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Diagnosis and Treatments of Invasive Fungal Diseases

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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 (24 March 2023) | Viewed by 18905

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Dr. Rodrigo Almeida-Paes

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Laboratory of Mycology, Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz. Foundation (FIOCRUZ), Rio de Janeiro 21040-360, RJ, Brazil
Interests: mycosis; molecular diagnosis; serology; fungal identification; new antifungal drugs; therapy; translational medicine
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Dr. Rosely Maria Zancopé-Oliveira

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Dear Colleagues,

In recent years, important changes have occurred at an impressive rate in the epidemiology, etiology, and clinical manifestations of fungal diseases. There has been an emergence of new pathogens, appearance of new at-risk patient groups, and occurrence of advances of great magnitude in laboratory methods. Therefore, innovations in the medical mycology field are necessary, and in fact, several research groups are now working to improve diagnosis and treatment of invasive fungal diseases. Now, it is time that basic science research translates to clinical practice, to curb the spread of fungal pathogens and their diseases. The purpose of this Special Issue is to highlight recent advances related to current fungal diagnostics and treatment, as well explore some of the most innovative technology that has emerged with the potential to shift the paradigm of clinical mycology. Therefore, this Special Issue will present new, important, and innovative research on this topic, which will certainly promote translational applications in medical mycology, improving the survival and quality of life of patients.

Dr. Rodrigo Almeida-Paes
Dr. Rosely Maria Zancopé-Oliveira
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

mycosis
molecular diagnosis
serology
fungal identification
new antifungal drugs
therapy
translational medicine

Published Papers (9 papers)

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Research

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12 pages, 320 KiB

Open AccessArticle

Performance of a Real-Time PCR Assay for the Detection of Five Candida Species in Blood Samples from ICU Patients at Risk of Candidemia

by Gabriel N. Felix, Vera L. T. de Freitas, Afonso R. da Silva Junior, Marcello M. C. Magri, Flavia Rossi, Odeli N. E. Sejas, Edson Abdala, Luiz M. S. Malbouisson, Thais Guimarães, Gil Benard and Gilda M. B. Del Negro

J. Fungi 2023, 9(6), 635; https://doi.org/10.3390/jof9060635 - 31 May 2023

Cited by 1 | Viewed by 1675

Abstract

The gold standard for diagnosing invasive candidiasis still relies on blood cultures, which are inefficient and time-consuming to analyze. We developed an in-house qPCR assay to identify the 5 major Candida species in 78 peripheral blood (PB) samples from ICU patients at risk of candidemia. Blood cultures and (1,3)-β-D-glucan (BDG) testing were performed concurrently to evaluate the performance of the qPCR. The qPCR was positive for DNA samples from all 20 patients with proven candidemia (positive PB cultures), showing complete concordance with Candida species identification in blood cultures, except for detection of dual candidemia in 4 patients, which was missed by blood cultures. Additionally, the qPCR detected Candida species in six DNA samples from patients with positive central venous catheters blood (CB) but negative PB cultures. BDG values were similarly high in these six samples and the ones with proven candidemia, strongly suggesting the diagnosis of a true candidemia episode despite the negative PB cultures. Samples from patients neither infected nor colonized yielded negative results in both the qPCR and BDG testing. Our qPCR assay was at least as sensitive as blood cultures, but with a shorter turnaround time. Furthermore, negative results from the qPCR provided strong evidence for the absence of candidemia caused by the five major Candida species. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

19 pages, 2406 KiB

Open AccessArticle

Phenotypic Array for Identification and Screening of Antifungals against Aspergillus Isolates from Respiratory Infections in KwaZulu Natal, South Africa

by Sarla Naicker, Viresh Mohanlall, Sandile Ngubane, John Mellem and Nokuthula Peace Mchunu

J. Fungi 2023, 9(6), 616; https://doi.org/10.3390/jof9060616 - 26 May 2023

Viewed by 1448

Abstract

The rapid emergence of invasive fungal infections correlates with the increasing population of immunocompromised individuals, with many cases leading to death. The progressive increase in the incidence of Aspergillus isolates is even more severe due to the clinical challenges in treating invasive infections in immunocompromised patients with respiratory conditions. Rapid detection and diagnosis are needed to reduce mortality in individuals with invasive aspergillosis-related infections and thus efficient identification impacts clinical success. The phenotypic array method was compared to conventional morphology and molecular identification on thirty-six Aspergillus species isolated from patients with respiratory infections at the Inkosi Albert Luthuli Hospital in Kwa-Zulu Natal. In addition, an antimicrobial array was also carried out to screen for possible novel antimicrobial compounds for treatment. Although traditional morphological techniques are useful, genetic identification was the most reliable, assigning 26 to Aspergillus fumigatus species, 8 Aspergillus niger, and 2 Aspergillus flavus including cryptic species of A. niger, A. tubingensis and A. welwitschiae. The phenotypic array technique was only able to identify isolates up to the genus level due to a lack of adequate reference clinical species in the database. However, this technique proved crucial in assessing a wide range of possible antimicrobial options after these isolates exhibited some resistance to azoles. Antifungal profiles of the thirty-six isolates on the routine azole voriconazole showed a resistance of 6%, with 61% having moderate susceptibility. All isolates resistant to the salvage therapy drug, posaconazole pose a serious concern. Significantly, A. niger was the only species resistant (25%) to voriconazole and has recently been reported as the species isolated from patients with COVID-19-associated pulmonary aspergillosis (CAPA). Phenotypic microarray showed that 83% of the isolates were susceptible to the 24 new compounds and novel compounds were identified for potentially effective combination treatment of fungal infections. This study also reports the first TR34/98 mutation in Aspergillus clinical isolates which is located in the cyp51A gene. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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14 pages, 873 KiB

Open AccessArticle

Evaluation of Five Non-Culture-Based Methods for the Diagnosis of Meningeal Sporotrichosis

by Fernando Almeida-Silva, Marcos de Abreu Almeida, Vanessa Brito de Souza Rabello, Rosely Maria Zancopé-Oliveira, Lilian Cristiane Baeza, Cristiane da Cruz Lamas, Marco Antonio Lima, Priscila Marques de Macedo, Maria Clara Gutierrez-Galhardo, Rodrigo Almeida-Paes and Dayvison Francis Saraiva Freitas

J. Fungi 2023, 9(5), 535; https://doi.org/10.3390/jof9050535 - 30 Apr 2023

Cited by 4 | Viewed by 1089

Abstract

Sporotrichosis is the main subcutaneous mycosis worldwide. Several complications, including meningeal forms, can be observed in immunocompromised individuals. The sporotrichosis diagnosis is time-consuming due to the culture’s limitations. The low fungal burden in cerebrospinal fluid (CSF) samples is another important drawback in the diagnosis of meningeal sporotrichosis. Molecular and immunological tests can improve the detection of Sporothrix spp. in clinical specimens. Therefore, the following five non-culture-based methods were evaluated for the detection of Sporothrix spp. in 30 CSF samples: (i) species-specific polymerase chain reaction (PCR); (ii) nested PCR; (iii) quantitative PCR; (iv) enzyme-linked immunosorbent assay (ELISA) for IgG detection; and (v) ELISA for IgM detection. The species-specific PCR was unsuccessful in the diagnosis of the meningeal sporotrichosis. The other four methods presented substantial levels of sensitivity (78.6% to 92.9%) and specificity (75% to 100%) for the indirect detection of Sporothrix spp. Both DNA-based methods presented similar accuracy (84.6%). Both ELISA methods were concomitantly positive only for patients with sporotrichosis and clinical signs of meningitis. We suggest that these methods should be implemented in clinical practice to detect Sporothrix spp. in CSF early, which may optimize treatment, augment the chances of a cure, and improve the prognosis of affected individuals. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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15 pages, 1566 KiB

Open AccessArticle

A Dedicated Mycosis Flask Increases the Likelihood of Identifying Candidemia Sepsis

by Magnus G. Ahlström, Valeria S. Antsupova, Michael Pedersen, Helle Krogh Johansen, Dennis Schrøder Hansen and Inge Jenny Dahl Knudsen

J. Fungi 2023, 9(4), 441; https://doi.org/10.3390/jof9040441 - 04 Apr 2023

Viewed by 949

Abstract

Introduction: Candidemia is a severe condition associated with high mortality, and fungi are often not covered by empiric antimicrobial regimes for sepsis. Therefore, the shortest possible time to detection of yeast in the blood is of the essence. Materials and methods: We performed a cohort study of blood culture flasks drawn from patients aged 18 or older in the capital region of Denmark. In 2018 a blood cultures set consisted of two aerobic and two anaerobic flasks. This was changed in 2020 to two aerobic, one anaerobic, and one mycosis flask. We used time-to-event statistics to model time to positivity and compared 2018 with 2020; further, we stratified analyses on the blood culture system used (BacTAlert™ vs. BACTEC™) and high-risk vs. low-risk departments. Results: We included 175,416 blood culture sets and 107,077 unique patients. We found an absolute difference in the likelihood of identifying fungi in a blood culture set of 1.2 (95% CI: 0.72; 1.6) pr. 1.000 blood culture sets corresponding to the number needed to treat 853 (617; 1382). In high-risk departments, the absolute difference was profound, whereas it was negligible and statistically non-significant in low-risk departments 5.2 (95% CI: 3.4; 7.1) vs. 0.16 (−0.17; 0.48) pr. 1.000 blood culture sets. Conclusions: We found that including a mycosis flask in a blood culture set increases the likelihood of identifying candidemia. The effect was mainly seen in high-risk departments. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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18 pages, 3793 KiB

Open AccessArticle

Mebendazole Inhibits Histoplasma capsulatum In Vitro Growth and Decreases Mitochondrion and Cytoskeleton Protein Levels

by Marcos Abreu Almeida, Andrea Reis Bernardes-Engemann, Rowena Alves Coelho, Camila Jantoro Guzman Lugones, Iara Bastos de Andrade, Dario Corrêa-Junior, Simone Santiago Carvalho de Oliveira, André Luis Souza dos Santos, Susana Frases, Márcio Lourenço Rodrigues, Richard Hemmi Valente, Rosely Maria Zancopé-Oliveira and Rodrigo Almeida-Paes

J. Fungi 2023, 9(3), 385; https://doi.org/10.3390/jof9030385 - 21 Mar 2023

Cited by 3 | Viewed by 1760

Abstract

Histoplasmosis is a frequent mycosis in people living with HIV/AIDS and other immunocompromised hosts. Histoplasmosis has high rates of mortality in these patients if treatment is unsuccessful. Itraconazole and amphotericin B are used to treat histoplasmosis; however, both antifungals have potentially severe pharmacokinetic drug interactions and toxicity. The present study determined the minimal inhibitory and fungicidal concentrations of mebendazole, a drug present in the NIH Clinical Collection, to establish whether it has fungicidal or fungistatic activity against Histoplasma capsulatum. Protein extracts from H. capsulatum yeasts, treated or not with mebendazole, were analyzed by proteomics to understand the metabolic changes driven by this benzimidazole. Mebendazole inhibited the growth of 10 H. capsulatum strains, presenting minimal inhibitory concentrations ranging from 5.0 to 0.08 µM. Proteomics revealed 30 and 18 proteins exclusively detected in untreated and mebendazole-treated H. capsulatum yeast cells, respectively. Proteins related to the tricarboxylic acid cycle, cytoskeleton, and ribosomes were highly abundant in untreated cells. Proteins related to the nitrogen, sulfur, and pyrimidine metabolisms were enriched in mebendazole-treated cells. Furthermore, mebendazole was able to inhibit the oxidative metabolism, disrupt the cytoskeleton, and decrease ribosomal proteins in H. capsulatum. These results suggest mebendazole as a drug to be repurposed for histoplasmosis treatment. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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9 pages, 9850 KiB

Open AccessArticle

The Comparative Evaluation of the Fujifilm Wako β-Glucan Assay and Fungitell Assay for Diagnosing Invasive Fungal Disease

by Shreya Singh, Rimjhim Kanaujia, Sourav Agnihotri, Harsimran Kaur, Arunaloke Chakrabarti and Shivaprakash M. Rudramurthy

J. Fungi 2023, 9(1), 6; https://doi.org/10.3390/jof9010006 - 20 Dec 2022

Cited by 4 | Viewed by 1485

Abstract

Serum 1,3-β-d-glucan(BDG) is a broad fungal biomarker for invasive fungal disease (IFD). More data is still required to support the Fujifilm Wako assay as a valuable alternative to the widely used Fungitell assay. We included archived serum samples from 157 individuals (97 cases; 33-IA, 64-IC, and 60 controls) for the comparative performance evaluation of the Fungitell assay and the Fujifilm Wako assay for IFD diagnosis. The BDG value was significantly higher in patients with IFD vs. controls (70.79 pg/mL vs. 3.03 pg/mL, p: 0.0002). An area under the curve (AUC) for the IFD, IC, and IA diagnosis was 0.895, 0.910, and 0.866, respectively, for the Fujifilm Wako assay. Based on the highest Youden’s index (0.667), a cutoff of 5 pg/mL was selected as the optimum for the Fujifilm Wako assay with good sensitivity (79.4%), specificity (88.3%) and agreement (84.7%, Cohen’s k:0.691) with the Fungitell assay. The mean run-time of the Fujifilm Wako assay was 70.12 min, and real-time observation allowed earlier time to result in Fujifilm Wako vs. Fungitell assay (37 vs. 120 min, p: < 0.0001). Thus, our findings support the diagnostic value of the Fujifilm Wako assay for the diagnosis of IFD. However, there is still a need to validate diagnostic protocols to optimize their use in multi-centre studies with different patient groups. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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Review

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35 pages, 1806 KiB

Open AccessReview

Fungal Vaccine Development: State of the Art and Perspectives Using Immunoinformatics

by Moisés Morais Inácio, André Luís Elias Moreira, Vanessa Rafaela Milhomem Cruz-Leite, Karine Mattos, Lana O’Hara Souza Silva, James Venturini, Orville Hernandez Ruiz, Fátima Ribeiro-Dias, Simone Schneider Weber, Célia Maria de Almeida Soares and Clayton Luiz Borges

J. Fungi 2023, 9(6), 633; https://doi.org/10.3390/jof9060633 - 31 May 2023

Cited by 4 | Viewed by 2404

Abstract

Fungal infections represent a serious global health problem, causing damage to health and the economy on the scale of millions. Although vaccines are the most effective therapeutic approach used to combat infectious agents, at the moment, no fungal vaccine has been approved for use in humans. However, the scientific community has been working hard to overcome this challenge. In this sense, we aim to describe here an update on the development of fungal vaccines and the progress of methodological and experimental immunotherapies against fungal infections. In addition, advances in immunoinformatic tools are described as an important aid by which to overcome the difficulty of achieving success in fungal vaccine development. In silico approaches are great options for the most important and difficult questions regarding the attainment of an efficient fungal vaccine. Here, we suggest how bioinformatic tools could contribute, considering the main challenges, to an effective fungal vaccine. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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19 pages, 790 KiB

Open AccessReview

Non-albicans Candida Species: Immune Response, Evasion Mechanisms, and New Plant-Derived Alternative Therapies

by Manuela Gómez-Gaviria, Uriel Ramírez-Sotelo and Héctor M. Mora-Montes

J. Fungi 2023, 9(1), 11; https://doi.org/10.3390/jof9010011 - 21 Dec 2022

Cited by 8 | Viewed by 4180

Abstract

Fungal infections caused by Candida species have become a constant threat to public health, especially for immunocompromised patients, who are considered susceptible to this type of opportunistic infections. Candida albicans is known as the most common etiological agent of candidiasis; however, other species, such as Candida tropicalis, Candida parapsilosis, Nakaseomyces glabrata (previously known as Candida glabrata), Candida auris, Candida guilliermondii, and Pichia kudriavzevii (previously named as Candida krusei), have also gained great importance in recent years. The increasing frequency of the isolation of this non-albicans Candida species is associated with different factors, such as constant exposure to antifungal drugs, the use of catheters in hospitalized patients, cancer, age, and geographic distribution. The main concerns for the control of these pathogens include their ability to evade the mechanisms of action of different drugs, thus developing resistance to antifungal drugs, and it has also been shown that some of these species also manage to evade the host’s immunity. These biological traits make candidiasis treatment a challenging task. In this review manuscript, a detailed update of the recent literature on the six most relevant non-albicans Candida species is provided, focusing on the immune response, evasion mechanisms, and new plant-derived compounds with antifungal properties. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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16 pages, 1611 KiB

Open AccessReview

Oral Chronic Hyperplastic Candidiasis and Its Potential Risk of Malignant Transformation: A Systematic Review and Prevalence Meta-Analysis

by Alejandro I. Lorenzo-Pouso, Alba Pérez-Jardón, Vito Carlo Alberto Caponio, Francesca Spirito, Cintia M. Chamorro-Petronacci, Óscar Álvarez-Calderón-Iglesias, Pilar Gándara-Vila, Lorenzo Lo Muzio and Mario Pérez-Sayáns

J. Fungi 2022, 8(10), 1093; https://doi.org/10.3390/jof8101093 - 17 Oct 2022

Cited by 14 | Viewed by 3134

Abstract

Chronic hyperplastic candidiasis (CHC) is a prototypical oral lesion caused by chronic Candida infection. A major controversy surrounding CHC is whether this oral lesion owns malignant transformation (MT) potential. The aim of the present study was to evaluate current evidence on the MT of CHC and to determine the variables which have the greatest influence on cancer development. Bibliographical searches included PubMed, Embase, Web of Science, Scopus and LILACS. The cohort studies and case series used to investigate the MT of CHC were deemed suitable for inclusion. The quality of the enrolled studies was measured by the Joanna Briggs Institute scale. Moreover, we undertook subgroup analyses, assessed small study effects, and conducted sensitivity analyses. From 338 studies, nine were finally included for qualitative/quantitative analysis. The overall MT rate for CHC across all studies was 12.1% (95% confidential interval, 4.1–19.8%). Subgroup analysis showed that the MT rate increased when pooled analysis was restricted to poor quality studies. It remains complex to affirm whether CHC is an individual and oral, potentially malignant disorder according to the retrieved evidence. Prospective cohort studies to define the natural history of CHC and a consensus statement to clarify a proper set of diagnostic criteria are strongly needed. PROSPERO ID: CRD42022319572. Full article

(This article belongs to the Special Issue Diagnosis and Treatments of Invasive Fungal Diseases)

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