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Diagnostic and Therapeutic Challenges of Human Fungal Infections

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A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 34981

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Special Issue Editors

Prof. Dr. Timoleon-Achilleas Vyzantiadis

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First Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: applied laboratory medicine; infectious diseases; clinical microbiology; fungal infections; diagnosis and monitoring of fungal infections; antifungal agents
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Dr. Athanasios Tragiannidis

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Childhood & Adolescent Haematology Oncology Unit, Second Department of Paediatrics, Aristotle University of Thessaloniki, AHEPA Hospital, 53646 Thessaloniki, Greece
Interests: paediatric haematology oncology; infectious complications in the immunocompromised host; invasive fungal infections; antifungal agents; children
Special Issues, Collections and Topics in MDPI journals

Dr. Eleni Gavriilaki

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Guest Editor

Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Interests: hematologic malignancies; thrombosis; complement; cellular therapy; lymphoma; myeloma; COVID-19
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fungal infections, either invasive and disseminated or cutaneous and superficial, are an important and increasing cause of morbidity. The first category consists of a major factor of severe disease and mortality, especially in immunocompromised and debilitated patients. However, the second category can also cause serious concerns in matters of human health, not forgetting that it is extremely widespread.

Several causes like the broadly used chemotherapies and immunosuppressive treatments, hematopoietic cell transplantation and novel cellular therapies, several iatrogenic interventions, the aging of the population, severe underlying diseases, massive population movements and excessive travelling, changing of social habits, broad climate change, epidemiology alteration in terms of fungal species and antifungal sensitivities, other infections, co-infections, and super-infections are all parts of a dense net of factors that make fungal infections an important issue of public health at both the community and hospital level.

In addition, fungi are a complex and greatly evolved kingdom of living entities that are very adept at surviving and expanding. The eukaryotic organisation and the resistance of their cells and the multitude of invading and escaping mechanisms they possess make them a serious opponent in terms of disease.

Due to all the above reasons, there are important challenges in the diagnostic procedure but also in the treatment of the relevant infections in both the paediatric and the adult population. Since the onset of the COVID pandemic, we have realised once more how vulnerable we become when a second invader, like the fungi, takes advantage of the exhausting of our organism's resistance resources and how much more difficult diagnosis and treatment can become.

This Special Issue has the ambition of focussing on the available and evolving diagnostic and therapeutic approaches for the two big types of fungal infection (invasive or superficial), investigating and presenting the challenges that exist in these matters, and studying at least some of the factors that, as already described, turn fungi into a serious concern.

Both reviews and original articles are welcome.

Prof. Dr. Timoleon-Achilleas Vyzantiadis
Prof. Dr. Athanasios Tragiannidis
Dr. Eleni Gavriilaki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Fungi is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

invasive fungal infections
systemic fungal infections
superficial fungal infections
mycoses
antifungal agents
treatment of fungal infections
diagnosis of fungal infections
monitoring of fungal infections
epidemiology
antifungal resistance

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Published Papers (12 papers)

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Research

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17 pages, 971 KiB

Open AccessArticle

COVID-19-Associated Pulmonary Aspergillosis (CAPA) in Northern Greece during 2020–2022: A Comparative Study According to the Main Consensus Criteria and Definitions

by Panagiotis Siasios, Kostoula Arvaniti, Evangelia Zachrou, Aikaterini Poulopoulou, Pinelopi Pisanidou, Georgia Vasileiadou, Evangelos Kaimakamis, Athina Georgopoulou, Foteini Renta, Dimitrios Lathyris, Foteini Veroniki, Eleni Geka, Ioanna Soultati, Eleni Argiriadou, Eleni Apostolidou, Pinelopi Amoiridou, Konstantinos Ioannou, Leonidas Kouras, Ioanna Mimitou, Konstantinos Stokkos, Elliniki Flioni, Evangelos Pertsas, Maria Sileli, Christina Iasonidou, Evdokia Sourla, Georgia Pitsiou and Timoleon-Achilleas Vyzantiadis Show full author list Hide full author list

J. Fungi 2023, 9(1), 81; https://doi.org/10.3390/jof9010081 - 5 Jan 2023

Cited by 3 | Viewed by 2474

Abstract

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as an important complication among patients with acute respiratory failure due to SARS-CoV-2 infection. Almost 2.5 years since the start of the COVID-19 pandemic, it continues to raise concerns as an extra factor that contributes to increased mortality, which is mostly because its diagnosis and management remain challenging. The present study utilises the cases of forty-three patients hospitalised between August 2020 and February 2022 whose information was gathered from ten ICUs and special care units based in northern Greece. The main aim was to describe the gained experience in diagnosing CAPA, according to the implementation of the main existing diagnostic consensus criteria and definitions, and present the different classification of the clinical cases due to the alternative algorithms. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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11 pages, 1497 KiB

Open AccessArticle

Performance of Two Commercial Assays for the Detection of Serum Aspergillus Galactomannan in Non-Neutropenic Patients

by Rodrigo Almeida-Paes, Marcos de Abreu Almeida, Priscila Marques de Macedo, Diego H. Caceres and Rosely Maria Zancopé-Oliveira

J. Fungi 2022, 8(7), 741; https://doi.org/10.3390/jof8070741 - 18 Jul 2022

Cited by 11 | Viewed by 2536

Abstract

Besides the relevance of aspergillosis in neutropenic patients, this mycosis has gained significance among non-neutropenic patients in last years. The detection of Aspergillus galactomannan has been used for aspergillosis diagnosis and follow-up in neutropenic patients. This study evaluated the applicability of two commercial tests for galactomannan detection in non-neutropenic patients with different clinical forms of aspergillosis. Serum samples from patients with chronic pulmonary aspergillosis, aspergilloma, invasive aspergillosis, and COVID-19 associated pulmonary aspergillosis were evaluated using the IMMY sōna AGM lateral flow assay and the Bio-Rad Platelia sandwich ELISA. Serum specimens from patients with tuberculosis, histoplasmosis, paracoccidioidomycosis, and from healthy individuals were used as controls. The Bio-Rad Platelia sandwich ELISA presented greater sensitivity, whereas the IMMY sōna AGM lateral flow assay presented greater specificity. The accuracies of the tests were similar, as demonstrated by a receiver operator characteristic analysis. Moreover, the best cut-off values determined by this analysis were closer to that recommended by both manufacturers for neutropenic patients. The galactomannan indexes determined by different methodologies were strongly related, and a substantial agreement was observed between results. Both tests can be used in non-neutropenic patients with the cut-off values defined by the manufacturers. Histoplasma cross-reactions may occur in areas where histoplasmosis is endemic. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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10 pages, 1232 KiB

Open AccessArticle

Comparative Fungicidal Activities of N-Chlorotaurine and Conventional Antiseptics against Candida spp. Isolated from Vulvovaginal Candidiasis

by Mayram Hacioglu, Ozlem Oyardi, Fatima Nur Yilmaz and Markus Nagl

J. Fungi 2022, 8(7), 682; https://doi.org/10.3390/jof8070682 - 28 Jun 2022

Cited by 2 | Viewed by 2520

Abstract

N-chlorotaurine (NCT), the N-chloro derivative of the amino acid taurine, is a long-lived oxidant produced by stimulated human leucocytes. NCT has antimicrobial activities which are generally enhanced in the presence of organic material. The aim of this study was to investigate fungicidal effects of NCT and conventional antiseptics against Candida isolated from vulvovaginal candidiasis (VVC). Chlorhexidine (CHX, 1.6%), octenidine dihydrochloride (OCT, 0.08%), povidone iodine (PVP-I, 8%), boric acid (8%), and NCT (0.1% (5.5 mM)) were evaluated against forty-four Candida isolates, according to European Standard methods, at 30, 60, 90, and 120 min and 24 h in the presence of skim milk as an organic material. CHX, OCT, and PVP-I showed rapid fungicidal activity against all Candida isolates with 5–6 log₁₀ reduction of viable counts after 30 min, whereas boric acid and NCT needed 1 h against Candida albicans and 2 h against non-albicans Candida for a significant 3 log₁₀ reduction. NCT showed fungicidal activity (defined as ≥4 log₁₀ reduction) against C. albicans within 90 min and C. non–albicans within 24 h. Based upon all presently available data, including our results, NCT could be used as a new agent for treatment of local fungal infections such as VVC. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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8 pages, 1008 KiB

Open AccessArticle

Clinical Presentations, Cluster Analysis and Laboratory-Based Investigation of Aspergillus Otomycosis—A Single Center Experience

by Mila Bojanović, Aleksandra Ignjatović, Marko Stalević, Valentina Arsić-Arsenijević, Marina Ranđelović, Vladimir Gerginić, Zorica Stojanović-Radić, Ognjen Stojković, Emilija Živković-Marinkov and Suzana Otašević

J. Fungi 2022, 8(3), 315; https://doi.org/10.3390/jof8030315 - 18 Mar 2022

Cited by 6 | Viewed by 4049

Abstract

Species of Aspergillus (A.) niger complex and A. flavus complex are predominant molds that are causative agents of otomycoses. The goal of this study was to investigate the clinical presentation, diagnostic procedure, and appearance of relapse in patients with Aspergillus-otomycosis, as well as to determine the biofilm production ability of species isolated in relapse. Thirty patients with laboratory evidenced Aspergillus-otomycosis followed by two check-ups (30 and 60 days after initiation of treatment with antimycotics for local application) were included in the study. For isolation and identification of Aspergillus spp. the standard mycological procedure was applied. Results showed very high sensitivity of microscopy, but 16.7% Aspergillus species required the optimal temperature of 27–28 °C for cultivation. Applied statistical cluster analysis showed a defined specific cluster/group of patients with A. niger complex-otomycosis. Sixty days after diagnosis and treatment initiation, six patients had a relapse, with the same species of Aspergillus genus being the cause. To establish the ability of biofilm production, the modified method described by Pierce and Kvasničková was performed, and all six species isolated in the relapse episode had the ability to produce biofilm. Official criteria and recommendations are needed due to the possibility of misdiagnosis, which leads to the prolongation and complication of the disease. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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17 pages, 2453 KiB

Open AccessArticle

Antifungal Activity of Human Cathelicidin LL-37, a Membrane Disrupting Peptide, by Triggering Oxidative Stress and Cell Cycle Arrest in Candida auris

by Irfan A. Rather, Jamal S. M. Sabir, Amer H. Asseri and Sajad Ali

J. Fungi 2022, 8(2), 204; https://doi.org/10.3390/jof8020204 - 20 Feb 2022

Cited by 29 | Viewed by 3635

Abstract

Candida auris, an evolving multidrug-resistant pathogenic yeast, is known for causing severe invasive infections associated with high mortality rates in hospitalized individuals. Distinct from other Candida species, C. auris can persist for longer periods on different surfaces and is resistant to all of the major classes of antifungal drugs. Therefore, there is an urgent need for new antimycotic drugs with improved efficacy and reduced toxicity. The development of new antifungals based on antimicrobial peptides from various sources is considered a promising alternative. In this study, we examined the in vitro anti-yeast activity of the human cathelicidin peptides LL-37 against clinical strains of C. auris alone and in combination with different antifungal drugs by broth microdilution assay. To understand the antifungal mechanism of action, cell envelopes, cell cycle arrest, and effect on oxidative stress enzymes were studied using standard protocols. The minimum inhibitory and fungicidal concentrations of cathelicidin LL-37 ranged from 25–100 and 50–200 µg/mL, respectively. A combination interaction in a 1:1 ratio (cathelicidin LL-37: antifungal drug) resulted in 70% synergy with fluconazole and 100% synergy with amphotericin B and caspofungin. Assessment of the C. auris membrane by using propidium iodide assay after exposure to cathelicidin LL-37 linked membrane permeabilization with inhibition of C. auris cell growth and viability. These results were backed up by scanning electron microscopy studies demonstrating that exposure with cathelicidin LL-37 caused C. auris cells to undergo extensive surface changes. Spectrophotometric analysis revealed that cathelicidin LL-37 caused oxidative stress in C. auris, as is evident from the significant increase in the activity of primary antioxidant enzymes. In addition, cathelicidin LL-37 inhibited the cell cycle and accumulated cells in the S phase. Therefore, these results specify the potential of cathelicidin LL-37 for developing a new and effective anti-Candida agent. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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Review

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12 pages, 1410 KiB

Open AccessReview

Recurrent Scedosporium apiospermum Cutaneous Infection in a Patient with Rheumatoid Arthritis: The Potent Role of IL-6 Signaling Pathway Blockade: A Case-Based Review

by Antigone Pieta, Aliki I. Venetsanopoulou, Christos Kittas, Eirini Christaki and Paraskevi V. Voulgari

J. Fungi 2023, 9(6), 683; https://doi.org/10.3390/jof9060683 - 18 Jun 2023

Cited by 8 | Viewed by 1716

Abstract

Rheumatoid arthritis (RA) patients deal with a higher risk of bacterial and fungal infections compared to the general population because of their dysregulated immune system as well as the immunosuppressive therapy they usually receive. Scedosporium spp. is a fungal pathogen responsible for cutaneous, lung, central nervous system, and eye infections, mostly in immunocompromised patients, leading to death in disseminated cases. We report the case of an 81-year-old woman with rheumatoid arthritis treated with steroids and an IL-6 inhibitor who was diagnosed with scedosporiosis of the upper limb. She was treated with voriconazole for one month, which was discontinued due to adverse events, and when scedosporiosis relapsed, she switched to itraconazole. We also reviewed the current literature on RA patients presenting with Scedosporium infections. Early and accurate diagnosis of scedosporiosis has therapeutic and prognostic implications, as traditionally this fungus is resistant to commonly used antifungals. Clinical alertness regarding uncommon infections, including fungal, in patients with autoimmune diseases on immunomodulatory agents is essential for effective treatment. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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14 pages, 319 KiB

Open AccessReview

Dermatophytic Biofilms: Characteristics, Significance and Treatment Approaches

by Anthi-Marina Markantonatou, Konstantinos Samaras and Timoleon-Achilleas Vyzantiadis

J. Fungi 2023, 9(2), 228; https://doi.org/10.3390/jof9020228 - 9 Feb 2023

Cited by 8 | Viewed by 2044

Abstract

Microbes are found in the environment, possibly more often as biofilms than in planktonic forms. Biofilm formation has been described for several important fungal species. The presence of a dermatophytoma in a dermatophytic nail infection was the basis for the proposal that dermatophytes form biofilms as well. This could explain treatment failure and recurrent dermatophytic infections. Several investigators have performed in vitro and ex vivo experiments to study the formation of biofilms by dermatophytes and their properties. The nature of the biofilm structure itself contributes to fungal protection mechanisms against many harmful external agents, including antifungals. Thus, a different approach should be carried out regarding susceptibility testing and treatment. Concerning susceptibility testing, methods to evaluate either the inhibition of biofilm formation, or the ability to eradicate it, have been introduced. As for treatment, in addition to classical antifungal agents, some natural formulations, such as plant extracts or biosurfactants, and alternative approaches, such as photodynamic therapy, have been proposed. Studies that connect the results of the in vitro and ex vivo experimentation with clinical outcomes are required in order to verify the efficacy of these approaches in clinical practice. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

18 pages, 327 KiB

Open AccessReview

Acute Lymphoblastic Leukemia and Invasive Mold Infections: A Challenging Field

by Christos Stafylidis, Panagiotis Diamantopoulos, Eleni Athanasoula, Elena Solomou and Amalia Anastasopoulou

J. Fungi 2022, 8(11), 1127; https://doi.org/10.3390/jof8111127 - 26 Oct 2022

Cited by 2 | Viewed by 2828

Abstract

Acute lymphoblastic leukemia (ALL) patients comprise a highly immunocompromised group due to factors associated either with the treatment or the disease itself. Invasive mold infections (IMIs) are considered to be responsible for higher morbidity and mortality rates in patients with hematologic malignancies, including ALL. Defining the exact incidence of IMIs in ALL patients has been rather complicated. The available literature data report a highly variable incidence of IMIs, ranging from 2.2% to 15.4%. Although predisposing factors for IMIs in the setting of ALL are ill-defined, retrospective studies have indicated that a longer duration of neutropenia, treatment with high-dose corticosteroids, and a lack of antimold prophylaxis are associated with an increased risk of IMIs. Additionally, the influence of novel ALL treatments on the susceptibility to fungal infections remains obscure; however, initial data suggest that these treatments may induce prolonged neutropenia and thus an increased risk of IMIs. Administering primary antimold prophylaxis in these patients has been challenging since incorporating azole antifungal agents is troublesome, considering the drug-to-drug interactions (DDIs) and increased toxicity that may occur when these agents are coadministered with vincristine, a fundamental component of ALL chemotherapy regimens. Isavuconazole, along with several novel antifungal agents such as rezafungin, olorofim, and manogepix, may be appealing as primary antimold prophylaxis, given their broad-spectrum activity and less severe DDI potential. However, their use in ALL patients needs to be investigated through more clinical trials. In summary, this review outlines the epidemiology of IMI and the use of antifungal prophylaxis in ALL patients. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

9 pages, 242 KiB

Open AccessReview

Fungal Infections and Nail Psoriasis: An Update

by Aikaterini Kyriakou, Sofia-Chrysovalantou Zagalioti, Myrto-Georgia Trakatelli, Christina Fotiadou, Zoe Apalla, Elizabeth Lazaridou and Aikaterini Patsatsi

J. Fungi 2022, 8(2), 154; https://doi.org/10.3390/jof8020154 - 3 Feb 2022

Cited by 9 | Viewed by 5659

Abstract

The relationship between psoriasis and onychomycosis is controversial, and the exact nature of this association remains to be clearly elucidated. In healthy nails, the compact nail plate acts as a barrier, preventing any infection. In psoriatic nails, the nail plate involvement, together with abnormalities in the blood capillaries, may lead to decreased natural defenses against microorganisms. Moreover, onycholysis (detachment of the nail plate) induces a humid environment that may favor fungal proliferation. Treatment with immunosuppressive drugs may additionally enhance onychomycosis. In this comprehensive review, we present data regarding the incidence and pathogenic action of dermatophytes and other fungi in the development of fungal infection in psoriatic nails. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

Other

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8 pages, 680 KiB

Open AccessBrief Report

Dual Disseminated Aspergillosis and Mucormycosis Diagnosed at Autopsy: A Report of Two Cases of Coinfection and a Review of the Literature

by Jason Murray, Zhen A. Lu, Karin Miller, Alex Meadows, Marissa Totten and Sean X. Zhang

J. Fungi 2023, 9(3), 357; https://doi.org/10.3390/jof9030357 - 15 Mar 2023

Cited by 4 | Viewed by 1737

Abstract

Coinfection with invasive aspergillosis and mucormycosis in immunocompromised patients has been reported but is rarely confirmed by tissue histology or autopsy. Serum fungal biomarkers and culture are the primary diagnostic tools but are suboptimal for detecting fungal coinfection. Here, we present the cases of two patients who were immunocompromised due to hematologic malignancy where disseminated aspergillosis and mucormycosis coinfection was only diagnosed upon autopsy despite extensive fungal diagnostic workup, and also review recent literature of such instances of coinfection. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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7 pages, 4196 KiB

Open AccessCase Report

Successful Multimodal Therapy with Intracerebral Liposomal Amphotericin B and Systemic High-Dose Isavuconazole in Proven Disseminated Aspergillosis

by Simon Feys, Franceska Dedeurwaerdere, Katrien Lagrou, Jeroen Van Lerbeirghe and Dries Deeren

J. Fungi 2023, 9(3), 327; https://doi.org/10.3390/jof9030327 - 7 Mar 2023

Cited by 2 | Viewed by 1764

Abstract

We report the case of a 32-year-old man receiving chemotherapeutics for an acute B-lymphoblastic leukemia who developed proven cerebral and pulmonary aspergillosis with Aspergillus flavus. Because of progressive fungal disease with neurological deterioration despite adequate systemic antifungal therapy and surgical debridement, intracerebral administration of liposomal amphotericin B was initiated at 5 mg twice weekly. This led to improvement of the cerebral infection. Surgical debridement of a pleural Aspergillus empyema was necessary, and pleural trough level of isavuconazole was found to be subtherapeutic despite adequate blood trough levels, which led us to increase the dose of isavuconazole. We conclude that intralesional amphotericin B might be beneficial at 5 mg twice weekly in cerebral aspergillosis if systemic antifungals and surgical debridement fail. In Aspergillus empyema, measurement of pleural isavuconazole trough levels should be considered. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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10 pages, 14833 KiB

Open AccessCase Report

Long-Term Kinetics of Serum Galactomannan during Treatment of Complicated Invasive Pulmonary Aspergillosis

by Athanasios Tragiannidis, Christina Linke, Carlos L. Correa-Martinez, Heidrun Herbrüggen, Frieder Schaumburg and Andreas H. Groll

J. Fungi 2023, 9(2), 157; https://doi.org/10.3390/jof9020157 - 24 Jan 2023

Viewed by 2337

Abstract

Several studies have evaluated the serum galactomannan (GM) antigen assay in pediatric patients, and there is convincing evidence for its usefulness as a diagnostic tool for invasive Aspergillus infections in patients with acute leukemias or post allogeneic hematopoietic cell transplantation (HCT). Less is known about the utility of the assay in monitoring responses to treatment in patients with established invasive aspergillosis (IA). Here, we present the long-term kinetics of serum galactomannan in two severely immunocompromised adolescents with invasive pulmonary aspergillosis (IPA) who were cured after complicated clinical courses. We also review the utility of the GM antigen assay in serum as a prognostic tool around the time of diagnosis of IA and as a biomarker to monitor disease activity in patients with established IA and assess responses to systemic antifungal therapy. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Challenges of Human Fungal Infections)

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