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Infectious Disease Clinics of North... Jun 2021Mucormycosis is a rare but aggressive fungal disease that mainly affects patients with poorly controlled diabetes mellitus and those who are severely immunocompromised,... (Review)
Review
Mucormycosis is a rare but aggressive fungal disease that mainly affects patients with poorly controlled diabetes mellitus and those who are severely immunocompromised, including patients with hematological malignancies and solid organ transplant recipients. Early recognition of infection is critical for treatment success, followed by prompt initiation of antifungal therapy with lipid formulation amphotericin B. Posaconazole and isavuconazole should be used for stepdown and salvage therapy. Surgical debridement is key for tissue diagnosis and treatment and should be pursued urgently whenever possible. In addition to surgery and antifungal therapy, reverting the underlying risk factor for infection is important for treatment response.
Topics: Antifungal Agents; Diabetes Mellitus, Type 2; Humans; Immunocompromised Host; Mucorales; Mucormycosis
PubMed: 34016285
DOI: 10.1016/j.idc.2021.03.009 -
Microbiology Spectrum Jun 2017Fungi must meet four criteria to infect humans: growth at human body temperatures, circumvention or penetration of surface barriers, lysis and absorption of tissue, and... (Review)
Review
Fungi must meet four criteria to infect humans: growth at human body temperatures, circumvention or penetration of surface barriers, lysis and absorption of tissue, and resistance to immune defenses, including elevated body temperatures. Morphogenesis between small round, detachable cells and long, connected cells is the mechanism by which fungi solve problems of locomotion around or through host barriers. Secretion of lytic enzymes, and uptake systems for the released nutrients, are necessary if a fungus is to nutritionally utilize human tissue. Last, the potent human immune system evolved in the interaction with potential fungal pathogens, so few fungi meet all four conditions for a healthy human host. Paradoxically, the advances of modern medicine have made millions of people newly susceptible to fungal infections by disrupting immune defenses. This article explores how different members of four fungal phyla use different strategies to fulfill the four criteria to infect humans: the Entomophthorales, the Mucorales, the Ascomycota, and the Basidiomycota. Unique traits confer human pathogenic potential on various important members of these phyla: pathogenic Onygenales comprising thermal dimorphs such as and ; the spp. that infect immunocompromised as well as healthy humans; and important pathogens of immunocompromised patients-, , and spp. Also discussed are agents of neglected tropical diseases important in global health such as mycetoma and paracoccidiomycosis and common pathogens rarely implicated in serious illness such as dermatophytes. Commensalism is considered, as well as parasitism, in shaping genomes and physiological systems of hosts and fungi during evolution.
Topics: Ascomycota; Basidiomycota; Biological Evolution; Body Temperature; Entomophthorales; Fungi; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunocompromised Host; Mucorales; Mycetoma; Mycoses; Opportunistic Infections; Phylogeny; Virulence
PubMed: 28597822
DOI: 10.1128/microbiolspec.FUNK-0014-2016 -
Medical Mycology Apr 2018The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common... (Review)
Review
The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.
Topics: Antifungal Agents; Combined Modality Therapy; Debridement; Diagnostic Imaging; Early Diagnosis; Humans; Microbiological Techniques; Molecular Diagnostic Techniques; Mucorales; Mucormycosis
PubMed: 29538730
DOI: 10.1093/mmy/myx101 -
Frontiers in Cellular and Infection... 2023Mucormycosis (MCR) is an emerging and frequently lethal fungal infection caused by the Mucorales family, with , , and , accounting for > 90% of all cases. MCR is seen in... (Review)
Review
Mucormycosis (MCR) is an emerging and frequently lethal fungal infection caused by the Mucorales family, with , , and , accounting for > 90% of all cases. MCR is seen in patients with severe immunosuppression such as those with hematologic malignancy or transplantation, Diabetes Mellitus (DM) and diabetic ketoacidosis (DKA) and immunocompetent patients with severe wounds. The recent SARS COV2 epidemy in India has resulted in a tremendous increase in MCR cases, typically seen in the setting of uncontrolled DM and corticosteroid use. In addition to the diversity of affected hosts, MCR has pleiotropic clinical presentations, with rhino-orbital/rhino-cerebral, sino-pulmonary and necrotizing cutaneous forms being the predominant manifestations. Major insights in MCR pathogenesis have brought into focus the host receptors (GRP78) and signaling pathways (EGFR activation cascade) as well as the adhesins used by Mucorales for invasion. Furthermore, studies have expanded on the importance of iron availability and the complex regulation of iron homeostasis, as well as the pivotal role of mycotoxins as key factors for tissue invasion. The molecular toolbox to study Mucorales pathogenesis remains underdeveloped, but promise is brought by RNAi and CRISPR/Cas9 approaches. Important recent advancements have been made in early, culture-independent molecular diagnosis of MCR. However, development of new potent antifungals against Mucorales remains an unmet need. Therapy of MCR is multidisciplinary and requires a high index of suspicion for initiation of early Mucorales-active antifungals. Reversal of underlying immunosuppression, if feasible, rapid DKA correction and in selected patients, surgical debulking are crucial for improved outcomes.
Topics: Humans; Mucormycosis; Antifungal Agents; COVID-19; Mucorales; Diabetes Mellitus; Iron
PubMed: 37808914
DOI: 10.3389/fcimb.2023.1254919 -
Microbiology Spectrum Jun 2016Filamentous mycoses are often associated with significant morbidity and mortality. Prompt diagnosis and aggressive treatment are essential for good clinical outcomes in... (Review)
Review
Filamentous mycoses are often associated with significant morbidity and mortality. Prompt diagnosis and aggressive treatment are essential for good clinical outcomes in immunocompromised patients. The host immune response plays an essential role in determining the course of exposure to potential fungal pathogens. Depending on the effectiveness of immune response and the burden of organism exposure, fungi can either be cleared or infection can occur and progress to a potentially fatal invasive disease. Nonspecific cellular immunity (i.e., neutrophils, natural killer [NK] cells, and macrophages) combined with T-cell responses are the main immunologic mechanisms of protection. The most common potential mold pathogens include certain hyaline hyphomycetes, endemic fungi, the Mucorales, and some dematiaceous fungi. Laboratory diagnostics aimed at detecting and differentiating these organisms are crucial to helping clinicians make informed decisions about treatment. The purpose of this chapter is to provide an overview of the medically important fungal pathogens, as well as to discuss the patient characteristics, antifungal-therapy considerations, and laboratory tests used in current clinical practice for the immunocompromised host.
Topics: Antibodies, Fungal; Antifungal Agents; Aspergillus fumigatus; CD4-Positive T-Lymphocytes; Histoplasma; Humans; Immunocompromised Host; Mucorales; Mycoses
PubMed: 27337469
DOI: 10.1128/microbiolspec.DMIH2-0002-2015 -
Clinical Infectious Diseases : An... Sep 2022Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of...
BACKGROUND
Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of serum Mucorales quantitative polymerase chain reaction (qPCR) for the early diagnosis and follow-up of mucormycosis.
METHODS
We prospectively enrolled 232 patients with suspicion of invasive mold disease, evaluated using standard imaging and mycological procedures. Thirteen additional patients with proven or probable mucormycosis were included to analyze DNA load kinetics. Serum samples were collected twice-a-week for Mucorales qPCR tests targeting the Mucorales genera Lichtheimia, Rhizomucor, and Mucor/Rhizopus.
RESULTS
The sensitivity was 85.2%, specificity 89.8%, and positive and negative likelihood ratios 8.3 and 0.17, respectively in this prospective study. The first Mucorales qPCR-positive serum was observed a median of 4 days (interquartile range [IQR], 0-9) before sampling of the first mycological or histological positive specimen and a median of one day (IQR, -2 to 6) before the first imaging was performed. Negativity of Mucorales qPCR within seven days after liposomal-amphotericin B initiation was associated with an 85% lower 30-day mortality rate (adjusted hazard ratio = 0·15, 95% confidence interval [.03-.73], P = .02).
CONCLUSIONS
Our study argues for the inclusion of qPCR for the detection of circulating Mucorales DNA for mucormycosis diagnosis and follow-up after treatment initiation. Positive results should be added to the criteria for the consensual definitions from the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC), as already done for Aspergillus PCR.
Topics: Amphotericin B; Antifungal Agents; Early Detection of Cancer; Humans; Mucorales; Mucormycosis; Polymerase Chain Reaction; Prospective Studies
PubMed: 34986227
DOI: 10.1093/cid/ciab1066 -
Clinical Microbiology and Infection :... Jan 2019The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The epidemiology of mucormycosis in the era of modern diagnostics is relatively under-explored.
OBJECTIVES
To examine the contemporary epidemiology, clinical manifestations, diagnosis and causative pathogens of mucormycosis.
DATA SOURCES
Ovid MEDLINE and Ovid EMBASE from January 2000 to January 2017.
STUDY ELIGIBILITY CRITERIA
Published case reports/series of proven/probable mucormycosis.
PARTICIPANTS
Patients ≥18 years old.
METHODS
Patient characteristics, disease manifestations and causative pathogens were summarized descriptively. Categorical variables were assessed by chi-square test or Fischer's exact test, and continuous variables by the Wilcoxon-Mann-Whitney or Kruskal-Wallis test. Risk factors for the different clinical manifestations of mucormycosis were identified using multivariate logistic regression.
RESULTS
Initial database searches identified 3619 articles of which 600 (851 individual patient cases) were included in the final analysis. Diabetes mellitus was the commonest underlying condition (340/851, 40%) and was an independent risk for rhino-orbital-cerebral mucormycosis (odds ratio (OR) 2.49; 95% CI 1.77-3.54; p < 0.001). Underlying haematological malignancy was associated with disseminated infection (OR 3.86; 95% CI 1.78-8.37; p 0.001), whereas previous solid organ transplantation was associated with pulmonary (OR 3.19; 95% CI 1.50-6.82; p 0.003), gastrointestinal (OR 4.47; 95% CI 1.69-11.80; p 0.003), or disseminated (OR 4.20; 95% CI 1.68-10.46; p 0.002) mucormycosis. Eight genera (24 species) of Mucorales organisms were identified in 447/851 (53%) cases, of which Rhizopus spp. (213/447, 48%) was the most common. Compared with other genera, Rhizopus spp. was predominantly observed in patients with rhino-orbital-cerebral mucormycosis (75/213, 35% versus 34/234, 15%; p < 0.001). Death was reported in 389/851 (46%) patients. Mortality associated with Cunninghamella infections was significantly higher than those caused by other Mucorales (23/30, 71% versus 185/417, 44%; p < 0.001). However, Cunninghamella spp. were isolated primarily in patients with pulmonary (17/30, 57%) or disseminated disease (10/30, 33%).
CONCLUSIONS
Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.
Topics: Diabetes Mellitus; Hematologic Neoplasms; Humans; Mucorales; Mucormycosis; Rhizopus; Risk Factors
PubMed: 30036666
DOI: 10.1016/j.cmi.2018.07.011 -
Medecine Sciences : M/S Mar 2013
Topics: France; Humans; Immunocompromised Host; Mucorales; Mucormycosis
PubMed: 23510517
DOI: 10.1051/medsci/201329s101 -
Current Opinion in Infectious Diseases Dec 2013Mucormycosis is an increasingly common fungal infection with unacceptably high mortality. The recent sequencing genome projects of Mucorales and the development of gene... (Review)
Review
PURPOSE OF REVIEW
Mucormycosis is an increasingly common fungal infection with unacceptably high mortality. The recent sequencing genome projects of Mucorales and the development of gene manipulation have enabled significant advances in understanding the pathogenesis of mucormycosis. Therefore, we review the pathogenesis of mucormycosis and highlight potential development of novel diagnostic and therapeutic modalities against this lethal disease.
RECENT FINDINGS
Much of the work has been focused on the role of iron uptake in the virulence of Mucorales. Additionally, host receptors and fungal ligands involved in the process of tissue invasion as well as sporangiospore size and sex loci and their contribution to virulence of Mucorales are discussed. Finally, the role of innate and adaptive immunity in protection against Mucorales and new evidence about drug-induced apoptosis in these fungi are discussed.
SUMMARY
Recent discoveries introduce several potentially novel diagnostic and therapeutic modalities, which are likely to improve management and outcome for mucormycosis. Future preclinical and clinical research is warranted to develop these diagnostic and therapeutic strategies.
Topics: Antifungal Agents; Azoles; Host-Pathogen Interactions; Humans; Immunocompromised Host; Iron; Mucorales; Mucormycosis; Risk Factors
PubMed: 24126718
DOI: 10.1097/QCO.0000000000000008 -
Genes Mar 2020The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited... (Review)
Review
The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis.
Topics: Drug Resistance, Fungal; Genes, Fungal; Host-Pathogen Interactions; Metabolic Networks and Pathways; Mucorales
PubMed: 32188171
DOI: 10.3390/genes11030317