DÄ internationalArchive16/2019Invasive Fungal Infection

Review article

Invasive Fungal Infection

New treatments to meet new challenges

Dtsch Arztebl Int 2019; 116(16): 271-8; DOI: 10.3238/arztebl.2019.0271

von Lilienfeld-Toal, M; Wagener, J; Einsele, H; Cornely, O A; Kurzai, O

Background: The incidence of invasive fungal infection is approximately 6 cases per 100 000 persons per year. It is estimated that only half of such infections are detected during the patient’s lifetime, making this one of the more common overlooked causes of death in intensive-care patients. The low detection rate is due in part to the complexity of the diagnostic work-up, in which the clinical, radiological, and microbiological findings must be considered. Fungi with resistance to antimycotic drugs have been found to be on the rise around the world.

Methods: This review is based on pertinent publications retrieved from a selective search in PubMed, with special attention to guidelines on the diagnosis and treatment of invasive fungal infections caused by Candida spp., Aspergillus spp., Mucorales, and Fusarium spp.

Results: The clinical risk factors for invasive fungal infection include, among others, congenital immune deficiency, protracted (>10 days) marked granulocytopenia (<0.5 x 109/L), allogeneic stem-cell transplantation, and treatment with immunosuppressive drugs or corticosteroids. High-risk groups include patients in intensive care and those with structural pulmonary disease and/or complicated influenza. The first line of treatment, supported by the findings of randomized clinical trials, consists of echinocandins for infections with Candida spp. (candidemia response rates: 75.6% for anidulafungin vs. 60.2% for fluconazole) and azole antimycotic drugs for infections with Aspergillus spp. (response rates: 52.8% for voriconazole vs. 31.6% for conventional amphotericin B). The recommended first-line treatment also depends on the local epidemiology. This challenge should be met by interdisciplinary collaboration. Therapeutic decision-making should also take account of the often severe undesired effects of antimycotic drugs (including impairment of hepatic and/or renal function) and the numerous interactions that some of them have with other drugs.

Conclusion: Invasive fungal infections are often overlooked in routine hospital care. They should be incorporated into antimicrobial stewardship programs as an essential component. There is also a pressing need for the development of new classes of antimycotic drug.

LNSLNS

Since the start of the new millennium, fungal infections have drastically increased in different ecosystems (1). Bat populations in North America have undergone a 70% reduction as a result of fungal infections; several species of amphibians have become extinct (e1, e2). Overall no group of microorganisms causes species extinction as frequently as fungi (1). Fungal infections are also among the most important causes for crop failures (e3). In spite of this ecological relevance, invasive fungal infections in humans are rare.

Epidemiology

According to estimates, more than 10% of Germany’s population is affected by fungal infections. Superficial skin and nail mycoses are most common in this setting. Data on life-threatening infections are lacking, and valid conclusions can therefore not be drawn (2). On the basis of discharge diagnoses, in France the total incidence of invasive fungal infections has been found to be 5.9/100 000 cases/year, with a mortality of 27.6%, Both the incidence and mortality increased during the observation period (2001–2010) (3).

Yeasts of the Candida genus are the most common pathogens causing invasive fungal infections in Germany (2). They are responsible for a relevant proportion of all nosocomial bloodstream infections. According to data from the German nosocomial infection surveillance system (Krankenhaus-Infektions-Surveillance-System, KISS), 6.5% of bloodstream infections in intensive care wards are caused by this pathogen (4) (Table 1). Apart from Candida albicans, Candida glabrata is most commonly implicated (e4).

Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)
Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)
Table 1
Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)

Infections with Aspergillus spp. are the most common mold infections in Germany. They mostly occur in patients with cell-mediated immune defects (Table 1) (2). Review articles of autopsy studies showed that invasive aspergillosis is one of the most commonly overlooked diagnoses and that according to estimates, only about half of all invasive fungal infections are diagnosed pre-death (5, 6) (Table 1). In addition to Aspergillus fumigatus (>80%) other species have been found in locally varying but clearly lower numbers. Determining the species is relevant because of partly varying resistance profiles.

Different pathogens from the large group of Mucorales, as well as Fusarium spp., rarely cause invasive infections, but always present a therapeutic challenge because of numerous resistances. It is not possible to give data on case numbers as these infections are very rare. Fusarium spp. are also the most common pathogens causing fungal keratitis, which in about half of all affected patients has severe sequelae, including the loss of the affected eye (in 3 out of 15 cases in a German case series) (7). Furthermore, there are numerous descriptions of invasive fungal infections caused by rare or undescribed pathogens. In 2018, the National Reference Center for Invasive Fungal Infections (Nationales Referenzzentrum für invasive Mykosen, NRZMyk) documented some 80 different species obtained from clinical specimens. The present article focuses on invasive infections caused by Candida spp., aspergillosis, mucormycosis, and fusariosis as the most common invasive fungal infections in Germany. Because of the particularities of the treatment, we exempted Pneumocystis jirovecii from this study. The same holds true for Cryptococcus neoformans, a pathogen that is highly prevalent especially in Africa, but occurs only very rarely in Germany (e5).

The therapeutic challenges associated with invasive fungal infections have changed over the past 20 years (8):

  • Since the mid-1990s, Aspergillus fumigatus isolates with resistance to azoles have been increasingly identified. Azole-resistant isolates have also been identified in Germany and at individual centers were responsible for a substantial proportion of invasive infections (9).
  • With the increased use of echinocandins, resistant Candida isolates started to be seen worldwide (e6).
  • Since 2009, the new species Candida auris has spread globally. Nosocomial transmissions of this pathogen have caused institutions of the public healthcare system to issue warnings (e7).

New therapeutic options have become available to meet these challenges. Since the start of the new millennium, the portfolio of antimycotics has expanded (eFigure 2). For the fungal infections that are the subject of this review article, three main classes of substance are available: polyenes, azoles, and echinocandins (eFigure 3). In this article, the authors aim to provide—on the basis of the recent literature and guidelines—an overview of the diagnostic evaluation and therapy of invasive fungal infections.

eFigure 2

Diagnostic evaluation

The safe and early diagnosis of invasive fungal infections is the central challenge in routine clinical practice and forms the crucial basis for targeted treatment (1017). The diagnosis of an invasive fungal infection is based on three elements: the clinical examination, imaging, and confirmation/proof of the causative agent.

The clinical diagnostic criteria for invasive fungal infections were defined by an international working group (the (EORTC/MSG Study Group). These criteria selectively apply to immunosuppressed patients and were conceived primarily for clinical studies (18). In addition to congenital immunodeficiencies (Table 1), the relevant clinical risk factors include:

  • Prolonged (>10 days) deep granulocytopenia (<0.55 × 109/L)
  • Allogeneic stem cell transplantation
  • Medication-induced immunosuppression, or
  • Treatment with prednisone (the equivalent of at least 0.3 mg/kg/d for a minimum of 3 weeks).

This list is by no means complete and excludes important but less well-defined risk groups. Examples include patients in intensive care wards, patients with structural lung disease, and patients with severe influenza (Table 1) (19, 20).

Tomography imaging yields crucial clues (eFigure 1). Infections of the respiratory tract require computed tomography (CT), neurological infections require magnetic resonance imaging (MRI), and abdominal infections require CT or MRI scanning in order to identify abscesses that are characteristic for the special variety of hepatolienal candidiasis. Abdominal infections can also be visualized by using sonography.

Where a diagnosis is suspected, the next step will be confirmation of the pathogen (eTable 1). Bloodstream infections with Candida spp. are almost exclusively confirmed by blood cultures. The identification of Candida in specimens taken from the respiratory tract does not indicate an invasive infection (21); for other, non-sterile specimens, a decision always has to be made on the basis of the individual clinical situation as to whether it is a case of colonization or a clinically relevant situation. Because of their wide environmental spread, the confirmation of molds from physiologically non-sterile material should be interpreted with caution; this is also the case for all specimens from the respiratory tract.

Diagnosing invasive fungal infections
Diagnosing invasive fungal infections
eTable 1
Diagnosing invasive fungal infections

For serological diagnostic evaluation, Candida antigen/antibody confirmation is not recommended in current guidelines because of the lack of pertinent studies. Beta D-glucan (BDG) is not specific for Candida , but it does indicate an invasive fungal infection. A patient’s risk profile, symptoms, and imaging results will narrow down this differential diagnosis, however. The sensitivity and specificity of this marker vary substantially between different patient populations and depend on the test system used (e8e10). To confirm A. fumigatus, galactomannan (“aspergillus antigen”) is available—in addition to BDG—which can be determined from serum and bronchial secretions (and, if applicable, cerebrospinal fluid). The sensitivity for serum is about 78%, the specificity is 85%, depending on the cut-off value and the patient population (22). To confirm invasive aspergillosis, furthermore, reference protocols for molecular diagnostics have been developed that function as examples for molecular diagnostic evaluation of infections and, in combination with other methods, contribute to improved diagnostics (2325).

Resistances and testing for resistance

In recent years, increasing rates of resistant pathogens have been confirmed worldwide. In Candida spp., acquired echinocandin resistance now occurs, in addition to the long familiar fluconazole resistance (at least in Candida glabrata). In Denmark, the rates of resistant C. glabrata from blood cultures rose from 0.9% (2008/2009) to 3.1% (2012/2013) (e6). In the US, resistant C. glabrata is already much more common; one center posted a rise in the resistance rate from 4.9% in 2001 to 12.3% in 2010 (e11). In Germany, such strains are currently still rare. Because of lacking data, concrete resistance rates cannot be reliably determined. Most guidelines, meanwhile, are recommending testing all “clinically relevant” isolates of Candida spp. for sensitivity/susceptibility to azoles. For echinocandins, EUCAST recommends because of the lacking reproducibility of the caspofungin test to test only for anidulafungin or micafungin. If the isolate proves susceptible to these two substances on testing, treatment can also consist of administering caspofungin.

Since the 1990s, azole-resistant strains of A. fumigatus have been described in particular in the Netherlands and in Great Britain (26). The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends testing for resistance to azole antimycotics (16). Overall, we hold that resistance in Germany is currently not a problem. However, raised resistance rates have been found in patients with cystic fibrosis who were chronically colonized with A. fumigatus (e12). Only where rates of azole resistant A. fumigatus have increased locally, consideration should be given to whether, until a susceptible pathogen has been confirmed, a treatment should be selected that includes strains with azole resistance. In Essen, Germany, for example, a resistance rate of 30% in cases of invasive aspergillosis was found in isolates of A. fumigatus that were detected on culture (9). A recent Dutch guideline recommends—in view of the high rates of azole resistant A. fumigatus in the Netherlands (12.9%)—for the first time treatment with a combination of voriconazole and either echinocandin or liposomal amphotericin B (L-AmB) until sensitivity/susceptibility has been confirmed (e13).

Systemic therapy

Principles

Depending on the indication, a choice needs to be made between prophylactic treatment, empirical treatment, or pre-emptive treatment. Antimycotic prophylaxis is recommended primarily for hematology/oncology patients (27). After allogeneic stem cell transplantation, prophylaxis against yeasts is usually sufficient. By contrast, a high-risk constellation—such as granulocytopenia after myelosuppressive induction therapy or graft-versus-host disease—requires prophylaxis that is effective against molds. Data for other patient populations are less clear-cut. For patients with complications after abdominal surgery, for patients requiring intensive care and who have relevant risk factors, and for patients who have undergone lung transplantation surgery, prophylaxis can make sense (12). However, these indications are not sufficiently supported by study results. Empirical therapy is used if an invasive fungal infection is suspected. The therapeutic approach described in the following section is based on confirmation of the pathogen and should follow available guidelines (eTable 2). Essentially, the main therapeutic options are substances from three classes of antimycotic drugs (Table 2).

Selected guidelines for invasive fungal infections
Selected guidelines for invasive fungal infections
eTable 2
Selected guidelines for invasive fungal infections

Invasive Candida infection

Several guidelines are available to support the selection of treatment of invasive Candida infections (eTable 2). The therapeutic schemes depend on the underlying disease and organ involvement (1214, 17, 28, 29). Determining the species is extremely important because of intrinsic resistance patterns (Table 2). In most clinical situations, echinocandins are the treatment of choice in adult patients. In a randomized study of the treatment of candidemia, anidulafungin was at least equivalent to fluconazole; a secondary analysis even found that it was superior (response rate for fluconazole 60.2%, for anidulafungin 75.6%, difference 15.4% [95% confidence interval: 3.9; 27.0]). For this reason, fluconazole should be used only in patients without critical illness and at a high initial dosage (800 mg/d) (12). Fluconazole is, however, still relevant for oral treatment continuation after successful initial treatment with an echinocandin. L-AmB constitutes an alternative where resistance to other classes of substances is confirmed. Furthermore, L-AmB is important in treating chronically disseminated candidosis/candidiasis, endocarditis due to Candida, and in pediatric patients (12, 13). Voriconazole usually does not provide any additional benefits over fluconazole—with the exception of infection with C. krusei or where additionally a mold infection is suspected.

Candidemia should be treated for at least two weeks after the bloodstream infection has disappeared (28). The exact treatment duration can be defined only after follow-up blood cultures have been produced. In continuing symptoms or granulocytopenia, the treatment should be continued for longer. Chronically disseminated candidosis should be treated for a minimum of 8–12 weeks, and in some cases for several months, until the lesions have resolved (12, 14, 17, 28). Central venous catheters should be removed if at all possible. If this is not possible then the patient should be treated with an echinocandin or L-AmB, because of their effectiveness against biofilms in vitro (12, 14, 17, 28). Because of possible relocation of the pathogen into the eyes, funduscopy is recommended during intravenous therapy (12, 14, 17, 28).

Invasive aspergillosis

The prognosis for invasive aspergillosis has improved substantially over the past decade. The treatment of choice usually consists of the administration of voriconazole or isavuconazole. Both azoles are effective fungicides against A. fumigatus (16, 31, 32) (e14) (Table 2). In a randomized controlled study, voriconazole was superior to treatment with conventional amphotericin B (21.2% greater response [52.8% versus 31.6%], 95% confidence interval [10.4; 32.9]; longer survival rates for voriconazole (33). Voriconazole reaches effective concentrations even for neurological infections (Table 2) (e15). In a randomized controlled clinical trial of the treatment of invasive mold infections, isavuconazole was non-inferior to treatment with voriconazole (34). L-AmB is an alternative—after taking into consideration prior prophylactic administration of azoles (the class should be changed), comorbidities, resistance of the pathogen, medication interactions, and local epidemiology. L-AmB is also recommended for initial therapy if co-infection with Mucorales is suspected. The value of combination therapy (for example, using voriconazole plus echinocandin) is unclear (e16). In addition to systemic administration, local instillation of L-AmB may make sense, for example in aspergillosis of the central nervous system (e17). In all cases, surgical treatment should be considered in addition to medication treatment (16, 31). Supportive measures include the administration of granulocyte colony stimulating factor (G-CSF) or, in long-term granulocytopenia, granulocyte transfusions (16, 31).

The duration of treatment depends on the patient’s individual clinical development while taking into account the type and extent of immunosuppression (16); it usually takes about 6–12 weeks (31). Radiological checkups make sense, but the guidelines currently do not provide any indication of optimal time points (35). After the start of the treatment and especially after granulocyte levels have risen in patients with neutropenia, the radiological imaging will usually show an increase in lesion size. But a week after the start of therapy, lesions should not enlarge any more but can be expected to shrink until day 14 (35). In order to undertake these checkups, serial CT scans at the start of therapy and one and two weeks subsequently are our current recommendation. Changes to the galactomannan titer during treatment also provide information about the course (e18).

Rare invasive mycoses

No randomized controlled trials exist of the treatment of invasive mycoses caused by rare pathogens. Therapy is guided by the broad spectrum effectiveness of the antimycotics and by case series (Table 2). Mycormycoses are caused by a large group of different pathogens with different sensitivity/susceptibility profiles. To treat these, L-AmB (at a minimum dosage of 5 mg/kg; 10 mg/kg if the central nervous system is affected) and azoles with effectiveness against Mucorales (isovuconazole, posaconazole) are the medications of choice (11). The surgical resection of infected tissue is an essential component of the therapeutic concept (11).

Invasive infections with Fusarium spp. should be treated with voriconazole or L-AmB—in combination until the results of sensitivity/susceptibility testing become available—with posaconazole available as second-line treatment (15). Surgical removal of infected tissue should be considered, and possible immunosuppression should be lowered. Keratitis caused by Fusarium spp. requires local therapy using natamycin (eyedrops 5%) and systemic therapy with voriconazole (e19e21). A Cochrane review found that local therapy with natamycin 5% was superior to other treatments (36). The benefits of systemic treatment with voriconazole was shown in a randomized controlled clinical trial (e20). In spite of antimycotic therapy, penetrating keratoplasty will be required in many cases (for example, in two thirds of cases in [7]). Individual guidelines also comment on the treatment of further, rare pathogens (10, 15). The search engine www.FungiQuest.net provides a web based tool that lists case histories for extremely rare invasive mycoses. However, this cannot be a substitute for expert consultation.

Conclusions and outlook

The number and heterogeneity of patients at risk for invasive fungal infections have increased. For example, the number of stem cell transplantations in Europe almost doubled between 2000 and 2016 (e22, e23). At the same time, new at-risk populations were identified—examples include hospital inpatients with severe influenza or chronic obstructive pulmonary disease (19, 20). The emergence of new and/or resistant pathogens is matched by a growing repertoire of antimycotics. Antimycotic treatment needs to be initiated more frequently, and the selection of the optimal therapeutic strategy has become more complex. Additional classes of antimycotics are therefore well overdue (37) (e24). These trends have added to the challenges for mycological diagnostics, for example with regard to resistance testing. The treatment of fungal infections should be anchored in antimicrobial stewardship programs. Resistance development in fungal pathogens will need to be integrated into national action plans, such as the German Antimicrobial Resistance Strategy (Deutsche Antibiotika Resistenzstrategie, DART). Restricting such programs to bacterial infections means enabling the further spread of resistance to antimycotics.

Funding

The work of the National Reference Center for Invasive Fungal Infections (NRZMyk) is supported by the Robert Koch-Institute using funding from Germany’s Federal Ministry of Health (funding reference 1369–240). Research projects at the NRZMyk are supported by the German Federal Ministry of Education and Research in the context of the consortium InfectControl 2020 (Programm Zwanzig20—Partnerschaft für InnovationProgramme [Program Twenty20—a Partnership for Innovation program]). The activities of the authors (HE, OK) are supported by the German Research Foundation (DFG) in the context of the collaborative research center Transregio FungiNet (TR124, projects A2 and C3).

Conflict of interest statement
Professor Lilienfeld-Toal received consultancy fees from Gilead and MSD. Conference delegate fees and travel expenses were paid on her behalf by Gilead and Astellas. She received lecture honoraria from Gilead, MSD, Pfizer, Astellas, and Chugai. She received third-party funding from Gilead.

PD Dr Wagener received study support (third-party funding) from Fujifilm Wako Chemicals Europe and Euroimmun Medizinische Labordiagnostika [which provides immunodiagnostic laboratory solutions].

Prof. Cornely received consultancy fees from Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys IK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, IQVIA, Matinas, MedPace, Menarini Ricerche, Merck/MSD, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphas, and Vical. He received study support (third-party funding) from Actelion, Amplyx, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Pfizer, Scynexis, and Merck/MSD. He received conference delegate fees and reimbursement of travel expenses and consultancy fees from Astellas, Basilea, Gilead, Merck/MSD, and Pfizer.

Professor Kurzai received consultancy fees from Basilea. He received reviewer honoraria relating to the subject of the article from BG Chemische Industrie. He received lecture honoraria from Heidelberg Engineering GmbH, Pfizer, and Astellas. He received study support from Astellas, Pfizer, MSD, Gilead, Virotech, Novartis, and Fujifilm Wako Chemicals.

Professor Einsele declares that no conflict of interest exists.

Manuscript received on 29 June 2018, revised version accepted on 14 February 2019.

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
Prof. Dr. med. Oliver Kurzai
Institut für Hygiene und Mikrobiologie
Lehrstuhl für Medizinische Mikrobiologie und Mykologie
Julius-Maximilians-Universität Würzburg
Josef-Schneider-Str. 2/E1
97080 Würzburg, Germany
okurzai@hygiene.uni-wuerzburg.de

Cite this as:
von Lilienfeld-Toal M, Wagener J, Einsele H, Cornely OA, Kurzai O:
Invasive fungal infection—new treatments to meet new challenges.
Dtsch Arztebl Int 2019; 116: 271–8. DOI: 10.3238/arztebl.2019.0271

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref1619

eFigures, eTables:
www.aerzteblatt-international/19m0271

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e1.
Frick WF, Pollock JF, Hicks AC, et al.: An emerging disease causes regional population collapse of a common North American bat species. Science 2010; 329: 679–82 CrossRef MEDLINE
e2.
Crawford AJ, Lips KR, Bermingham E: Epidemic disease decimates amphibian abundance, species diversity, and evolutionary history in the highlands of central Panama. Proc Natl Acad Sci USA 2010; 107: 13777–82 CrossRef MEDLINE PubMed Central
e3.
Dean R, Van Kan JA, Pretorius ZA, et al.: The Top 10 fungal pathogens in molecular plant pathology. Mol Plant Pathol 2012; 13: 414–30 CrossRef CrossRef MEDLINE
e4.
Duggan S, Leonhardt I, Hünniger K, Kurzai O: Host response to Candida albicans bloodstream infection and sepsis. Virulence 2015; 6: 316–26 MEDLINE PubMed Central
e5.
Rajasingham R, Smith RM, Park BJ, et al.: Global burden of disease of
HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17: 873–81 CrossRef
e6.
Arendrup MC, Perlin DS: Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis 2014; 27: 484–92 CrossRef MEDLINE PubMed Central
e7.
Jeffery-Smith A, Taori SK, Schelenz S, et al.: Candida auris: a Review of the Literature. Clin Microbiol Rev 2017; 31: pii: e00029–17.
e8.
Friedrich R, Rappold E, Bogdan C, Held J: Comparative analysis of the wako beta-glucan test and the fungitell assay for diagnosis of candidemia and pneumocystis jirovecii pneumonia. J Clin Microbiol 2018; 56: pii: e00464–18 MEDLINE PubMed Central
e9.
Held J, Kohlberger I, Rappold E, Busse Grawitz A, Hacker G: Comparison of (1->3)-beta-D-glucan, mannan/anti-mannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. J Clin Microbiol 2013; 51: 1158–64 CrossRef MEDLINE PubMed Central
e10.
Dichtl K, Seybold U, Wagener J: Serological biomarkers of candidemia: a retrospective evaluation of three assays. Infection 2018: doi: 10.1007/s15010–018–1224–3. [Epub ahead of print] CrossRef
e11.
Alexander BD, Johnson MD, Pfeiffer CD, et al.: Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 2013; 56: 1724–32 CrossRef MEDLINE PubMed Central
e12.
Seufert R, Sedlacek L, Kahl B, et al.: Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany. J Antimicrob Chemother 2018; 73: 2047–53 CrossRef MEDLINE
e13.
Kullberg BJ, Blijlevens NMA, Janssen JJWM, et al.: Stichting Werkgroep Antibioticabeleid. https://www.swab.nl/swab/cms3.nsf/uploads/3AA7A56CE879587BC12581F80061297F/$FILE/SWAB%20Richtlijn%20Mycosen%202017%20(final).pdf (last accessed on 19. March 2019).
e14.
Tissot F, Agrawal S, Pagano L, et al.: ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 2017; 102: 433–44 CrossRef MEDLINE PubMed Central
e15.
Schwartz S, Ruhnke M, Ribaud P, et al.: Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005; 106: 2641–5 CrossRef MEDLINE
e16.
Marr KA, Schlamm HT, Herbrecht R, et al.: Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162: 81–9 CrossRef MEDLINE
e17.
Elgamal EA, Murshid WR: Intracavitary administration of amphotericin B in the treatment of cerebral aspergillosis in a non immune-compromised patient: case report and review of the literature. Br J Neurosurg 2000; 14: 137–41 CrossRef
e18.
Kovanda LL, Kolamunnage-Dona R, Neely M, Maertens J, Lee M, Hope WW: Pharmacodynamics of isavuconazole for invasive mold disease: role of galactomannan for real-time monitoring of therapeutic response. Clin Infect Dis 2017; 64: 1557–63 CrossRef MEDLINE PubMed Central
e19.
Behrens-Baumann W, Finis D, MacKenzie C, Roth M, Geerling G: [Keratomycosis—therapy standards and new developments]. Klin Monbl Augenheilkd 2015; 232: 754–64 MEDLINE
e20.
Prajna NV, Krishnan T, Rajaraman R, et al.: Adjunctive oral voriconazole treatment of fusarium keratitis: a secondary analysis from the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol 2017; 135: 520–5 CrossRef CrossRef MEDLINE PubMed Central
e21.
Prajna NV, Krishnan T, Rajaraman R, et al.: Effect of oral voriconazole on fungal keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): a randomized clinical trial. JAMA Ophthalmol 2016; 134: 1365–72 CrossRef MEDLINE PubMed Central
e22.
Passweg JR, Baldomero H, Bader P, et al.: Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant 2018; 53: 1139–48 CrossRef MEDLINE PubMed Central
e23.
Passweg JR, Baldomero H, Bader P, et al.: Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant 2016; 51: 786–92 CrossRef MEDLINE PubMed Central
e24.
McCarthy MW, Walsh TJ: Drug development challenges and strategies to address emerging and resistant fungal pathogens. Expert Rev Anti Infect Ther 2017; 15: 577–84 CrossRef MEDLINE
e25.
Anesi JA, Baddley JW: Approach to the solid organ transplant patient with suspected fungal infection. Infect Dis Clin North Am 2016; 30: 277–96 CrossRef MEDLINE PubMed Central
e26.
Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N: Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother 2011; 66 (Suppl 1): i5–14 CrossRef MEDLINE
e27.
Clark NM, Weigt SS, Fishbein MC, Kubak B, Belperio JA, Lynch JP, 3rd: Fungal infections complicating lung transplantation. Semin Respir Crit Care Med 2018; 39: 227–54 CrossRef MEDLINE
e28.
Caira M, Candoni A, Verga L, et al.: Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study). Haematologica 2015; 100: 284–92 CrossRef MEDLINE PubMed Central
e29.
Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R: Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 1994; 220: 751–8 CrossRef
e30.
Maskarinec SA, Johnson MD, Perfect JR: Genetic susceptibility to fungal infections: What is in the Genes? Curr Clin Microbiol Rep 2016; 3: 81–91 CrossRef MEDLINE PubMed Central
e31.
Kumar V, Cheng SC, Johnson MD, et al.: Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia. Nat Commun 2014; 5: 4675 CrossRef MEDLINE PubMed Central
e32.
Warris A: Immunopathology of aspergillus infections in children with chronic granulomatous disease and cystic fibrosis. Pediatr Infect Dis J 2018: doi: 10.1097/INF.0000000000002265. [Epub ahead of print] CrossRef
e33.
Cunha C, Goncalves SM, Duarte-Oliveira C, et al.: IL-10 overexpression predisposes to invasive aspergillosis by suppressing antifungal immunity. J Allergy Clin Immunol 2017; 140: 867–70.e9.
e34.
Lemarie E, Lemaire B, Saudeau D, Lavandier M, Renoux M, Renoux G: Disseminated aspergillosis in a patient with bronchiectasis. A 15-month clinical and immunological follow-up. Respiration 1986; 49: 235–40 MEDLINE
e35.
Pegues DA, Lasker BA, McNeil MM, Hamm PM, Lundal JL, Kubak BM: Cluster of cases of invasive aspergillosis in a transplant intensive care unit: evidence of person-to-person airborne transmission. Clin Infect Dis 2002; 34: 412–6 CrossRef MEDLINE
e36.
Oken MM, Creech RH, Tormey DC, et al.: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–55 CrossRef MEDLINE
e37.
Anderson TM, Clay MC, Cioffi AG, et al.: Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 2014; 10: 400–6 CrossRef MEDLINE PubMed Central
e38.
Clancy CJ, Pappas PG, Vazquez J, et al.: Detecting Infections Rapidly and Easily for Candidemia Trial, Part 2 (DIRECT2): a prospective, multicenter study of the T2Candida Panel. Clin Infect Dis 2018; 66: 1678–86 CrossRef MEDLINE
e39.
Brasnu E, Bourcier T, Dupas B, et al.: In vivo confocal microscopy in fungal keratitis. Br J Ophthalmol 2007; 91: 588–91 CrossRef MEDLINE PubMed Central
e40.
Labbe A, Khammari C, Dupas B, et al.: Contribution of in vivo confocal microscopy to the diagnosis and management of infectious keratitis. Ocul Surf 2009; 7: 41–52 CrossRef
National Reference Center for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (HKI) , Jena: Prof. Dr. med. Marie von Lilienfeld-Toal,
PD Dr. med. Johannes Wagener, Prof. Dr. med. Oliver Kurzai
Clinic of Internal Medicine II, University Hospital Jena:
Prof. Dr. med. Marie von Lilienfeld-Toal
Institute for Hygiene and Microbiology, University of Würzburg,
Chair of Medical Microbiology and Mycology, Würzburg:
PD Dr. med. Johannes Wagener, Prof. Dr. med. Oliver Kurzai
Department of Internal Medicine II, University Hospital of Würzburg: Prof. Dr. med. Hermann Einsele
InfectControl 2020, Jena/Würzburg:
Prof. Dr. med. Hermann Einsele, Prof. Dr. med. Oliver Kurzai
Cologne Excellence Cluster on Cellular Stress Responses
in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, at the University Hospital of Cologne,
European Excellence Center for Medical Mycology (ECMM),
DGerman Center for Infection Research(DZIF)
Partner Site Bonn Köln, Cologne University:
Prof. Dr. med. Oliver A. Cornely
Key messages
Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)
Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)
Table 1
Epidemiology of the most important invasive fungal infections in Germany (Candida, Aspergillus)
eFigure 2
Diagnosing invasive fungal infections
Diagnosing invasive fungal infections
eTable 1
Diagnosing invasive fungal infections
Selected guidelines for invasive fungal infections
Selected guidelines for invasive fungal infections
eTable 2
Selected guidelines for invasive fungal infections
1.Fisher MC, Henk DA, Briggs CJ, et al.: Emerging fungal threats to animal, plant and ecosystem health. Nature 2012; 484: 186–94 CrossRef MEDLINE PubMed Central
2.Ruhnke M, Groll AH, Mayser P, et al.: Estimated burden of fungal infections in Germany. Mycoses 2015; 58 (Suppl 5): 22–8. CrossRefMEDLINE
3.Bitar D, Lortholary O, Le Strat Y, et al.: Population-based analysis of invasive fungal infections, France, 2001–2010. Emerg Infect Dis 2014; 20: 1149–55 CrossRef MEDLINE PubMed Central
4.Meyer E, Geffers C, Gastmeier P, Schwab F: No increase in primary nosocomial candidemia in 682 German intensive care units during 2006 to 2011. Euro Surveill 2013; 18: pii: 20505.
5.Dignani MC: Epidemiology of invasive fungal diseases on the basis of autopsy reports. F1000Prime Rep 2014; 6: 81 CrossRef MEDLINE PubMed Central
6.Winters B, Custer J, Galvagno SM, Jr., et al.: Diagnostic errors in the intensive care unit: a systematic review of autopsy studies. BMJ Qual Saf 2012; 21: 894–902 CrossRef MEDLINE
7.Walther G, Stasch S, Kaerger K, et al.: Fusarium Keratitis in Germany. J Clin Microbiol 2017; 55: 2983–95 CrossRef MEDLINE PubMed Central
8.Wagener J, Walther G, Kurzai O: Antimykotikaresistenz bei klinisch relevanten Erregern invasiver Pilzinfektionen in Deutschland. Der Mikrobiologe 2018; 28: 13–8.
9.Steinmann J, Hamprecht A, Vehreschild MJ, et al.: Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J Antimicrob Chemother 2015; 70: 1522–6 CrossRef MEDLINE
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 CrossRef MEDLINE
11.Cornely OA, Arikan-Akdagli S, Dannaoui E, et al.: ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 2014; 20 (Suppl 3): 5–26 CrossRef MEDLINE
12.Cornely OA, Bassetti M, Calandra T, et al.: ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012; 18 (Suppl 7): 19–37 CrossRef MEDLINE
13.Hope WW, Castagnola E, Groll AH, et al.: ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp. Clin Microbiol Infect 2012; 18 (Suppl 7): 38–52 CrossRefMEDLINE
14.Lortholary O, Petrikkos G, Akova M, et al.: ESCMID* guideline for the diagnosis and management of Candida diseases 2012: patients with HIV infection or AIDS. Clin Microbiol Infect 2012; 18 (Suppl 7): 68–77 CrossRef MEDLINE
15.Tortorano AM, Richardson M, Roilides E, et al.: 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 CrossRef MEDLINE
16.Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al.: Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect 2018; 24 (Suppl 1): e1–e38 CrossRef MEDLINE
17.Ullmann AJ, Akova M, Herbrecht R, et al.: ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin Microbiol Infect 2012; 18 (Suppl 7): 53–67 CrossRef MEDLINE
18.De Pauw B, Walsh TJ, Donnelly JP, 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; 46: 1813–21 CrossRef MEDLINE PubMed Central
19.Schauwvlieghe A, Rijnders BJA, Philips N, et al.: Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med 2018; 6: 782–92 CrossRef
20.Mohedano Del Pozo RB, Rubio Alonso M, Cuetara Garcia MS: Diagnosis of invasive fungal disease in hospitalized patients with chronic obstructive pulmonary disease. Rev Iberoam Micol 2018; 35: 117–22 CrossRef MEDLINE
21.Meersseman W, Lagrou K, Spriet I, et al.: Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med 2009; 35: 1526–31 CrossRef MEDLINE
22.Leeflang MM, Debets-Ossenkopp YJ, Wang J, et al.: Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 2015: CD007394 CrossRef
23.Barnes RA, White PL, Morton CO, et al.: Diagnosis of aspergillosis by PCR: Clinical considerations and technical tips. Medical Mycol 2018; 56: 60–72 CrossRef MEDLINE
24.Boch T, Reinwald M, Spiess B, et al.: Detection of invasive pulmonary aspergillosis in critically ill patients by combined use of conventional culture, galactomannan, 1–3-beta-D-glucan and Aspergillus specific nested polymerase chain reaction in a prospective pilot study. J Crit Care 2018; 47: 198–203 CrossRef MEDLINE
25.Heng SC, Chen SC, Morrissey CO, et al.: Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies. Diagn Microbiol Infect Dis 2014; 79: 322–7 CrossRef MEDLINE
26.Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE: Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R Soc Lond B Biol Sci 2016; 371: pii: 20150460 CrossRef MEDLINE PubMed Central
27.Mellinghoff SC, Panse J, Alakel N, et al.: Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol 2018; 97: 197–207 CrossRef MEDLINE PubMed Central
28.Pappas PG, Kauffman CA, Andes DR, et al.: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62: e1–e50 CrossRef
29.Ruhnke M, Rickerts V, Cornely OA, et al.: Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. Mycoses 2011; 54: 279–310 CrossRef MEDLINE
30.Reboli AC, Rotstein C, Pappas PG, et al.: Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356: 2472–82 CrossRef MEDLINE
31.Patterson TF, Thompson GR 3rd, Denning DW, et al.: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63: e1– e 60.
32.Mousset S, Buchheidt D, Heinz W, et al.: Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2014; 93: 13–32 CrossRef MEDLINE PubMed Central
33.Herbrecht R, Denning DW, Patterson TF, et al.: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15 CrossRef MEDLINE
34.Maertens JA, Raad, II, Marr KA, et al.: Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387: 760–9 CrossRef
35.Vehreschild JJ, Heussel CP, Groll AH, et al.: Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis. Eur Radiol 2017; 27: 3275–82 CrossRef MEDLINE
36.FlorCruz NV, Evans JR: Medical interventions for fungal keratitis. Cochrane Database Syst Rev 2015; 4: CD004241.
37.McCarthy MW, Kontoyiannis DP, Cornely OA, Perfect JR, Walsh TJ: Novel agents and drug targets to meet the challenges of resistant fungi. J Infect Dis 2017; 216: S474–S83 CrossRef MEDLINE
38.Kullberg BJ, Arendrup MC: Invasive Candidiasis. N Engl J Med 2015; 373: 1445–56 CrossRef MEDLINE
39.Cunha C, Aversa F, Lacerda JF, et al.: Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med 2014; 370: 421–32 CrossRef MEDLINE
40.Geissel B, Loiko V, Klugherz I, et al.: Azole-induced cell wall carbohydrate patches kill Aspergillus fumigatus. Nat Commun 2018; 9: 3098 CrossRef MEDLINE PubMed Central
e1.Frick WF, Pollock JF, Hicks AC, et al.: An emerging disease causes regional population collapse of a common North American bat species. Science 2010; 329: 679–82 CrossRef MEDLINE
e2.Crawford AJ, Lips KR, Bermingham E: Epidemic disease decimates amphibian abundance, species diversity, and evolutionary history in the highlands of central Panama. Proc Natl Acad Sci USA 2010; 107: 13777–82 CrossRef MEDLINE PubMed Central
e3.Dean R, Van Kan JA, Pretorius ZA, et al.: The Top 10 fungal pathogens in molecular plant pathology. Mol Plant Pathol 2012; 13: 414–30 CrossRef CrossRef MEDLINE
e4.Duggan S, Leonhardt I, Hünniger K, Kurzai O: Host response to Candida albicans bloodstream infection and sepsis. Virulence 2015; 6: 316–26 MEDLINE PubMed Central
e5.Rajasingham R, Smith RM, Park BJ, et al.: Global burden of disease of
HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17: 873–81 CrossRef
e6.Arendrup MC, Perlin DS: Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis 2014; 27: 484–92 CrossRef MEDLINE PubMed Central
e7.Jeffery-Smith A, Taori SK, Schelenz S, et al.: Candida auris: a Review of the Literature. Clin Microbiol Rev 2017; 31: pii: e00029–17.
e8.Friedrich R, Rappold E, Bogdan C, Held J: Comparative analysis of the wako beta-glucan test and the fungitell assay for diagnosis of candidemia and pneumocystis jirovecii pneumonia. J Clin Microbiol 2018; 56: pii: e00464–18 MEDLINE PubMed Central
e9.Held J, Kohlberger I, Rappold E, Busse Grawitz A, Hacker G: Comparison of (1->3)-beta-D-glucan, mannan/anti-mannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. J Clin Microbiol 2013; 51: 1158–64 CrossRef MEDLINE PubMed Central
e10.Dichtl K, Seybold U, Wagener J: Serological biomarkers of candidemia: a retrospective evaluation of three assays. Infection 2018: doi: 10.1007/s15010–018–1224–3. [Epub ahead of print] CrossRef
e11.Alexander BD, Johnson MD, Pfeiffer CD, et al.: Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 2013; 56: 1724–32 CrossRef MEDLINE PubMed Central
e12.Seufert R, Sedlacek L, Kahl B, et al.: Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany. J Antimicrob Chemother 2018; 73: 2047–53 CrossRef MEDLINE
e13.Kullberg BJ, Blijlevens NMA, Janssen JJWM, et al.: Stichting Werkgroep Antibioticabeleid. https://www.swab.nl/swab/cms3.nsf/uploads/3AA7A56CE879587BC12581F80061297F/$FILE/SWAB%20Richtlijn%20Mycosen%202017%20(final).pdf (last accessed on 19. March 2019).
e14.Tissot F, Agrawal S, Pagano L, et al.: ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 2017; 102: 433–44 CrossRef MEDLINE PubMed Central
e15.Schwartz S, Ruhnke M, Ribaud P, et al.: Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005; 106: 2641–5 CrossRef MEDLINE
e16.Marr KA, Schlamm HT, Herbrecht R, et al.: Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015; 162: 81–9 CrossRef MEDLINE
e17.Elgamal EA, Murshid WR: Intracavitary administration of amphotericin B in the treatment of cerebral aspergillosis in a non immune-compromised patient: case report and review of the literature. Br J Neurosurg 2000; 14: 137–41 CrossRef
e18.Kovanda LL, Kolamunnage-Dona R, Neely M, Maertens J, Lee M, Hope WW: Pharmacodynamics of isavuconazole for invasive mold disease: role of galactomannan for real-time monitoring of therapeutic response. Clin Infect Dis 2017; 64: 1557–63 CrossRef MEDLINE PubMed Central
e19.Behrens-Baumann W, Finis D, MacKenzie C, Roth M, Geerling G: [Keratomycosis—therapy standards and new developments]. Klin Monbl Augenheilkd 2015; 232: 754–64 MEDLINE
e20.Prajna NV, Krishnan T, Rajaraman R, et al.: Adjunctive oral voriconazole treatment of fusarium keratitis: a secondary analysis from the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol 2017; 135: 520–5 CrossRef CrossRef MEDLINE PubMed Central
e21.Prajna NV, Krishnan T, Rajaraman R, et al.: Effect of oral voriconazole on fungal keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): a randomized clinical trial. JAMA Ophthalmol 2016; 134: 1365–72 CrossRef MEDLINE PubMed Central
e22.Passweg JR, Baldomero H, Bader P, et al.: Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant 2018; 53: 1139–48 CrossRef MEDLINE PubMed Central
e23.Passweg JR, Baldomero H, Bader P, et al.: Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant 2016; 51: 786–92 CrossRef MEDLINE PubMed Central
e24.McCarthy MW, Walsh TJ: Drug development challenges and strategies to address emerging and resistant fungal pathogens. Expert Rev Anti Infect Ther 2017; 15: 577–84 CrossRef MEDLINE
e25.Anesi JA, Baddley JW: Approach to the solid organ transplant patient with suspected fungal infection. Infect Dis Clin North Am 2016; 30: 277–96 CrossRef MEDLINE PubMed Central
e26.Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N: Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother 2011; 66 (Suppl 1): i5–14 CrossRef MEDLINE
e27.Clark NM, Weigt SS, Fishbein MC, Kubak B, Belperio JA, Lynch JP, 3rd: Fungal infections complicating lung transplantation. Semin Respir Crit Care Med 2018; 39: 227–54 CrossRef MEDLINE
e28.Caira M, Candoni A, Verga L, et al.: Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study). Haematologica 2015; 100: 284–92 CrossRef MEDLINE PubMed Central
e29.Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R: Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 1994; 220: 751–8 CrossRef
e30.Maskarinec SA, Johnson MD, Perfect JR: Genetic susceptibility to fungal infections: What is in the Genes? Curr Clin Microbiol Rep 2016; 3: 81–91 CrossRef MEDLINE PubMed Central
e31.Kumar V, Cheng SC, Johnson MD, et al.: Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia. Nat Commun 2014; 5: 4675 CrossRef MEDLINE PubMed Central
e32.Warris A: Immunopathology of aspergillus infections in children with chronic granulomatous disease and cystic fibrosis. Pediatr Infect Dis J 2018: doi: 10.1097/INF.0000000000002265. [Epub ahead of print] CrossRef
e33.Cunha C, Goncalves SM, Duarte-Oliveira C, et al.: IL-10 overexpression predisposes to invasive aspergillosis by suppressing antifungal immunity. J Allergy Clin Immunol 2017; 140: 867–70.e9.
e34.Lemarie E, Lemaire B, Saudeau D, Lavandier M, Renoux M, Renoux G: Disseminated aspergillosis in a patient with bronchiectasis. A 15-month clinical and immunological follow-up. Respiration 1986; 49: 235–40 MEDLINE
e35.Pegues DA, Lasker BA, McNeil MM, Hamm PM, Lundal JL, Kubak BM: Cluster of cases of invasive aspergillosis in a transplant intensive care unit: evidence of person-to-person airborne transmission. Clin Infect Dis 2002; 34: 412–6 CrossRef MEDLINE
e36.Oken MM, Creech RH, Tormey DC, et al.: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–55 CrossRef MEDLINE
e37.Anderson TM, Clay MC, Cioffi AG, et al.: Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat Chem Biol 2014; 10: 400–6 CrossRef MEDLINE PubMed Central
e38.Clancy CJ, Pappas PG, Vazquez J, et al.: Detecting Infections Rapidly and Easily for Candidemia Trial, Part 2 (DIRECT2): a prospective, multicenter study of the T2Candida Panel. Clin Infect Dis 2018; 66: 1678–86 CrossRef MEDLINE
e39.Brasnu E, Bourcier T, Dupas B, et al.: In vivo confocal microscopy in fungal keratitis. Br J Ophthalmol 2007; 91: 588–91 CrossRef MEDLINE PubMed Central
e40.Labbe A, Khammari C, Dupas B, et al.: Contribution of in vivo confocal microscopy to the diagnosis and management of infectious keratitis. Ocul Surf 2009; 7: 41–52 CrossRef