A Novel Strategy to Identify Haematology Patients at High Risk of Developing Aspergillosis

Abstract

Invasive Aspergillosis (IA), typically caused by the fungus Aspergillus fumigatus, is a leading cause of morbidity and mortality in immunocompromised patients. IA remains a significant burden in haematology patients, despite improvements in the diagnosis and treatment of Aspergillus infection. Diagnosing IA is challenging, requiring multiple factors to classify patients into possible, probable and proven IA cohorts. Given the low incidence of IA, using negative results as exclusion criteria is optimal. However, frequent false positives and severe IA mortality rates in haematology patients have led to the empirical use of toxic, drug-interactive and often ineffective anti-fungal therapeutics. Improvements in IA diagnosis are needed to reduce unnecessary anti-fungal therapy. Early IA diagnosis is vital for positive patient outcomes; therefore, a pre-emptive approach is required. In this study, we examined the sequence and expression of four C-type Lectin-like receptors (Dectin-1, Dectin-2, Mincle, Mcl) from 42 haematology patients and investigated each patient’s anti-Aspergillus immune response (IL-6, TNF). Correlation analysis revealed novel IA disease risk factors which we used to develop a pre-emptive patient stratification protocol to identify haematopoietic stem cell transplant patients at high and low risk of developing IA. This stratification protocol has the potential to enhance the identification of high-risk patients whilst reducing unnecessary treatment, minimizing the development of anti-fungal resistance, and prioritising primary disease treatment for low-risk patients.

Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR1

“…Several factors influence MRD status and the subsequent outcomes of patients with IR-AML, including the chemotherapy intensity, infection, HSCT application, and survival [33][34][35]. Recently, a study indicates that highintensity relative to low-intensity chemotherapy results in higher rates of MRD-negative cases [35]; another study indicates that induction therapy of IDAC with daunorubicin and omacetaxine mepesuccinate increases survival in patients with AML aged 15-55 years relative to conventional-dose cytarabine [36].…”

Diagnosis values of Dectin-1 and IL-17 levels in plasma for invasive pulmonary aspergillosis in bronchiectasis

“…Similarly In a study of acute myeloid leukemia (AML) with Invasive fungal disease, it was found that Dectin-1 mRNA expression during hematopoietic regeneration was significantly lower compared to the later time point when the blood count was restored ( Fischer et al., 2016 ). Previous studies have shown that AML patients who developed Invasive Aspergillosis were 10.2 times more likely to have low Dectin-1 expression ( Griffiths et al., 2021b ). These study shows that during hematologic disease induced immunosuppression, the body’s immune response to fungal pathogens declines due to decreased Dectin-1 mRNA levels.…”

The Use of Host Biomarkers for the Management of Invasive Fungal Disease

“…Interestingly, patients that produced a TNF/IL-6 response following ex vivo PBMC stimulation did not develop IA. Suggesting this biomarker may reduce or even exclude patient's IA risk [90]. The results warrant further investigation primarily examining these host biomarkers in larger patient cohorts and combining them with conventional fungal and clinical biomarkers to enhance the predictive model.…”

“…The study retrospectively showed that 62.5% of SCT patients developed IA, when their PBMCs did not produce IL-6 or TNF in response to ex vivo stimulation with A. fumigatus while they produced IL-6 or TNF in response to LPS. The incidence of IA in a subset of SCT patients increased to 80% when IL-6/TNF production in response to A. fumigatus and LPS was combined with expression levels of Dectin-1 and Mcl as discussed in the previous section [90]. This study indicates that IL-6/TNF levels in response to A. fumigatus and LPS have the potential to be used as host biomarkers to demonstrate increased risk of IA but possibly aid diagnosis when used in combination with other host factors and mycological evidence.…”

“…Whilst the results lacked power due to sample size, patient groups with lower Dectin-1 expression were 10 times more likely to develop IA whilst patient groups with higher Mcl expression appeared less likely to develop IA. Interestingly, when results were combined with other biomarkers a predictive IFD incidence model was generated with promising retrospective conclusions that merit further investigation [90].…”