarium spp, Aspergillus spp, and Pseudallescheria/Scedosporium spp are indistinguishable by histology alone. (Hematoxylineeosin stain; original magnification: 360.)

In patients with persistently positive blood cultures, imaging should be performed to determine if a metastatic focus is present.21 Given that [50% of patients with invasive candidiasis have negative blood cultures, other nonculture diagnostic methods have been proposed or are under development and are discussed later.22 Blood cultures of mucormycetes are not reliably positive.23 Blood cultures rarely return positive for Aspergillus spp,

Fig 8. Scedosporium can demonstrate brown-pigmented structures on hematoxylineeosin-stained sections. (Original magnification: 340.)

and a positive blood polymerase chain reaction study may be caused by contamination.24-26 Fusarium spp are capable of sporulating in vivo, which has been postulated as the reason why Fusarium has a high frequency of positive blood cultures compared with Aspergillus spp.27 (Supplemental Fig 2). Blood culture usually becomes positive at 3 days, and is strongly suggestive of fusariosis in patients with prolonged neutropenia.28

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Fig 9. Phaeohyphomycosis has pigmented hyphae and spores. (Hematoxylineeosin stain; original magnification: 360.)

IMAGING Key points d

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Imaging can be helpful to identify other organ involvement in angioinvasive fungal infections Computed tomography imaging of the sinuses and chest is necessary for suspected rhinocerebral and disseminated mucormycosis, respectively In disseminated candidiasis, with elevated liver enzymes or hepatosplenomegaly, computed tomography and magnetic resonance imaging are 90% sensitive in determining hepatosplenic involvement The brain and respiratory tract are preferred sites for disseminated aspergillosis Computed tomography imaging of the brain and chest are indicated in high-risk patients with neurologic or respiratory symptoms

Imaging may be performed depending upon additional symptoms and history. If the primary nidus of infection is unknown or to determine the extent of infection, full-body imaging may be used. With specific symptoms, more directed imaging may be used. Specific imaging examinations and modalities are tailored to symptoms and the suspected infectious etiology.29-39 Table III highlights the etiology, the pathologic condition, the imaging of choice, and the most common findings on imaging.

ADDITIONAL TESTS Key points d

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When negative, galactomannan antigen and 1,3-beta-D-glucan assays are useful for ruling out disseminated mucormycosis The galactomannan antigen assay is positive in Aspergillus spp, but also cross reacts with Fusarium spp, Talaromyces marneffei, and Histoplasma capsulatum

The 1,3-beta-D-glucan assay can detect Aspergillus spp, Candida spp, Pneumocystis jiroveci, Pseudomonas aeruginosa, and occasionally Cryptococcus neoformans The T2Candida assay is a panel that can detect very low levels of candidemia caused by C albicans, Candida tropicalis, Candida parapsilosis, C glabrata, and C krusei

In the workup of a patient with an angioinvasive fungal infection, baseline laboratory studies including a complete blood cell count and comprehensive metabolic panel are often necessary to provide general information on the status of the patient. When histopathology supports a diagnosis of angioinvasive fungal infection but exact speciation is not possible, additional tests and imaging may help expedite the diagnosis. Galactomannan antigen and 1,3-beta-D-glucan (BDG) assay tests are the most commonly used tests to help differentiate Aspergillus spp from other fungi. Most notably, galactomannan antigen and BDG assays can help differentiate aspergillosis from mucormycosis, because these assays do not cross-react with Mucorales spp.40 Among fungal organisms that cause disease that may be confused for an angioinvasive fungal infection, Cryptococcus and Blastomyces are notably BDG-negative, but alternate antigen assays exist for their detection. The galactomannan antigen test is more of a ‘‘rule out’’ than a ‘‘rule in’’ assay.41,42 Unfortunately, sensitivity decreases when antifungal therapy is administered concomitantly, including prophylactic therapy with posaconazole, which is becoming widely used.43 Cross reactivity has been documented with Fusarium spp,44 Talaromyces marneffei,45 and Histoplasma capsulatum.46 False positives have been reported in patients receiving, and up to 5 days after discontinuing, intravenous piperacillintazobactam, although 1 study reports that this problem has been resolved.47,48 False positives also can occur #100 days after hematopoietic cell transplant and in patients with gastrointestinal tract mucositis caused by chemotherapy or graft-versushost disease.49 The consumption of frozen ice pops may also result in a false positive because of galactomannan absorption in the gut.50 The BDG assay can be used nonspecifically for the detection of invasive fungal disease when cultures and histologic examination return negative.51 In addition to Aspergillus spp, the BDG assay can detect Candida spp, P jiroveci, P aeruginosa, and occasionally C neoformans.52,53 Mucormycetes do not cross-react with this assay.

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Table II. Features of angioinvasive fungi on tissue culture Organism

Time to growth

Notes

Mucorales spp

24-48 hours

Aspergillus and Fusarium spp

3-4 days

Scedosporium/Pseudallescheria spp

Within 1 week

Phaeohyphomycotic spp Candida spp

5 days to 3 weeks 1-3 days; Candida glabrata, 3-5 days

Hyphae delicate; notify microbiology laboratory to avoid grinding or homogenization when differential diagnosis includes mucormycosis14 May inadvertently be detected in routine bacterial culture Diagnosis dependent upon imaging consistent with infection and positive culture from normally sterile site15; a biopsy specimen should be obtained from suspicious tissue because blood cultures are unreliable16 d Grow more easily in solid-type culture; Candida glabrata shows unique preference for anaerobic conditions17

Table III. Imaging examinations to assess the extent of angioinvasive fungal disease Etiology

Suspected condition

Mucormycosis

Rhinocerebral

Pulmonary

Candidiasis

Hepatosplenic

Aspergillosis

Cerebral

Pulmonary

Fusariosis

Pulmonary

Scedosporiosis CNS

Imaging modality

Notes

CT sinus

Destruction of the paranasal sinuses with local invasion; in severe cases, direct extension into the frontal or temporal lobes; air fluid levels rarely seen CT chest Annular consolidation with central hypoattenuation/ground glass appearance (‘‘reversed halo’’ sign), which is pathognomonic; 94% sensitive during first week of illness29; sputum and BAL only 25% sensitive30 CT/MRI abdomen 90% sensitive31; predominantly peripheral, hypoattenuated lesions in the liver and spleen; blood cultures often negative in chronic disseminated candidiasis32 CT head In high-risk patients with focal neurologic deficits or mental status changes; lesions variable in appearance; may or may not be ring-enhanced, and may or may not be hemorrhagic; tends to involve perforating artery territories33 CT chest Hemorrhagic infarcts produce nodules surrounded by ground glass attenuation (‘‘halo’’ sign); annular, wedge-shaped areas of consolidation34; a separation of necrotic lung from the surrounding lung parenchyma (‘‘air crescent’’ sign) seen 2-3 weeks after initiation of effective therapy35 CT chest 92% sensitive; no ‘‘halo’’ sign, as seen with aspergillosis36; nodular and infiltrative lesions; nonspecific, used to determine extent of disease, not diagnostically useful37; CXR only 45% sensitive MRI head and CT Patient with history of near-drowning with headache, fever, and angiogram focal neurologic deficits38; scattered ring-enhancing lesions with associated ventriculitis39; intravascular foci may appear as saccular aneurysms on 3-dimensional reconstructions of CT angiogram39

BAL, Bronchoalveolar lavage; CNS, central nervous system; CT, computed tomography; CXR, chest radiograph; MRI, magnetic resonance imaging.

False positives may occur in the setting of hemodialysis or intravenous medications involving cellulose membranes, intravenous immunoglobulin therapy, intravenous albumin, and those with gauze packing

on serosal surfaces.52 Because of the ubiquity of beta-D-glucan in the environment and its presence in a wide variety of fungi, negative tests have much more utility than positive ones, which are very

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Table IV. Molecular diagnostic methods to aid the diagnosis of angioinvasive fungal infections Diagnostic method

Organisms

Notes

Fluorescence in situ hybridization

Aspergillus spp vs Fusarium spp vs Scedosporium/Pseudallescheria spp Candida albicans vs Candida glabrata

Broad range polymerase chain reaction

Mucor/Rhizopus spp vs Lichtheimia complex spp vs Rhizomucor spp56 Aspergillus spp

Performed on microscopically positive tissue biopsy specimen11 Detectible within hours of culture turning positive55 Target the 18S rDNA found in the serum57 Targets 28S ribosomal subunit and ITS/5.8S ribosomal operon58; diagnostic sensitivity increased when combined with galactomannan assay59 Important because of differing antifungal therapy susceptibilities60 Targets 16S rDNA ITS doman61

T2Candida panel

Matrix-assisted laser desorption/ ionization-time of flight mass spectrometry

Lateral flow device

Scedosporium apiospermum spp vs Scedosporium prolificans Alternaria spp vs Curvularia spp (causes of phaeohyphomycosis) Detects C albicans, Candida parapsilosis, C glabrata, and Candida krusei Candida spp

Aspergillus spp

Sensitivity 91%; specificity 99.1%62; unique PCR chemistry allows for detection of low levels of fungemia Any positive fungal culture analysis for extracellular Candida spp proteins; results available within 30 min; limited by necessity of culturing the organism before analysis63 Not species-specific; not yet approved by the FDA; a monoclonal antibody to JF5, an Aspergillus sppespecific epitope64

FDA, US Food and Drug Administration; PCR, polymerase chain reaction.

common in practice relative to the prevalence of fungal infection. Given that the gold standard diagnostic tests are often falsely negative, new highly specific and sensitive diagnostic molecular testing methods are coming into standard use.54-64 Similar to other testing methods mentioned above, the results of these tests require clinicopathologic correlation. Table IV highlights some of these tests.

TREATMENT Key points d

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Empiric therapy, such as liposomal or lipidbased amphotericin B and posaconazole, should be started promptly in severely ill patients with suspected angioinvasive fungal infection Intravenous echinocandin therapy is firstline for disseminated candidiasis and fluconazole is no longer recommended because of resistance

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For severe invasive aspergillosis, voriconazole and an echinocandin agent should be used in immunocompromised patients Empiric treatment with intravenous liposomal amphotericin B and aggressive surgical debridement is recommended in patients with suspected mucormycosis

Angioinvasive fungal infections require systemic therapy, and empiric antifungals should be started promptly because of the high risk of mortality and morbidity (Table V). For severely ill patients with suspected but unconfirmed angioinvasive fungal infections or when awaiting speciation, liposomal or lipid-based amphotericin B (AmB) and posaconazole are recommended to cover all species including Candida spp, Aspergillus spp, and Mucorales spp. Amphotericin-resistant organisms are uncommon, but Aspergillus terreus, Paecilomyces lilacinus, Scedosporium prolificans, Candida lusitaniae, Candida guilliermondii, and Candida auris can be intrinsically amphotericin-

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Table V. Antifungal pharmacotherapy dosing21,65,66 Class

Polyene

Agent

Amphotericin B (lipid-based and liposomal)

Echinocandins Anidulafungin Caspofungin Micafungin Triazoles Voriconazole

Posaconazole Isavuconazole

Allylamine

Fluconazole Terbinafine

Loading dose

Maintenance dose

NLDN

3-5 mg/kg every 24 hrs; can be increased to 10 mg/kg every 24 hrs in severe or progressive disease 200 mg IV once 100 mg IV every 24 hrs 70 mg IV once 50 mg IV every 24 hrs NLDN 100 mg IV every 24 hrs 6 mg/kg IV every 12 hrs for 2 doses IV: 4 mg/kg every 12 hrs; PO: 200 mg every 12 hrs, can gradually increase to 300 mg every 12 hrs if disease progresses 300 mg IV or PO every 12 hrs 300 mg IV or PO (extended-release for 2 doses tablet) every 24 hrs 200 mg IV or PO every 8 hrs for 200 mg IV or PO every 24 hrs 48 hrs 800 mg IV or PO once 400 mg IV or PO every 24 hrs NLDN 250 mg PO every 24 hrs

IV, Intravenous; NLDN, no loading dose necessary; PO, per os.

resistant, emphasizing the addition of posaconazole, and the importance of a species-level identification. Etiology-specific therapies are discussed below. Candida spp Intravenous echinocandin (EC) therapy with caspofungin, micafungin, and anidulofungin is the first-line treatment for disseminated candidiasis, especially in patients with neutropenia.21 EC therapy is associated with increased survival compared with patients treated with AmB and fluconazole.65 Also, because of the emergence of fluconazole-resistant Candida spp, fluconazole is no longer the empiric pharmacologic agent for disseminated disease.66 As epidemiology of candida infection evolves and resistance patterns are similarly changing, clinicians are advised to refer to their local hospital and regional resistance patterns and to work with infectious disease colleagues to identify the best therapeutic option. Various dosing regimens exist for treatment of disseminated candidiasis (Tables VI and VII). Aspergillus spp Voriconazole and an EC agent should be used in cases of confirmed severe invasive aspergillosis infection, in neutropenic or immunocompromised hosts, and in cases of hematologic malignancy.43,67,68 However, 1 study reported equivalent survival rates between those on combination therapy compared with those on voriconazole monotherapy.69 For those intolerant to voriconazole, lipid-based AmB

Table VI. Treatment regimens for systemic candidiasis Regimen

Agent

First-line

Anidulafungin Caspofungin Micafungin Liposomal or lipid-based amphotericin B* Fluconazoley Posaconazolez

Second-line

*Renal function and electrolyte levels should be checked regularly for patients who are taking liposomal or lipid-based amphotericin B. y Not recommended for patients on previous azole prophylaxis. z For patient previously on echinocandin prophylaxis or recent echinocandin therapy.

or isavuconazole are recommended.70 AmB plus caspofungin combination therapy compared with high-dose AmB monotherapy demonstrated survival benefit in small studies with an 18% survival increase with combination therapy if patients failed AmB monotherapy.71,72 Aspergillus calidoustus (commonly azoleresistant), Aspergillus terreus (amphotericin-resistant but usually susceptible to azole), or other highly drug-resistant causes of aspergillosis require that susceptibility profiles be performed.73 Some cryptic species may be resistant to all available antifungal agents.74 Salvage treatment includes ruling out infection caused by another pathogen, changing the class of antifungal therapy, and additional debridement.75 For those on monotherapy, an EC agent should be added (Table VIII).76,77

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Table VII. Systemic candidiasis therapy recommendations in special circumstances21,66 Circumstances

Agent

EC-resistant infection, history of EC prophylaxis, recent EC use, or infections caused by Candida glabrata, Candida krusei, or Candida parapsilosis

Note

Posaconazole and amphotericin B (liposomal or lipid-based) Voriconazole

Posaconazole

Fluconazole

Empiric treatment until susceptibility testing results are available Approved for patients not on fluconazole prophylaxis; transition to oral therapy when patient can tolerate PO and after repeat negative blood cultures For patient previously on fluconazole or EC prophylaxis, or those who have recently received EC therapy Oral therapy recommended in patient able to tolerate PO

EC, Echinocandin; PO, per os.

Table VIII. Treatment regimens for disseminated aspergillosis43,70,72 Regimen

First-line

Agent

Note

Voriconazole

Patients on PO therapy: after 1 week of oral treatment, target blood levels 1-5.5 g/mL Combination therapy: voriconazole plus Recommended first-line for severe invasive disease in anidulafungin or caspofungin patients with hematologic malignancy or profound neutropenia Second-line Lipid-based or liposomal amphotericin B Recommended for patients who are intolerant to Isavuconazole* voriconazole Third-line Combination therapy: lipid-based amphotericin B plus For all patients refractory to monotherapy, consider caspofungin adding caspofungin or best-tolerated EC to regimen EC, Echinocandin; PO, per os. *Preferred treatment for patients with chronic kidney disease.

Mucorales spp Treatment should be started empirically in patients when the suspicion of mucormycosis is high, because treatment delays significantly increase mortality.78 Intravenous liposomal AmB should be started at 5 mg/kg daily with increase to 10 mg/kg daily in cases of extensive disease. Aggressive surgical debridement of involved tissue also may be used.28 Elimination of predisposing factors, including immune reconstitution, if possible, should occur because it offers the greatest chances of survival. In patients that cannot tolerate AmB, intravenous posaconazole can be used,79 although it is contraindicated in patients with end-stage renal disease because of the betadex sulfobutyl ether sodium vehicle. Intravenous or oral isavuconazole can be used in posaconazole-intolerant patients (Table IX).80 Scedosporium spp Scedosporium spp are a group of antifungalresistant fungi with unique susceptibility profiles, as

Table IX. Treatment regimens for mucormycosis79,80 Regimen

First-line Second-line Third-line

Agent

Amphotericin B, liposomal* Posaconazoley Isavuconazole

*Dose can be increased to 10 mg/kg in patients with extensive disease. y First-line treatment for infections caused by Cunninghamella spp; contraindicated in patients with end-stage renal disease, and oral posaconazole contraindicated in patients with gastrointestinal malabsorption.

AmB and certain azoles are ineffective against specific Scedosporium spp.81,82 Causes of scedosporiosis are often divided into 2 groups (Scedosporium apiospermum complex and Scedosporium prolificans group) because of different treatment approaches. For otherwise asymptomatic patients, lesions limited to the skin may be cured by debridement alone.83 For symptomatic patients with

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Table X. Treatment regimens for species of the Scedosporium apiospermum complex60,84,85 Species

Regimen

Agent(s)

Note

Scedosporium apiospermum complex* First-line Voriconazole Second-line Itraconazole and posaconazole Third-line Isavuconazole Documented in vitro activity against some isolates Fourth-line Terbinafine and echinocandins Less and variably efficacious, respectively Scedosporium aurantiacum First-line Echinocandins Most resistant species in the S apiospermum complex; no cases in the skin yet reported *S apiospermum complex species include S apiospermum, Scedosporium boydii, Pseudallescheria angusta, Scedosporium minutisporum, Scedosporium dehoogii, and S aurantiacum.

invasive disease, the S apiospermum complex, in general, is most susceptible to voriconazole (Table X).81,84,85 Fusarium spp Intravenous lipid-based AmB is the recommended first-line therapy. Intravenous voriconazole is second-line therapy in patients who cannot tolerate AmB. Voriconazole and AmB are often given together because of high rates of resistance or in a patient with multiple skin lesions and repeatedly positive blood cultures. Deoxycholate AmB is discouraged because of nephrotoxicity and lower response rate.86 Terbinafine and EC agents lack efficacy as monotherapies.87 Phaeohyphomycetes Phaeohyphomycetes are susceptible to voriconazole, itraconazole, posaconazole, AmB, terbinafine, flucytosine, and EC agents, but prolonged therapy is often required.88-92 Surgical debridement is also recommended for localized disease. Adjunctive therapies Adjunctive therapies include surgical debridement, central venous catheter removal, and immune reconstitution. For immunocompromised patients, surgical debridement of necrotic and infected tissue for patients with localized disease is associated with increased survival and reduced fungal burden.93-96 Aggressive surgical debridement is indicated in patients with known infectious foci who have not responded to intravenous antifungal monotherapy. Several studies have shown advantages to immune reconstitution. Survival advantages have been documented in persistently neutropenic patients to whom granulocyte-colony stimulating factor has been administered. Granulocytecolony stimulating factor coadministered with

dexamethasone-stimulated neutrophils observed a 73% 90-day survival, compared with an average 20% to 40% survival rate in immunocompromised patients with fusariosis.97 In patients with aspergillosis or scedosporiosis, immune reconstitution via neutrophil transfusions or the use of granulocytecolony stimulating factor is favored despite limited clinical data.98-100

COMPLICATIONS Key point d

Prompt initiation of treatment is essential to prevent severe morbidity and mortality

Angioinvasive fungal infections are aggressive infections that result in significant morbidity and, if left untreated, carry mortality rates ranging from 50% to 100% depending upon the etiologic organism.101 Complications include dissemination to visceral organs with subsequent organ dysfunction, which is often fatal.102 More severe immunosuppression is associated with a higher risks of mortality.102,103 Early identification and initiation of treatment is essential to help prevent death in many of these patients. Severe complications related to undertreatment vary depending upon the etiologic organism.30,38,94,100,104-117 Table XI details some of the complications associated with specific organisms. In conclusion, angioinvasive fungal infections share similar themes in initial diagnosis, workup, treatment, and potential for morbidity and mortality. Severe immunosuppression is often a complicating factor in patients, and profound immunosuppression significantly increases the risk and severity of angioinvasive fungal infections. The skin can be a presenting sign of the disease, and dermatologists need to be aware of these infections, the need for urgent diagnosis and workup, and knowledge of first-line therapies to help contribute to patient care.

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Table XI. Complications of undertreating angioinvasive fungal infections Etiology

Candida spp Mucorales spp

Aspergillus spp

Scedosporium spp

Fusarium spp

Phaeohyphomyotic spp

Complication

Mortality

Failure to initiate antifungal therapy after removal of central venous catheter Hematogenous spread in neutropenic patient with rhinocerebral mucormycosis106; trigeminal perineural invasion with extension to the brainstem in diabetic and immunocompromised patients with rhinocerebral mucormycosis107; thrombophlebitis and vascular occlusion resulting in focal ischemia and subsequent necrosis; lower respiratory tract mucormycosis in patients on glucocorticoid or deferoxamine therapy, and those with history of solid organ transport or hematologic malignancy30; most common fungal cause of infectious arthritis and osteomyelitis in diabetic and immunosuppressed patients108 Mortality is strongly associated with severity of persistent immunosuppression109; triazole (eg, voriconazole) resistance because of extensive use of antifungal prophylaxis110 Brain abscesses in immunosuppressed patients after solid organ transplantation117; after Mucorales spp, most common fungal cause of infectious arthritis and osteomyelitis108

With therapy, mortality rate is 54%104; without therapy, mortality rate is increased [50%105 Uniformly fatal if left untreated

Lymphangitic spread of deep lesions results in disseminated fusariosis113; lung tissue third most common infectious site, after skin and blood, presenting as fever and productive cough in patients with neutropenia94; fungal infectious arthritis in osteomyelitis and immunosuppressed patients108 Disseminated disease associated with endocarditis in patients with porcine valves

Multidisciplinary care is often mandated in these cases, and further knowledge on these infections may be helpful in the care of these patients.

5. 6.

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99. Gil-Lamaignere C, Roilides E, Mosquera J, Maloukou A, Walsh TJ. Antifungal triazoles and polymorphonuclear leukocytes synergize to cause increased hyphal damage to Scedosporium prolificans and Scedosporium apiospermum. Antimicrob Agents Chemother. 2002;46:2234-2237. 100. Rodriguez-Tudela JL, Berenguer J, Guarro J, et al. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol. 2009;47:359-370. 101. Badiee P, Hashemizadeh Z. Opportunistic invasive fungal infections: diagnosis and clinical management. Indian J Med Res. 2014;139:195-204. 102. Balla A, Pierson J, Hugh J, Wojewoda C, Gibson P, Greene L. Disseminated cutaneous Curvularia infection in an immunocompromised host; diagnostic challenges and experience with voriconazole. J Cutan Pathol. 2016;43: 383-387. 103. Carter E, Boudreaux C. Fatal cerebral phaeohyphomycosis due to Curvularia lunata in an immunocompetent patient. J Clin Microbiol. 2004;42:5419-5423. 104. Nucci M, Colombo AL, Silveira F, et al. Risk factors for death in patients with candidemia. Infect Control Hosp Epidemiol. 1998;19:846-850. 105. Bassetti M, Righi E, Ansaldi F, et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med. 2014;40:839-845. 106. Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54(suppl 1):S23-S34. 107. McLean FM, Ginsberg LE, Stanton CA. Perineural spread of rhinocerebral mucormycosis. AJNR Am J Neuroradiol. 1996;17: 114-116. 108. Koehler P, Tacke D, Cornely OA. Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi. Crit Rev Microbiol. 2016;42:158-171. 109. Karp JE, Burch PA, Merz WG. An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis. Am J Med. 1988;85:203-206. 110. Busca A, Tortorano AM, Pagano L. Reviewing the importance and evolution of fungal infections and potential antifungal resistance in haematological patients. J Glob Antimicrob Resist. 2015;3:237-241. 111. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-415. 112. Husain S, Munoz P, Forrest G, et al. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis. 2005;40:89-99. 113. Nucci M, Anaissie E. Cutaneous infection by Fusarium species in healthy and immunocompromised hosts: implications for diagnosis and management. Clin Infect Dis. 2002;35:909-920. 114. Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer. 2003;98:315-319. 115. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center and implications for management. Blood. 1997;90:999-1008. 116. Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG. Disseminated phaeohyphomycosis: review of an emerging mycosis. Clin Infect Dis. 2002;34:467-476. 117. Sharma A, Singh D. Scedosporium apiospermum causing brain abscess in a renal allograft recipient. Saudi J Kidney Dis Transpl. 2015;26:1253-1256.

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Supplemental Fig 1. Various culture media can be used to grow fungi. Rhizopus (shown) does not grow well on mycosol media (top tube), which contains cycloheximide. It grows best on nutrient-rich potato dextrose media (bottom tube) and more selectively grows on brain-heart infusion agar (middle tube).

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Supplemental Fig 2. Fusarium spp (within a vessel wall). When evaluating histopathology, close inspection of the vessel walls can help identify organisms. (Hematoxylineeosin stain; original magnification: 340.)

J AM ACAD DERMATOL

APRIL 2019