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

James S Griffiths,P Lewis White,Keith Wilson,Wendy Ingram,Selinda J Orr,Rosemary Barnes,Philip R Taylor,Diogo M Da Fonseca,Robert J Pickering,Aiysha Thompson

doi:10.3389/fimmu.2021.780160

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.

Highlights

Invasive aspergillosis (IA) has become a leading cause of death among immunocompromised patients [1,2,3]
The Dectin2 mutation resulted in an early stop codon and loss of the carbohydrate binding region whereas the Mcl mutation only resulted in a single amino acid substitution
Whilst we have described the significant association between Aspergillus-induced TNF and IL-6 and the incidence of IA, it was important to determine whether these results were specific for predicting IA or a more general indicator of poor patient prognosis

Summary

Introduction

Invasive aspergillosis (IA) has become a leading cause of death among immunocompromised patients [1,2,3]. The disease, mainly caused by Aspergillus fumigatus, affects ~ 10% of allogeneic stem cell transplant (SCT) patients and ~6% of acute myeloid leukaemia (AML) patients. IA is prevalent in patients with haematologic malignancies. This is attributed to the profound immune suppression and neutropenia brought about by the extensive therapeutic use of cytotoxic chemotherapies, radiation therapy, requirement for SCT and the use of corticosteroids and immunomodulatory therapies [10]. Whilst the diagnosis and treatment of Aspergillus infections is improving, severe IAassociated morbidity and mortality in haematology patients has led to the widespread, empirical use of anti-fungal prophylaxis in this patient group [11, 12]. Current anti-fungal therapeutics can be ineffective, encounter resistance, are poorly tolerated and highly drug interactive, often impacting patient’s primary cancer therapies [13]

Methods

Results

Discussion

Conclusion