Aspergillus-Associated Endophenotypes in Bronchiectasis

Abstract

Bronchiectasis is a chronic condition of global relevance resulting in permanent and irreversible structural airway damage. Bacterial infection in bronchiectasis is well studied; however, recent molecular studies identify fungi as important pathogens, either independently or in association with bacteria. Aspergillus species are established fungal pathogens in cystic fibrosis and their role is now increasingly being recognized in noncystic fibrosis bronchiectasis. While the healthy airway is constantly exposed to ubiquitously present Aspergillus conidia in the environment, anatomically damaged airways appear more prone to colonization and subsequent infection by this fungal group. Aspergilli possess diverse immunopathological mechanistic capabilities and when coupled with innate immune defects in a susceptible host, such as that observed in bronchiectasis, it may promote a range of clinical manifestations including sensitization, allergic bronchopulmonary aspergillosis, Aspergillus bronchitis, and/or invasive aspergillosis. How such clinical states influence “endophenotypes” in bronchiectasis is therefore of importance, as each Aspergillus-associated disease state has overlapping features with bronchiectasis itself, and can evolve, depending on underlying host immunity from one type into another. Concurrent Aspergillus infection complicates the clinical course and exacerbations in bronchiectasis and therefore dedicated research to better understand the Aspergillus-host interaction in the bronchiectasis airway is now warranted.

Clinical Aspergillus Signatures in COPD and Bronchiectasis

“…While our clinical, microbiological, and molecular understanding of Aspergillus signatures in COPD and bronchiectasis have advanced in recent years, an appreciation of the ‘overlap’ between the two conditions provides additional challenges [ 6 , 19 , 43 , 44 ]. In a prospective, observational, and cross-sectional study of individuals with COPD, bronchiectasis, and bronchiectasis-COPD overlap (BCO), those in the latter group demonstrated the highest frequency and clinical severity of ABPA compared to individuals with an absence of overlap [ 45 ].…”

“…Microorganisms, such as P. aeruginosa, H. influenzae , and non-tuberculous mycobacteria (NTM), are all commonly isolated in airways with bronchiectasis [ 24 , 108 , 110 , 111 ]. Fungi, notably Aspergillus, are increasingly being recognized as potential pathogens in both cystic fibrosis (CF) and non-CF bronchiectasis with an association with airway inflammation and disease severity [ 5 , 6 , 8 , 112 , 113 , 114 , 115 , 116 ]. Impaired mucociliary clearance and mucus-congested airways present an ideal environment for fungal colonization and sporulation.…”

“…A. fumigatus conidia evade phagocytic defenses and replicate in the airway, leading to further inflammation and damage [ 121 , 122 , 123 ]. Such complex airway interactions between the host and fungi induce airway remodeling, propagating further destruction and worsening bronchiectasis [ 5 , 6 ]. While traditional fungal culture and microscopy remain in routine use, they have more recently been superseded by molecular biology (qPCR) and NGS approaches [ 124 ].…”

“…Microbes play a central role in the pathogenesis and progression of chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD) and bronchiectasis [ 1 , 2 , 3 , 4 ]. While bacterial infection has been well-studied, the precise role of fungi remains uncertain [ 1 , 2 , 5 , 6 ]. Recent work by our group and others has brought about renewed interest and focus on this important knowledge gap, and demonstrates the important and underappreciated role of fungi and the mycobiome in COPD and bronchiectasis [ 5 , 7 , 8 , 9 , 10 ].…”

“…Patients with COPD and bronchiectasis remain predisposed to Aspergillus -associated conditions ranging from asymptomatic colonization to Aspergillus sensitization (AS) or Aspergillus bronchopulmonary aspergillosis (ABPA) in immune-hypersensitive patients. In those with relative or frank immunodeficiency, chronic and/or invasive pulmonary aspergillosis (CPA or IPA) may be seen, with the latter usually characterized by late diagnosis and high mortality [ 6 , 16 , 17 ]. Fungi represent a microbial kingdom comprising more than 1.5 million estimated species, with the majority being unculturable using standard laboratory media [ 21 , 22 ].…”