Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A . fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A . fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A . fumigatus . This review paper comprehensively discusses the current clinical challenges caused by A . fumigatus and provides insights on how to address them.

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“…2017 , Heldt et al. 2017 , 2018 , Jenks et al. 2019d ).…”

Section: Virulence Immunology and Pathogenesis Of Aspergillusmentioning

confidence: 99%

Aspergillus fumigatusand aspergillosis: From basics to clinics

Arastehfar

Carvalho

Houbraken

et al. 2021

Studies in Mycology

141

112

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“…In line with previous reports on hematological risk patients [ 21 , 22 , 23 ], we can also confirm IL-8 as a potential biomarker in a cohort also containing non-hematological patients, and further implement the utility and robustness of IL-8 measurement. Whereas IL-8 is mainly derived from the bronchopulmonary epithelium and antigen-presenting cells, such as alveolar macrophages [ 15 ], LBP mainly originates from hepatocytes [ 37 , 38 ], which might suggest induction via circulating fungal antigen after angioinvasion by Aspergillus hyphae or via systemic cytokine response. However, respiratory epithelial cells, known targets of A. fumigatus hyphae [ 39 ], were also shown to express LBP [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, these values strongly differ depending on the patient population addressed [ 8 ]. Although test sensitivity markedly increases in hematologic patients by implementation of serial testing [ 10 , 11 , 12 ], sensitivity rates are beneath 30% in patients receiving mold-active antifungal prophylaxis, in pediatric populations and in non-neutropenic patients, such as lung transplant recipients [ 13 , 14 , 15 , 16 ]. Testing of GM in BALF reveals higher sensitivity compared to GM in serum of neutropenic and non-neutropenic patients [ 16 ], but vary between 50% and 92% with corresponding specificities between 73% to 98% [ 14 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide Binding Protein and Bactericidal/Permeability-Increasing Protein as Biomarkers for Invasive Pulmonary Aspergillosis

Bülow

Heyd

Toelge

et al. 2020

JoF

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Early diagnosis of invasive pulmonary aspergillosis (IPA) is crucial to prevent lethal disease in immunocompromized hosts. So far, lipopolysaccharide binding protein (LBP) and bactericidal/permeability-increasing protein (BPI) levels have not been evaluated as biomarkers for IPA. IL-8, previously introduced as a biomarker for IPA, was also included in this study. Bronchoalveolar lavage fluid (BALF) of IPA patients and control patients with non-infectious lung disease was collected according to clinical indications. Measurements in BALF displayed significantly higher levels of LBP (p < 0.0001), BPI (p = 0.0002) and IL-8 (p < 0.0001) in IPA compared to control patients. Receiver operating characteristic curve analysis revealed higher AUC for LBP (0.98, 95% CI 0.95–1.00) than BPI (0.84, 95% CI 0.70–0.97; p = 0.0301). Although not significantly different, AUC of IL-8 (0.93, 95% CI 0.85–1.00) also tended to be higher than AUC for BPI (p = 0.0624). When the subgroup of non-hematological patients was analyzed, test performance of LBP (AUC 0.99, 95% CI 0.97–1.00), BPI (AUC 0.97, 95% CI 0.91–1.00) and IL-8 (AUC 0.96, 95% CI: 0.90–1.00) converged. In conclusion, LBP and—to a lesser extend—BPI displayed high AUCs that were comparable to those of IL-8 for diagnosis of IPA in BALF. Further investigations are worthwhile, especially in non-hematological patients in whom sensitive biomarkers for IPA are lacking.

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“…Given the reduced sensitivity of all diagnostic tests in the presence of mold-active antifungal prophylaxis or treatment, the combination of multiple diagnostic tests is warranted. Immunological markers may also be utilized as combination partners, and particularly high serum IL-8 levels (>300 pg/mL) have been shown to be highly specific for IA (50,(76)(77)(78), and have shown high sensitivity and specificity when combined with BALF LFD or BALF Aspergillus PCR (50). Larger multicenter studies are currently in progress to validate these findings.…”

Section: Nucleic-acid Based Assays/othersmentioning

confidence: 94%

Diagnosis of Breakthrough Fungal Infections in the Clinical Mycology Laboratory: An ECMM Consensus Statement

Jenks¹,

Gangneux²,

Schwartz³

et al. 2020

Preprint

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Breakthrough invasive fungal infections (bIFI) cause significant morbidity and mortality. Their diagnosis can be challenging due to reduced sensitivity of conventional culture techniques, serologic tests, and PCR-based assays in patients on antifungal therapy, and their diagnosis can be delayed contributing to poor patient outcomes. In this review, we provide consensus recommendations on behalf of the European Confederation for Medical Mycology (ECMM) for the diagnosis of bIFI caused by invasive yeasts, molds, and endemic mycoses, to guide diagnostic efforts in patients receiving antifungals and support the design of future clinical trials in the field of clinical mycology. The cornerstone of lab-based diagnosis of breakthrough infections for yeast and endemic mycoses remain conventional culture, to accurately identify the causative pathogen and allow for antifungal susceptibility testing. The impact of non-culture-based methods are not well-studied for the definite diagnosis of breakthrough invasive yeast infections. Non-culture-based methods have an important role for the diagnosis of breakthrough invasive mold infections, in particular invasive aspergillosis, and a combination of testing involving conventional culture, antigen-based assays, and PCR-based assays should be considered. Multiple diagnostic modalities, including histopathology, culture, antibody and/or antigen tests and occasionally PCR-based assays may be required to diagnose breakthrough endemic mycoses. A need exists for diagnostic tests that are effective, simple, cheap, and rapid to enable the diagnosis of bIFI in patients taking antifungals.

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Immune Parameters for Diagnosis and Treatment Monitoring in Invasive Mold Infection

Cited by 16 publications

References 75 publications

Aspergillus fumigatusand aspergillosis: From basics to clinics

Aspergillus fumigatusand aspergillosis: From basics to clinics

Lipopolysaccharide Binding Protein and Bactericidal/Permeability-Increasing Protein as Biomarkers for Invasive Pulmonary Aspergillosis

Diagnosis of Breakthrough Fungal Infections in the Clinical Mycology Laboratory: An ECMM Consensus Statement

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