Continuing medical education
Angioinvasive fungal infections impacting the skin: Diagnosis, management, and complications

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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.

Section snippets

Diagnosis and workup

Key points

  1. Obtaining a sterile punch biopsy specimen and a fungal culture are standard components of the diagnostic workup

  2. 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

  3. 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

Histopathology

Key points

  1. 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

  2. The presence of septated hyphae largely rules out Mucorales spp, which present as nonseptated and wide, ribbon-like organisms

  3. Septated and nonpigmented hyphae can represent several hyalohyphomycotic species, including Fusarium spp, Aspergillus spp, and Pseudallescheria spp

  4. Candida spp

Tissue culture

Key points

  1. Tissue culture provides pathogen speciation and treatment susceptibilities

  2. Aspergillus spp should be considered a true pathogen if isolated in an immunocompromised patient

  3. 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

Blood culture

Key points

  1. For disseminated candidiasis, positive blood culture is the gold standard

  2. 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

Imaging

Key points

  1. Imaging can be helpful to identify other organ involvement in angioinvasive fungal infections

  2. Computed tomography imaging of the sinuses and chest is necessary for suspected rhinocerebral and disseminated mucormycosis, respectively

  3. In disseminated candidiasis, with elevated liver enzymes or hepatosplenomegaly, computed tomography and magnetic resonance imaging are 90% sensitive in determining hepatosplenic involvement

  4. The brain and respiratory tract are preferred sites for disseminated

Additional tests

Key points

  1. When negative, galactomannan antigen and 1,3-beta-D-glucan assays are useful for ruling out disseminated mucormycosis

  2. The galactomannan antigen assay is positive in Aspergillus spp, but also cross reacts with Fusarium spp, Talaromyces marneffei, and Histoplasma capsulatum

  3. The 1,3-beta-D-glucan assay can detect Aspergillus spp, Candida spp, Pneumocystis jiroveci, Pseudomonas aeruginosa, and occasionally Cryptococcus neoformans

  4. The T2Candida assay is a panel that can detect very low levels of

Treatment

Key points

  1. Empiric therapy, such as liposomal or lipid-based amphotericin B and posaconazole, should be started promptly in severely ill patients with suspected angioinvasive fungal infection

  2. Intravenous echinocandin therapy is first-line for disseminated candidiasis and fluconazole is no longer recommended because of resistance

  3. For severe invasive aspergillosis, voriconazole and an echinocandin agent should be used in immunocompromised patients

  4. Empiric treatment with intravenous liposomal amphotericin B and

Complications

Key point

  1. 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

References (117)

  • P. Munoz et al.

    Impact of the BACTEC NR system in detecting Candida fungemia

    J Clin Microbiol

    (1990)
  • J.A. Ribes et al.

    Zygomycetes in human disease

    Clin Microbiol Rev

    (2000)
  • K.E. Sands et al.

    Epidemiology of sepsis syndrome in 8 academic medical centers

    JAMA

    (1997)
  • J. Guarner et al.

    Histopathologic diagnosis of fungal infections in the 21st century

    Clin Microbiol Rev

    (2011)
  • J.L. Frater et al.

    Histologic features of zygomycosis: emphasis on perineural invasion and fungal morphology

    Arch Pathol Lab Med

    (2001)
  • D.M. Elston

    Infectious Diseases of the Skin

    (2009)
  • R. Gerdsen et al.

    Sporotrichoid phaeohyphomycosis due to Alternaria infectoria

    Br J Dermatol

    (2001)
  • L.J. Wheat

    Approach to the diagnosis of the endemic mycoses

    Clin Chest Med

    (2009)
  • T.J. Walsh et al.

    Development of new strategies for early diagnosis of mucormycosis from bench to bedside

    Mycoses

    (2014)
  • B. De Pauw et al.

    Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

    Clin Infect Dis

    (2008)
  • B. Castiglioni et al.

    Pseudallescheria boydii (anamorph Scedosporium apiospermum). Infection in solid organ transplant recipients in a tertiary medical center and review of the literature

    Medicine (Baltimore)

    (2002)
  • D.H. Larone

    Medically Important Fungi: A Guide to Identification

    (1993)
  • M.A. Pfaller et al.

    Epidemiology of invasive candidiasis: a persistent public health problem

    Clin Microbiol Rev

    (2007)
  • T.A. Clark et al.

    Recent trends in the epidemiology of invasive mycoses

    Curr Opin Infect Dis

    (2002)
  • M. Kami et al.

    Effect of fluconazole prophylaxis on fungal blood cultures: an autopsy-based study involving 720 patients with haematological malignancy

    Br J Haematol

    (2002)
  • P.G. Pappas et al.

    Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America

    Clin Infect Dis

    (2016)
  • E. Reiss et al.

    Non-culture based diagnostic tests for mycotic infections

    Med Mycol

    (2000)
  • B. Spellberg et al.

    Novel perspectives on mucormycosis: pathophysiology, presentation, and management

    Clin Microbiol Rev

    (2005)
  • D. Neofytos et al.

    Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry

    Clin Infect Dis

    (2009)
  • D.P. Kontoyiannis et al.

    Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database

    Clin Infect Dis

    (2010)
  • D.P. Kontoyiannis et al.

    Significance of aspergillemia in patients with cancer: a 10-year study

    Clin Infect Dis

    (2000)
  • K. Liu et al.

    Morphologic criteria for the preliminary identification of Fusarium, Paecilomyces, and Acremonium species by histopathology

    Am J Clin Pathol

    (1998)
  • M. McCarthy et al.

    Mold infections of the central nervous system

    N Engl J Med

    (2014)
  • C. Legouge et al.

    The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?

    Clin Infect Dis

    (2014)
  • D.P. Kontoyiannis et al.

    Zygomycosis in the 1990s in a tertiary-care cancer center

    Clin Infect Dis

    (2000)
  • N.J. Moore et al.

    Systemic candidiasis

    Radiographics

    (2003)
  • L. Pagano et al.

    Chronic disseminated candidiasis in patients with hematologic malignancies. Clinical features and outcome of 29 episodes

    Haematologica

    (2002)
  • D.R. DeLone et al.

    Disseminated aspergillosis involving the brain: distribution and imaging characteristics

    AJNR Am J Neuroradiol

    (1999)
  • T. Franquet et al.

    Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings

    Radiographics

    (2001)
  • W.B. Gefter et al.

    Invasive pulmonary aspergillosis and acute leukemia. Limitations in the diagnostic utility of the air crescent sign

    Radiology

    (1985)
  • E.M. Marom et al.

    Imaging of pulmonary fusariosis in patients with hematologic malignancies

    AJR Am J Roentgenol

    (2008)
  • A. Tanase et al.

    Rare case of disseminated fusariosis in a young patient with graft vs. host disease following an allogeneic transplant

    Exp Ther Med

    (2016)
  • A. Katragkou et al.

    Scedosporium apiospermum infection after near-drowning

    Mycoses

    (2007)
  • M. Gopinath et al.

    An elusive diagnosis: Scedosporium apiospermum infection after near-drowning

    Ann Indian Acad Neurol

    (2010)
  • H.J. Cho et al.

    Clinical implications of serum galactomannan measurement in patients with acute invasive fungal rhinosinusitis

    Rhinology

    (2016)
  • J.A. Maertens et al.

    Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay

    Clin Infect Dis

    (2007)
  • R.Y. Hachem et al.

    Utility of galactomannan enzyme immunoassay and (1,3) beta-D-glucan in diagnosis of invasive fungal infections: low sensitivity for Aspergillus fumigatus infection in hematologic malignancy patients

    J Clin Microbiol

    (2009)
  • K.A. Marr et al.

    Combination antifungal therapy for invasive aspergillosis: a randomized trial

    Ann Intern Med

    (2015)
  • A.M. Tortorano et al.

    Cross-reactivity of Fusarium spp. in the Aspergillus Galactomannan enzyme-linked immunosorbent assay

    J Clin Microbiol

    (2012)
  • Y.T. Huang et al.

    Aspergillus galactomannan antigenemia in penicilliosis marneffei

    Aids

    (2007)
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    Date of release: April 2019

    Expiration date: April 2022

    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.

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