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Open Forum Infectious Diseases Jun 2024An early diagnosis and treatment of invasive fungal disease (IFD) is associated with improved outcome, but the moderate sensitivity of noninvasive diagnostic tests makes...
BACKGROUND
An early diagnosis and treatment of invasive fungal disease (IFD) is associated with improved outcome, but the moderate sensitivity of noninvasive diagnostic tests makes this challenging. Invasive diagnostic procedures such as bronchoalveolar lavage (BAL) have a higher yield but are not without risk. The detection and sequencing of microbial cell-free DNA (mcfDNA) may facilitate a noninvasive diagnosis.
MATERIALS
In a prospective observational study, we collected plasma in the 120 hours preceding or following a BAL in patients with hematological malignancies suspected for a pulmonary IFD. The EORTC/MSGERC2020 criteria were used for IFD classification. Sequencing was performed by Karius (Redwood City, CA) using their Karius Test (KT) on plasma and a "research use only test" on BAL fluid if available. Cases with a probable/proven IFD were identified based on standard diagnostic tests on serum and BAL (microscopy, polymerase chain reaction, galactomannan, culture) and used to calculate the sensitivity, specificity, and additional diagnostic value of the KT.
RESULTS
Of 106 patients enrolled, 39 (37%) had a proven/probable invasive aspergillosis, 7 (7%) a non- IFD, and 4 (4%) a mixed IFD. The KT detected fungal mcfDNA in 29 (28%) patients. Compared with usual diagnostic tests, the sensitivity and specificity were 44.0% (95% confidence interval [CI], 31.2-57.7) and 96.6% (95% CI, 88.5%-99.1%). Sensitivity of the KT was higher in non- IFD (:2/3, : 3/5). On BAL, the sensitivity was 72.2% (95% CI, 62.1-96.3), and specificity 83.3% (95% CI, 49.1-87.5).
CONCLUSIONS
Sequencing of mcfDNA may facilitate a noninvasive diagnosis of IFD in particular non- IFD. However, on plasma and similar to currently available diagnostics, it cannot be used as a "rule-out" test.
PubMed: 38868302
DOI: 10.1093/ofid/ofae252 -
BMC Infectious Diseases Jun 2024Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
Several antifungal agents are available for primary therapy in patients with invasive aspergillosis (IA). Although a few studies have compared the effectiveness of different antifungal agents in treating IA, there has yet to be a definitive agreement on the best choice. Herein, we perform a network meta-analysis comparing the efficacy of different antifungal agents in IA.
METHODS
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Clinical Trials databases to find studies (both randomized controlled trials [RCTs] and observational) that reported on treatment outcomes with antifungal agents for patients with IA. The study quality was assessed using the revised tool for risk of bias and the Newcastle Ottawa scale, respectively. We performed a network meta-analysis (NMA) to summarize the evidence on antifungal agents' efficacy (favourable response and mortality).
RESULTS
We found 12 studies (2428 patients) investigating 11 antifungal agents in the primary therapy of IA. There were 5 RCTs and 7 observational studies. When treated with monotherapy, isavuconazole was associated with the best probability of favourable response (SUCRA, 77.9%; mean rank, 3.2) and the best reduction mortality against IA (SUCRA, 69.1%; mean rank, 4.1), followed by voriconazole and posaconazole. When treated with combination therapy, Liposomal amphotericin B plus caspofungin was the therapy associated with the best probability of favourable response (SUCRA, 84.1%; mean rank, 2.6) and the best reduction mortality (SUCRA, 88.2%; mean rank, 2.2) against IA.
CONCLUSION
These findings suggest that isavuconazole, voriconazole, and posaconazole may be the best antifungal agents as the primary therapy for IA. Liposomal amphotericin B plus caspofungin could be an alternative option.
Topics: Antifungal Agents; Humans; Network Meta-Analysis; Aspergillosis; Treatment Outcome; Caspofungin; Randomized Controlled Trials as Topic; Invasive Fungal Infections; Triazoles; Amphotericin B; Voriconazole; Nitriles; Pyridines
PubMed: 38867163
DOI: 10.1186/s12879-024-09477-9 -
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 -
The Pediatric Infectious Disease Journal Jun 2024Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients...
INTRODUCTION
Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients as well as in immunocompetent patients. Here, we present disseminated aspergillosis in a child with nephrotic syndrome treated with long-term and aggressive systemic antifungal treatment and intraventricular (IVent) liposomal amphotericin B (L-AmB) as well as surgical excision and drainage due to difficulty in management.
CASE REPORT
A 10-year-old boy with nephrotic syndrome on steroid therapy was admitted with limping and weakness. The cranial magnetic resonance imaging showed multiple intraparenchymal scattered abscesses. The largest one was excised and drained. Abscess culture revealed Aspergillus fumigatus and histopathological examination revealed septate hyphae compatible with Aspergillosis. Intravenous (IV) voriconazole was started, and IV L-AmB was added. The size of lesions and perilesional edema continued to increase, and then IVent L-AmB was added. With IVent and systemic antifungal treatment, regression of the lesions was observed. He was followed up with oral voriconazole and weekly IVent L-AmB. After 2 and a half months, he was re-operated because of increased lesion size, number and perilesional edema, and IV voriconazole and other salvage antifungal therapies were started. Since the lesions had decreased and remained stable, IV voriconazole was switched to oral therapy, and he was followed up as an outpatient. Immunodeficiency diseases were excluded by immunological and genetic tests.
CONCLUSION
Management of central nervous system aspergillosis can be challenging despite long-term and aggressive systemic and IVent antifungal treatment as well as surgical excision and drainage.
PubMed: 38865571
DOI: 10.1097/INF.0000000000004422 -
American Journal of Respiratory and... Jun 2024The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA)...
RATIONALE
The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza- or COVID-19-associated pulmonary aspergillosis (IAPA or CAPA) is yet to be explored.
OBJECTIVES
To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity and outcome in severe influenza versus COVID-19 with or without aspergillosis.
METHODS
We performed a retrospective study in mechanically ventilated influenza and COVID-19 patients with or without invasive aspergillosis in whom bronchoalveolar lavage (BAL) for bacterial culture (with or without PCR) was obtained within two weeks after ICU admission. Additionally, 16S rRNA gene sequencing data and viral and bacterial load of BAL samples from a subset of these patients, and of patients requiring non-invasive ventilation, were analyzed. We integrated 16S rRNA gene sequencing data with existing immune parameter datasets.
MEASUREMENTS AND MAIN RESULTS
Potential bacterial pathogens were detected in 20% (28/142) of influenza and 37% (104/281) of COVID-19 patients, while aspergillosis was detected in 38% (54/142) of influenza and 31% (86/281) of COVID-19 patients. A significant association between bacterial pathogens in BAL and 90-day mortality was found only in influenza patients, particularly IAPA patients. COVID-19 but not influenza patients showed increased pro-inflammatory pulmonary cytokine responses to bacterial pathogens.
CONCLUSIONS
Aspergillosis is more frequently detected in lungs of severe influenza patients than bacterial pathogens. Detection of bacterial pathogens associates with worse outcome in influenza patients, particularly in those with IAPA, but not in COVID-19 patients. The immunological dynamics of tripartite viral-fungal-bacterial interactions deserve further investigation. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
PubMed: 38865563
DOI: 10.1164/rccm.202401-0145OC -
Mycopathologia Jun 2024Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive... (Review)
Review
Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive aspergillosis. The human lung provides an entry door for Aspergillus. Aspergillus has virulence characteristics such as conidia, rapid growth at body temperature, and the production of specific proteins, carbohydrates, and secondary metabolites that allow A. fumigatus to infiltrate the lung's alveoli and cause invasive aspergillosis. Alveolar epithelial cells play an important role in both fungus clearance and immune cell recruitment via cytokine release. Although the innate immune system quickly clears conidia in immunocompetent hosts, A. fumigatus has evolved multiple virulence factors in order to escape immune response such as ROS detoxifying enzymes, the rodlet layer, DHN-melanin and toxins. Bacterial co-infections or interactions can alter the immune response, impact Aspergillus growth and virulence, enhance biofilm formation, confound diagnosis, and reduce treatment efficacy. The gut microbiome's makeup influences pulmonary immune responses generated by A. fumigatus infection and vice versa. The real-time PCR for Aspergillus DNA detection might be a particularly useful tool to diagnose pulmonary aspergillosis. Metagenomics analyses allow quick and easy detection and identification of a great variety of fungi in different clinical samples, although optimization is still required particularly for the use of NGS techniques. This review will analyze the current state of aspergillosis in light of recent discoveries in the microbiota and mycobiota.
Topics: Humans; Aspergillosis; Mycobiome; Aspergillus fumigatus; Aspergillus; Virulence Factors; Microbiota; Virulence; Metagenomics; Host-Pathogen Interactions
PubMed: 38864956
DOI: 10.1007/s11046-024-00853-2 -
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 Clinical Microbiology Jun 2024The diagnosis of invasive pulmonary fungal disease depends on histopathology and mycological culture; there are few studies on touch imprints of bronchoscopic biopsies...
Performance of rapid on-site evaluation of touch imprints of bronchoscopic biopsies or lung tissue biopsies for the diagnosis of invasive pulmonary filamentous fungi infections in non-neutropenic patients.
The diagnosis of invasive pulmonary fungal disease depends on histopathology and mycological culture; there are few studies on touch imprints of bronchoscopic biopsies or lung tissue biopsies for the diagnosis of pulmonary filamentous fungi infections. The purpose of the present study was to explore the detection accuracy of rapid on-site evaluation of touch imprints of bronchoscopic biopsies or lung tissue biopsies for the filamentous fungi, and it aims to provide a basis for initiating antifungal therapy before obtaining microbiological evidence. We retrospectively analyzed the diagnosis and treatment of 44 non-neutropenic patients with invasive pulmonary filamentous fungi confirmed by glactomannan assay, histopathology, and culture from February 2017 to December 2023. The diagnostic positive rate and sensitivity of rapid on-site evaluation for these filamentous fungi identification, including diagnostic turnaround time, were calculated. Compared with the final diagnosis, the sensitivity of rapid on-site evaluation was 81.8%, and the sensitivity of histopathology, culture of bronchoalveolar lavage fluid, and glactomannan assay of bronchoalveolar lavage fluid was 86.4%, 52.3%, and 68.2%, respectively. The average turnaround time of detecting filamentous fungi by rapid on-site evaluation was 0.17 ± 0.03 hours, which was significantly faster than histopathology, glactomannan assay, and mycological culture. A total of 29 (76.3%) patients received earlier antifungal therapy based on ROSE diagnosis and demonstrated clinical improvement. Rapid on-site evaluation showed good sensitivity and accuracy that can be comparable to histopathology in identification of pulmonary filamentous fungi. Importantly, it contributed to the triage of biopsies for further microbial culture or molecular detection based on the preliminary diagnosis, and the decision on early antifungal therapy before microbiological evidence is available.
PubMed: 38856218
DOI: 10.1128/jcm.00479-24