Chronic Rhinosinusitis and the Evolving Understanding of Microbial Ecology in Chronic Inflammatory Mucosal Disease

Abstract

Chronic rhinosinusitis (CRS) encompasses a heterogeneous group of debilitating chronic inflammatory sinonasal diseases. Despite considerable research, the etiology of CRS remains poorly understood, and debate on potential roles of microbial communities is unresolved. Modern culture-independent (molecular) techniques have vastly improved our understanding of the microbiology of the human body. Recent studies that better capture the full complexity of the microbial communities associated with CRS reintroduce the possible importance of the microbiota either as a direct driver of disease or as being potentially involved in its exacerbation. This review presents a comprehensive discussion of the current understanding of bacterial, fungal, and viral associations with CRS, with a specific focus on the transition to the new perspective offered in recent years by modern technology in microbiological research. Clinical implications of this new perspective, including the role of antimicrobials, are discussed in depth. While principally framed within the context of CRS, this discussion also provides an analogue for reframing our understanding of many similarly complex and poorly understood chronic inflammatory diseases for which roles of microbes have been suggested but specific mechanisms of disease remain unclear. Finally, further technological advancements on the horizon, and current pressing questions for CRS microbiological research, are considered.

FIG 1

Publication output between 1970 and 2015 in the field of microbiology and CRS. Data for the number of publications per year were generated by using the following Scopus database search string: TITLE-ABS (“chronic rhinosinusitis” OR “chronic sinusitis”) AND (TITLE-ABS [bacteria OR bacterial OR virus OR viral OR fungus OR fungi OR fungal OR microbe OR microbial OR microbiota OR microbiome OR infectious OR infection]) AND NOT (TITLE-ABS [review]) AND (PUBYEAR > 1970) AND (EXCLUDE [PUBYEAR, 2016]) (search date, 13 May 2016).

FIG 2

Shift in the perspective of mucosa-associated microbial communities from the culture era to the sequencing era in healthy and CRS states. (A) Previous culture-based assessments of sinonasal-associated microbiology in healthy subjects led to the view of the sinuses as being a predominantly sterile site and identified a relatively simple bacterial community associated with the nasal cavity. (B) Early culture-based assessment of CRS patients highlighted the possible role of putative bacterial and fungal pathogens in the development or progressive course of CRS. (C and D) Sequencing-era assessment of the microbiota subsequently identified markedly more diverse microbial communities associated with both healthy (C) and CRS (D) states, with little consensus emerging on unique associations with CRS.

FIG 3

Phenotypic heterogeneity of CRS on the basis of polyposis. Computed tomography scans show the differential extent of inflammation and sinonasal blockage in healthy subjects (A), patients with chronic rhinosinusitis without nasal polyps (B), and patients with chronic rhinosinusitis with nasal polyps (C).

FIG 4

Multifaceted interactions that may influence our understanding of CRS and the progressive course of chronic mucosal inflammation. The interacting effects of epithelial barrier integrity, the host immune response, the resident microbiota (including bacteria, fungi, viruses, and archaea), and treatment courses on one another are likely multidirectional and complex and remain poorly understood.

FIG 5

Primary diagnoses for adult outpatient visits resulting in antibiotic prescriptions. ARTI, acute respiratory tract infection. *, other respiratory diseases include tonsillitis/adenoiditis, laryngitis/tracheitis, deviated septum, peritonsillar abscess, allergic rhinitis, adenoid/tonsil hypertrophy/vegetations, pneumonia, influenza, emphysema, asthma, bronchiectasis, extrinsic allergic alveolitis, chronic airway obstruction not otherwise specified, pneumoconiosis, pleurisy, pneumothorax, lung/mediastinal abscess, pulmonary congestion/hypostasis, postinflammatory pulmonary fibrosis, other alveolar diseases, other parieto/pneumopathies, sclerotic lung disease, acute chest syndrome, lung involvement in other disorders, and other respiratory diseases. (Adapted from reference with permission of Elsevier.)

FIG 6

Future directions in microbiological research on inflammatory mucosal disease. CRS research thus far remains limited to gene-targeted assessments of community membership and structure, including bacterial 16S rRNA gene sequencing, fungal internal transcribed spacer (ITS) region sequencing, and known viral genetic elements. Approaches that sequence all DNA (metagenomics) or all transcribed RNA (metatranscriptomics) or that identify proteins (metaproteomics) or metabolites (metabolomics) will provide greater insights into the true diversity and structure, as well as the full genetic potential and in situ activity, of the mucosa-associated microbiota.