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Journal de Mycologie Medicale Jun 2024Patients with hematological malignancies are at a high risk of developing invasive fungal infections (IFI) because they undergo several cycles of treatment leading to...
BACKGROUND
Patients with hematological malignancies are at a high risk of developing invasive fungal infections (IFI) because they undergo several cycles of treatment leading to episodes of neutropenia. In addition, they alternate between hospital stays and periods spent at home. Thus, when an IFI is diagnosed during their hospital stays, it is highly challenging to identify the origin of the fungal contamination. The objective of this study was to analyze at home fungal exposure of 20 patients with leukemia by taking air and water samples in their living residence.
METHODS
Air was sampled in 3 rooms of each home with a portable air system impactor. Tap water was collected at 3 water distribution points of each home. For positive samples, fungi were identified by mass spectrometry or on the basis of their morphological features.
RESULTS
85 % of homes revealed the presence in air of Aspergillus spp. and those belonging to the section Fumigati presented the highest concentrations and the greatest frequency of isolation. Concerning mucorales, Rhizopus spp. and Mucor spp. were isolated in air of 20 % and 5 % of dwellings, respectively. In 4 homes, more than 70 % of the fungal species identified in air were potential opportunists; these were mainly Aspergillus spp. with concentrations greater than 20 cfu/m. The water samples revealed the presence of Fusarium in 3 dwellings, with concentrations up to 80 cfu/L. Finally, for one patient, fungal species isolated during a period of hospitalization were phenotypically similar to those isolated in samples taken at home. For a second patient, a PCR Mucorale was positive on a sample of bronchoalveolar fluid while air samples taken at his home also revealed also the presence of mucorales.
CONCLUSION
The presence of opportunistic fungal species in the air of all the explored homes suggests the need for strengthened preventive measures in the home of immunocompromised patients. It would be interesting to compare the fungi isolated (from patients and from their environment) by genotyping studies aimed at specifying the correspondence existing between fungal species present in the patients' homes and those responsible for IFI in the same patients.
PubMed: 38865808
DOI: 10.1016/j.mycmed.2024.101492 -
Mycopathologia Jun 2024Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human...
Aspergillus fumigatus is a saprophytic fungal pathogen that causes opportunistic infections in animals and humans. Azole resistance has been reported globally in human A. fumigatus isolates, but the prevalence of resistance in isolates from animals is largely unknown. A retrospective resistance surveillance study was performed using a collection of clinical A. fumigatus isolates from various animal species collected between 2015 and 2020. Agar-based azole resistance screening of all isolates was followed by in vitro antifungal susceptibility testing and cyp51A gene sequencing of the azole-resistant isolates. Over the 5 year period 16 (11.3%) of 142 A. fumigatus culture-positive animals harbored an azole-resistant isolate. Resistant isolates were found in birds (15%; 2/13), cats (21%; 6/28), dogs (8%; 6/75) and free-ranging harbor porpoise (33%; 2/6). Azole-resistance was cyp51A mediated in all isolates: 81.3% (T-67G/)TR/L98H, 12.5% TR/Y121F/T289A. In one azole-resistant A. fumigatus isolate a combination of C(-70)T/F46Y/C(intron7)T/C(intron66)T/M172V/E427K single-nucleotide polymorphisms in the cyp51A gene was found. Of the animals with an azole-resistant isolate and known azole exposure status 71.4% (10/14) were azole naive. Azole resistance in A. fumigatus isolates from animals in the Netherlands is present and predominantly cyp51A TR-mediated, supporting an environmental route of resistance selection. Our data supports the need to include veterinary isolates in resistance surveillance programs. Veterinarians should consider azole resistance as a reason for therapy failure when treating aspergillosis and consider resistance testing of relevant isolates.
Topics: Aspergillus fumigatus; Animals; Azoles; Drug Resistance, Fungal; Aspergillosis; Antifungal Agents; Netherlands; Microbial Sensitivity Tests; Retrospective Studies; Fungal Proteins; Birds; Cats; Dogs; Cytochrome P-450 Enzyme System
PubMed: 38864903
DOI: 10.1007/s11046-024-00850-5 -
Nature Communications Jun 2024More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most...
More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.
Topics: Aspergillus fumigatus; Animals; Antifungal Agents; Protein Serine-Threonine Kinases; Fungal Proteins; Mice; Protein-Tyrosine Kinases; Dyrk Kinases; Azoles; Aspergillosis; Lung; Spores, Fungal; Female
PubMed: 38862481
DOI: 10.1038/s41467-024-48592-8 -
Turkish Journal of Ophthalmology Jun 2024A 78-year-old man with a history of lung cancer, chemotherapy, radiotherapy, and coronavirus disease 2019 infection experienced visual deterioration of two-weeks’...
A 78-year-old man with a history of lung cancer, chemotherapy, radiotherapy, and coronavirus disease 2019 infection experienced visual deterioration of two-weeks’ duration in his right eye. There was multifocal, yellowish-white retinitis foci, vascular engorgement, and scattered intraretinal hemorrhages extending from posterior pole to retinal periphery in the right eye, whereas the left eye was normal. Intravitreal vancomycin, ceftazidime, clindamycin, and dexamethasone were given for endogenous endophthalmitis initially. Vitreous culture confirmed the presence of Aspergillus lentulus, and he was treated with intravitreal amphotericin-B and voriconazole injections together with systemic amphotericin-B, voriconazole, posaconazole, and micafungin therapy. During follow-up, vitreoretinal surgery was performed because of rhegmatogenous retinal detachment, and he received one additional cycle of chemotherapy due to recurrence of the cancer. Although the retina was attached, enucleation was eventually required due to painful red eye. Atypical squamous cells beneath the neurosensory retina suggesting metastasis were noted on histopathological examination. Timely ocular examination is crucial for any immunocompromised patient having ocular symptoms. High level of suspicion for a fungal etiology is a must in these patients.
Topics: Humans; Endophthalmitis; Male; Aged; Eye Infections, Fungal; Immunocompromised Host; Lung Neoplasms; Aspergillosis; Aspergillus; Antifungal Agents; COVID-19; Vitreous Body; Intravitreal Injections; SARS-CoV-2
PubMed: 38860516
DOI: 10.4274/tjo.galenos.2024.44045 -
Journal of Inflammation Research 2024
Response to "Prevalence, Risk Factors, and Mortality of Invasive Pulmonary Aspergillosis in Patients with Anti-MDA5 + Dermatomyositis: A Retrospective Study in China" [Letter].
PubMed: 38855166
DOI: 10.2147/JIR.S479288 -
Communications Biology Jun 2024Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates....
Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.
Topics: Aspergillus fumigatus; Sirtuins; Virulence; Animals; Mice; Aspergillosis; Acetylation; Fungal Proteins; Gene Expression Regulation, Fungal; Virulence Factors; Moths
PubMed: 38851817
DOI: 10.1038/s42003-024-06383-3 -
European Journal of Case Reports in... 2024A patient initially treated with corticosteroids for cryptogenic organising pneumonia following pulmonary infarction, developed a worsening condition with progressive...
UNLABELLED
A patient initially treated with corticosteroids for cryptogenic organising pneumonia following pulmonary infarction, developed a worsening condition with progressive cavitary formations in both lower lung lobes. Contrast-enhanced chest computed tomography revealed a pulmonary embolism, and serum anti-Aspergillus IgG antibody analysis yielded a strong positive result. Consequently, the patient was diagnosed with pulmonary infarction with Aspergillus infection; organising pneumonia in surrounding areas reflected the repair process. Following treatment with anticoagulants and antifungal agents, the patient was successfully discharged. Hence, pulmonary infarction should be considered in cases of refractory lung lesions.
LEARNING POINTS
Pulmonary infarction should be considered in case of refractory lung lesions, even if the patient does not have the risk of embolism.Organising pneumonia should be assessed carefully because it may occur as a repair process of various lung diseases.
PubMed: 38846666
DOI: 10.12890/2024_004501 -
Therapeutic Advances in Infectious... 2024, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called... (Review)
Review
BACKGROUND
, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called aspergillosis. This study comprehensively analyzed data on aspergillosis in published articles from mainland China to investigate the prevalence of , and risk factors, mortality rate, and underlying condition associated with aspergillosis.
METHODS
Published articles were retrieved from Google Scholar, PubMed, and Science Direct online search engines. In the 101 analyzed studies, 3558 isolates were meticulously collected and classified. GraphPad Prism 8 was used to statistically examine the epidemiology and clinical characteristics of aspergillosis.
RESULTS
was prominently reported ( = 2679, 75.14%), followed by ( = 437, 12.25%), ( = 219, 6.14%), and ( = 119, 3.33%). Of a total of 9810 patients, 7513 probable cases accounted for the highest number, followed by confirmed cases ( = 1956) and possible cases ( = 341). In patients, cough emerged as the most common complaint ( = 1819, 18.54%), followed by asthma ( = 1029, 10.48%) and fever (1024, 10.44%). Of total studies, invasive pulmonary aspergillosis (IPA) was reported in 47 (45.53%) studies, exhibiting an increased prevalence in Beijing ( = 12, 25.53%), Guangdong ( = 7, 14.89%), and Shanghai ( = 6, 12.76%). Chronic pulmonary aspergillosis (CPA) was reported in 14 (13.86%) studies. Among the total of 14 studies, the occurrence of CPA was 5 (35.71%) in Beijing and 3 (21.42%) in Shanghai. Allergic bronchopulmonary aspergillosis (ABPA), was reported at a lower frequency ( = 8, 7.92%), Guangdong recorded a relatively high number ( = 3, 37.5%), followed by Beijing ( = 2, 25.0%), and Shanghai ( = 1, 12.5%). Percentage of death reported: IPA had the highest rate ( = 447, 68.87%), followed by CPA ( = 181, 27.88%) and ABPA ( = 14, 2.15%). Among the aspergillosis patients, 6220 had underlying conditions, including chronic lung disease ( = 3765, 60.53%), previous tuberculosis ( = 416, 6.68%), and organ transplant or organ failure ( = 648, 10.41%). Aspergillosis was also found in patients using corticosteroid therapy ( = 622, 10.0%).
CONCLUSION
This review sheds light on the prevalence patterns of species, risk factors of aspergillosis, and gaps in surveillance that could be helpful for the control and treatment of aspergillosis and guide the researchers in future studies.
REGISTRATION
This systematic review was prospectively registered on PROSPERO: Registration ID CRD42023476870.
PubMed: 38835831
DOI: 10.1177/20499361241252537 -
Contemporary Clinical Trials... Jun 2024During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections...
BACKGROUND
During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, those with severe COVID-19 infection were at risk for a number of opportunistic infections including COVID-19-associated pulmonary aspergillosis (CAPA). We initiated a randomized clinical trial to evaluate whether isavuconazole, a triazole antifungal, could prevent CAPA and improve survival in patients admitted to the ICU with severe COVID-19 infection.
METHODS
We designed a phase III/IV randomized, double-blind, two-arm, placebo-controlled trial evaluating standard of care (SOC) plus isavuconazole versus SOC plus placebo and were to enroll participants admitted to the ICU with severe COVID-19 infection at three medical centers in California, United States. The projected sample size was 162 participants.
RESULTS
Due to poor enrollment and the declining number of COVID-19 cases over time, the study was terminated after 7 participants were enrolled, all enrolled at one study site (UC San Diego Health). CAPA was suspected in two participants and they were started on open-label isavuconazole. One was withdrawn due to possible isavuconazole-related adverse side effects.
CONCLUSION
Enrollment was slower-than-expected due to multiple factors, including competing COVID-19-related studies and hesitancy from potential study participants or their families to join the study. Our experience highlights some of the difficulties in planning and running a clinical trial focused on fungal superinfections involving severely ill patients during the height of the COVID-19 pandemic. Lessons learned from this study will help in the design of proposed studies examining antifungal prophylaxis against aspergillosis following other severe respiratory viral infections.
PubMed: 38832095
DOI: 10.1016/j.conctc.2024.101310 -
Infection and Drug Resistance 2024Azole resistance in poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and...
PURPOSE
Azole resistance in poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and mutation profiles of isolates in Malaysia.
PATIENTS AND METHODS
Sixty clinical isolates were collected and subjected to antifungal susceptibility testing (AFST) and molecular analysis. The antifungal susceptibility testing was performed according to CLSI M38 guideline. The geometric mean (GM) minimum inhibitory concentration (MIC), MIC/MIC for voriconazole, itraconazole, posaconazole, amphotericin B, and isavuconazole against in non-invasive cases and invasive cases were calculated. In addition, the presence of mutations was also identified.
RESULTS
The present study revealed an overall resistance rate of 6.7% among the isolates. In non-invasive cases, isavuconazole and posaconazole demonstrated the lowest GM MIC of 0.08 µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.15µg/mL, 0.16µg/mL and 0.90µg/mL, respectively. Similarly, in invasive cases, isavuconazole and posaconazole exhibited the lowest GM MIC of 0.09µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.14µg/mL, 0.17µg/mL and 0.80µg/mL, respectively. Genotypic analysis revealed various mutations, including F46Y, M172V, N248K, R34L, V244A, V244S, and E427K. However, not all mutations corresponded to antifungal resistance.
CONCLUSION
The majority of clinical isolates demonstrated susceptibility to the antifungal agents tested, with isavuconazole and posaconazole demonstrating the lowest MIC values. However, mutations were discovered without a consistent correlation to antifungal resistance, emphasising the need for additional research.
PubMed: 38828376
DOI: 10.2147/IDR.S452619