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The Lancet. Infectious Diseases Jul 2024Current estimates of fungal disease incidence and mortality are imprecise. Population at risk denominators were used to estimate annual incidence for 2019-21. Extensive... (Review)
Review
Current estimates of fungal disease incidence and mortality are imprecise. Population at risk denominators were used to estimate annual incidence for 2019-21. Extensive literature searches from 2010 to 2023 were combined with over 85 papers on individual country and global disease burden. Crude and attributable mortality were estimated using a combination of untreated mortality, the proportion of patients who are treated, and percentage survival in treated patients. Awareness, guidelines, and accessibility of diagnostics and therapies informed the ratio of treated to untreated cases. Estimates do not include influenza or COVID-19 outbreaks. Data from more than 120 countries were included. Annually, over 2 113 000 people develop invasive aspergillosis in the context of chronic obstructive pulmonary disease, intensive care, lung cancer, or haematological malignancy, with a crude annual mortality of 1 801 000 (85·2%). The annual incidence of chronic pulmonary aspergillosis is 1 837 272, with 340 000 (18·5%) deaths. About 1 565 000 people have a Candida bloodstream infection or invasive candidiasis each year, with 995 000 deaths (63·6%). Pneumocystis pneumonia affects 505 000 people, with 214 000 deaths (42·4%). Cryptococcal meningitis affects 194 000 people, with 147 000 deaths (75·8%). Other major life-threatening fungal infections affect about 300 000 people, causing 161 000 deaths (53·7%). Fungal asthma affects approximately 11·5 million people and might contribute to 46 000 asthma deaths annually. These updated estimates suggest an annual incidence of 6·5 million invasive fungal infections and 3·8 million deaths, of which about 2·5 million (68%; range 35-90) were directly attributable.
Topics: Humans; Incidence; Global Health; Mycoses
PubMed: 38224705
DOI: 10.1016/S1473-3099(23)00692-8 -
Clinical Microbiology Reviews Sep 2023Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges... (Review)
Review
Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by and spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for spp. or galactomannan testing and PCR for spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for endocarditis or voriconazole therapy for endocarditis.
Topics: Humans; Mycoses; Endocarditis; Endocarditis, Bacterial; Antifungal Agents; Candidiasis; Candida; Aspergillus
PubMed: 37439685
DOI: 10.1128/cmr.00019-23 -
Molecular Aspects of Medicine Dec 2023Invasive fungal diseases are common complications in critically ill patients and in those with significant underlying imbalanced immune systems. Fungal co-, and/or... (Review)
Review
Invasive fungal diseases are common complications in critically ill patients and in those with significant underlying imbalanced immune systems. Fungal co-, and/or super-infections are emerging and have become a rising concern within the last few years. In Europe, cases of candidiasis and aspergillosis dominate, followed by mucormycosis in India. Epidemiological studies show an increasing trend in the incidence of all three entities. Parallel to this, a shift within the underlying fungal pathogens is observed. More non-albicans Candida infections and aspergillosis with cryptic species are on the rise; cryptic species may cover intrinsic resistance to azoles and other antifungal drugs. The recent COVID-19 pandemic led to a significantly increasing incidence of invasive fungal diseases among hospitalized patients.
Topics: Humans; Pandemics; Mycoses; Antifungal Agents; Aspergillosis
PubMed: 37804792
DOI: 10.1016/j.mam.2023.101215 -
Nature Reviews. Immunology Jul 2023Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and... (Review)
Review
Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.
Topics: Animals; Humans; Mycoses; Fungi; Antifungal Agents; Immunity; Mammals
PubMed: 36600071
DOI: 10.1038/s41577-022-00826-w -
Pharmacotherapy Oct 2023Triazole antifungals (i.e., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) are commonly used in clinical practice to prevent or treat invasive... (Review)
Review
Utility of triazole antifungal therapeutic drug monitoring: Insights from the Society of Infectious Diseases Pharmacists: Endorsed by the Mycoses Study Group Education and Research Consortium.
Triazole antifungals (i.e., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) are commonly used in clinical practice to prevent or treat invasive fungal infections. Most triazole antifungals require therapeutic drug monitoring (TDM) due to highly variable pharmacokinetics, known drug interactions, and established relationships between exposure and response. On behalf of the Society of Infectious Diseases Pharmacists (SIDP), this insight describes the pharmacokinetic principles and pharmacodynamic targets of commonly used triazole antifungals and provides the rationale for utility of TDM within each agent.
Topics: Humans; Antifungal Agents; Drug Monitoring; Pharmacists; Mycoses; Triazoles; Voriconazole; Communicable Diseases
PubMed: 37459118
DOI: 10.1002/phar.2850 -
Journal de Mycologie Medicale Aug 2023Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease characterized by a complex allergic inflammatory reaction of airways against Aspergillus affecting... (Review)
Review
Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease characterized by a complex allergic inflammatory reaction of airways against Aspergillus affecting patients with chronic respiratory diseases (asthma, cystic fibrosis). Exacerbation is often the way to diagnose ABPA and marks its evolution by its recurrent character leading to cortico-requirement or long-term antifungal treatment. Early diagnosis allows treatment of ABPA at an initial stage, preventing recurrence of exacerbations and long-term complications, mainly represented by bronchiectasis. This review of the literature aims to present the current state of the art in terms of diagnosis and treatment of ABPA from a multidisciplinary perspective. As there is no clinical, biological nor radiological specific sign, diagnostic criteria are regularly revised. They are mainly based on the elevation of total and specific IgE against Aspergillus fumigatus and the presence of suggestive CT abnormalities such as mucoid impaction and consolidations. ABPA management includes eviction of mold and pharmacological therapy. Exacerbations are treated in first line with a moderate dose of oral corticosteroids. Azole antifungal agents represent an alternative for the treatment of exacerbations and are the preferential strategy to reduce the future risk of exacerbations and for corticosteroids sparing. Asthma biologics may be of interest; however, their place remains to be determined. Avoiding complications of ABPA while limiting the side effects of systemic drugs remains a major challenge of ABPA management. Several drugs, including new antifungals and asthma biologics, are currently being tested and may be useful in the future.
Topics: Humans; Aspergillosis, Allergic Bronchopulmonary; Asthma; Aspergillus fumigatus; Adrenal Cortex Hormones; Antifungal Agents; Biological Products
PubMed: 37172543
DOI: 10.1016/j.mycmed.2023.101392 -
Molecular Aspects of Medicine Aug 2023The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp.,... (Review)
Review
The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches.
Topics: Humans; Antifungal Agents; Mycoses; Risk Factors; Immunocompromised Host
PubMed: 37207579
DOI: 10.1016/j.mam.2023.101190 -
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 -
Mycopathologia Oct 2023Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of... (Review)
Review
Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.
Topics: Humans; Aspergillosis; Antifungal Agents; Mycoses; Invasive Fungal Infections; Azoles; Drug Resistance, Fungal
PubMed: 37100963
DOI: 10.1007/s11046-023-00727-z -
The New England Journal of Medicine Feb 2024
Review
Topics: Humans; Blastomycosis; Coccidioidomycosis; Histoplasmosis; Immunocompetence
PubMed: 38324487
DOI: 10.1056/NEJMra2306821