Discussion
Our review demonstrates significant diversity in the various bacteria that were associated with AECRS. Staphylococci species were the most frequently identified bacteria, followed by Pseudomonas aeruginosa, Streptococcal species, and Haemophilus influenzae. Among the Staphylococcal species, various subspecies were identified including S. aureus, MRSA, and coagulase-negative Staphylococci. Of note, Rujanavej et al. demonstrated a substantial rise in MRSA isolates from intranasal cultures since the year 2000 and beyond, underscoring the need to consider MRSA coverage in cases of AECRS (Rujanavej et al., 2013). It is also interesting to note the high prevalence of Pseudomonas species; given the Pseudomonal ability to produce biofilms and multidrug resistance, these findings underscore the value of targeted, antimicrobial therapy (Bhattacharyya and Kepnes, 1999). Of note, there were multiple studies to indicate that anerobic bacteria are present as well, suggesting that the microbial population in AECRS is a mix of aerobic and anaerobic bacteria.
AECRS likely begins with a common viral upper respiratory infection that progresses into a secondary bacterial infection, potentially in an already dysbiotic setting (Brook et al., 2005; Brook, 2006; Cho et al., 2013; Rowan et al., 2015), followed by return to baseline CRS. An exacerbation may also be characterized by worsening sinonasal symptoms, presence of purulence on nasal endoscopy, and/or endoscopically-derived bacterial cultures (Wu et al., 2019; Wu et al., 2020). However, the specific microbiology of these exacerbations remains poorly understood.
Although positive bacterial cultures are identified in up to 90.9% of patients during acute exacerbations (Ikeda et al., 2011), many of the previously utilized treatment paradigms are largely based on the microbiomes of acute or chronic rhinosinusitis states, rather than the particular dysbiome in AECRS.
Currently, there are no consistent treatment guideline for AECRS, but management usually involves short-term antibiotics and/or nasal corticosteroids. Targeted treatment for AECRS requires a better understanding of its pathophysiology. Despite being poorly understood, several factors have been noted to drive this dysbiosis including mucosal inflammation, impaired mucociliary clearance, biofilm formation, chronic mucosal disruption, atrophic rhinitis, transient viral infections and immunologic changes, and arising antibiotic resistance (Lee et al., 2018). Colonization by opportunistic pathogens such as S. aureus and Pseudomonas aeruginosa have been shown to trigger inflammation that is worsened by defects in the innate immune response.
There is significant evidence that alterations of the sinonasal microbiome are a direct driver of CRS inflammation and acute exacerbations (Rank et al., 2013; Divekar et al., 2015). While not a specific focus of this study, it should be noted that while antibiotic sensitivities were not routinely obtained in all of the included studies, significant multidrug resistance was reported. Thus, there is a growing body of literature to support culture-directed antibiotics to address microbiome shifts that are likely contributing significantly to the underlying disease process.
These intermittent and persistent disorders of the upper airway (including but not limited to asthma, allergic rhinitis, bronchitis, etc.) may represent gradients along a spectrum rather than each being a distinct pathology. In this unified airway theme, inflammatory disruptions in one subsite may affect the homeostasis in others. While this has been studied primarily in allergic disease, less is known about the impact of other adjunct upper airway disorders. For example, new evidence suggests that nasal hyperreactivity to nonspecific allergens may trigger symptoms mimicking AECRS, confounding the clinical picture (Doulaptsi et al., 2020). Additionally, in recent years, the concept of severe chronic upper airway disease (SCUAD) has been proposed to define patients with CRS (with or without polyps) and allergic, nonallergic or occupational rhinitis, whose symptoms are refractory to traditional guideline based treatments. It is worth considering whether these patients represent a group of SCUAD patients, and if so, how to best address the multifactorial underlying etiologies driving the clinical worsening of symptoms (Prokopakis et al., 2014). Thus, cultures obtained during such episodes may not necessarily reflect a true microbiome picture of pure AECRS.
This concept of microbiome shifts during acute exacerbations also mirrors findings from other unified airway subsites. For example, sputum analysis done during acute exacerbations of both chronic obstructive pulmonary disease and chronic bronchitis demonstrate dysbiosis findings similar to those observed in the paranasal sinuses (Dickson et al., 2014; Jubinville et al., 2018). Elevated IL-6 levels have also been linked to patients suffering a CRS exacerbation, suggesting either a viral infection or an altered IL-6 pathway (Yaniv et al., 2020). More robust studies on pathophysiology and treatment options, including randomized controlled trials, are needed to better understand AECRS.
In addition, the articles reviewed included patients at various stages of intervention or recent antimicrobial treatment. It is also worth noting that patients with AECRS are known to have higher prevalence of comorbid conditions including allergic rhinitis, asthma, autoimmune, or other atopic diseases (Kwah et al., 2020). Most of the included studies lacked comprehensive demographic data regarding these and other relevant comorbidities such as respiratory pathologies, diabetes, or extensive obstructive polyposis. Additionally, no study mentioned the role of an odontogenic etiology driving the patient’s CRS, which is starting to become recognized as more prevalent than previously thought (Craig et al., 2021). Thus, characterizing this subtype of CRS requires a more thoughtful and comprehensive approach to identify high risk phenotypes and incorporate preventative measures to reduce exacerbation frequency (Kuiper et al., 2018).
It is worthwhile to consider that traditional culture methods may not adequately depict the in vivo polymicrobial host community, as standard cultures offer limited, predefined conditions in which microbial growth can occur. Thus, in vitro cultures may inadvertently bias growth to select for faster growing organisms, or those without niche or symbiotic growth needs. Additionally, standard cultures may not adequately represent the microbiome due to physical limitations in obtaining the culture; for example, Miller and Davis demonstrate significant variability in pathogens in cultures from the same patient when done via standard methods compared to those obtained intraoperatively (Feazel et al., 2011; Hauser et al., 2015; Miller and Davis, 2018). Thus, it may beneficial to utilize alternative molecular methods of amplification, such as polymerase chain reaction, which can identify up to an order of magnitude more taxa that might be otherwise missed in between 25%-99% of cases. In fact, direct comparisons between sequencing and culture results find that dominant bacteria determined by sequencing is apparent in culture results less than 50% of the time (Feazel et al., 2011).
Although this discussion regarding AECRS focuses primarily on underlying bacterial pathogens, it is important to keep in mind that viruses and fungi may also be drivers of AECRS. However, the literature is limited in understanding the delicate balance of the baseline microbiome or the role of other microbes. Although rhinovirus presence has been identified as being the most prevalent virus in CRS exacerbation in some studies, its mechanism of pathogenesis and relationship to bacterial dysbiosis is unclear (Cho et al., 2013; Yaniv et al., 2020).
There is also limited and conflicting literature to describe the role endoscopic sinus surgery (ESS) may play in altering the sinus microbiome, possibly via mechanisms that alter sinonasal aeration, mucociliary clearance, inflammatory profiles, nitric oxide levels, and others. Larson and Han describe their findings in 26 patients, demonstrating that ESS does not significant alter the pre and post-surgery microbiome (Larson and Han, 2011). Hai et al. specifically examined the effect of ESS on biofilm production, finding that although ESS does not completely eradicate biofilms, it does significantly reduce their density (Hai et al., 2010). Several other studies demonstrate worse patient outcomes after ESS where biofilms are involved (Bendouah et al., 2006; Psaltis et al., 2008; Zhang et al., 2009).
The above discussion illustrates the complexity in appropriately identifying and treating AECRS. In addition to diligent and thoughtful characterization of clinical symptoms, advancements in molecular technology are already enabling research in the unique endo- and phenotypes of this disease, and allow for customized, precision treatment, termed “precision medicine” (Vlastos et al., 2019).