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Tag: chronic rhinosinusitis (CRS)

Published on Leave a comment on Missing Bacteria In Chronic Sinusitis

What exactly are the differences between people with chronic sinusitis and those who are healthy and don't get sinusitis? I've written many times about the Abreu et al 2012 study that found that not only do chronic sinusitis sufferers lack L. sakei, they have too much of Corynebacterium tuberculostearicum (normally a harmless skin bacteria), and they also don't have the bacteria diversity in their sinuses that healthy people without sinusitis have.

In other words, the sinus microbiome (microbial community) is out of whack (dysbiosis). A number of studies found that there is a depletion of some bacterial species, and an increase in "abundance" of other species in those with chronic sinusitis.

Now a new analysis of 11 recent studies comparing people with chronic sinusitis to healthy people adds some additional information. Once again a conclusion was that those with sinusitis had "dysbiosis" (microbial communities out of whack) in their sinus microbiomes when compared to healthy people. And that an increased "abundance" of members of the genus Corynebacterium in the sinuses was associated with chronic sinusitis (studies so far point to C. tuberculostearicum and C. accolens). Nothing new there...

But what was new was that they found that bacteria of the genus Burkholderia and Propionibacterium seem to be "gatekeepers", whose presence may be important in maintaining a stable and healthy bacterial community in the sinuses. And that in chronic sinusitis the bacterial network of healthy communities is "fragmented". In other words, when a person is healthy, the community of microbes in the sinuses may provide a protective effect, and if the gatekeepers are removed (e.g., during illnesses or after taking antibiotics), then a "cycle of dysbiosis and inflammation" may begin.

PLEASE NOTE: Genus is a taxonomic category ranking used in biological classification that is below a family and above a species level. For example, Lactobacillus is the genus and sakei is the species. Also, the researchers discussed "gatekeepers" as being important for sinus health, while Susan Lynch discusses the importance of "keystone species" for sinus health.

OK... so which species of Burkholderia and Propionibacterium bacteria are found in the healthy microbiome? Unfortunately that was not answered in this study. And of course this needs to be tested further to see if the addition of the missing species of Burkholderia and Propionibacterium bacteria to the sinus microbiome will treat chronic sinusitis. Or perhaps other bacteria such as L. sakei and someother still unknown bacteria also need to be added to the mix.

Both Burkholderia and Propionibacterium have many species, but I have not seen any in probiotics. Species of Propionibacteria can be found all over the body and are generally nonpathogenic. However, P. acnes can cause the common skin condition acne as well as other infections.

One species - Propionibacterium freudenreichii (or P. shermanii)  - is found in Swiss type cheeses such as Emmental, Jarlsberg, and Leerdammer. Propionibacteria species are commonly found in milk and dairy products, though they have also been extracted from soil. There are many Burkholderia species, with a number of them causing illness (e.g., B. mallei and B. pseudomallei), but also beneficial species, such as those involved with plant growth and health. Burkholderia species are found all over, in the soil, in plants, soil, water (including marine water), rhizosphere, animals and humans. At this point it is unclear to me which are the species found in healthy sinuses.

But it is clear that while L. sakei works to treat chronic sinusitis in many people, the fact that L. sakei typically has to be used after each illness (cold, sore throat, etc,) means that the sinus microbiome may still be missing microbial species or that there is still some sort of "imbalance" (even though the person may feel totally healthy). The researchers noted that a variety of fungi and viruses are also part of a normal sinus microbiome, but they weren't discussed in the article. As you can see, much is still unknown. Stay tuned..,..

This was a very technical article - thus not easy to read. Keep in mind that the information about the conclusions about the bacteria species in the sinuses was from studies that used modern genetic sequencing data (16S rRNA sequence data) to determine what bacteria are in the sinuses. (These are called "culture independent technologies" and much, much better than using cultures in determining species of bacteria.) This way they could analyze differences in "sinonasal bacterial community composition" and see differences between healthy people and persons with CRS (chronic rhinosinusitis).

Excerpts from Environmental Microbiology: Bacterial community collapse: a meta-analysis of the sinonasal microbiota in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is a common, debilitating condition characterized by long-term inflammation of the nasal cavity and paranasal sinuses. The role of the sinonasal bacteria in CRS is unclear. We conducted a meta-analysis combining and reanalysing published bacterial 16S rRNA sequence data to explore differences in sinonasal bacterial community composition and predicted function between healthy and CRS affected subjects. The results identify the most abundant bacteria across all subjects as Staphylococcus, Propionibacterium, Corynebacterium, Streptococcus and an unclassified lineage of Actinobacteria.

The meta-analysis results suggest that the bacterial community associated with CRS patients is dysbiotic and ecological networks fostering healthy communities are fragmented. Increased dispersion of bacterial communities, significantly lower bacterial diversity, and increased abundance of members of the genus Corynebacterium are associated with CRS. Increased relative abundance and diversity of other members belonging to the phylum Actinobacteria and members from the genera Propionibacterium differentiated healthy sinuses from those that were chronically inflamed. Removal of Burkholderia and Propionibacterium phylotypes from the healthy community dataset was correlated with a significant increase in network fragmentation. This meta-analysis highlights the potential importance of the genera Burkholderia and Propionibacterium as gatekeepers, whose presence may be important in maintaining a stable sinonasal bacterial community.

The high density and diversity of host-associated microbial communities present in different body sites supports a near infinite number of potential host to microbe, and microbe to microbe interactions. A stable network of microbial interactions, established through processes such as niche competition, nutrient cycling, immune evasion, and biofilm formation help maintain homeostasis during health (Walter and Ley, 2011; Grice et al., 2009). Taxa that hold together the bacterial community by interacting with different parts of the network can be considered “gatekeepers” (sensu Freeman, 1980; Widder et al., 2014). During health, a consortium of microbes may provide a protective effect, and a breakdown in these networks due to the removal of gatekeepers may begin a self-perpetuating cycle of dysbiosis and inflammation (Vujkovic-Cvijin et al., 2013; Widder et al., 2014; Byrd and Segre, 2016).

The genus-level phylotype Corynebacterium was again associated with CRS bacterial communities, and Burkholderia was associated with healthy subjects.

In contrast to the variety of Actinobacteria and Betaproteobacteria phylotypes differentiating the healthy sinonasal bacterial communities, only one phylotype (Corynebacterium) was consistently associated with those individuals that were chronically inflamed. The significance of specific members of the genus Corynebacterium in CRS microbial communities is supported by findings in two previous studies (Abreu et al., 2012; Aurora et al., 2013). The relative abundance of C. tuberculostearicum and C. accolens was significantly higher in subjects with CRS in two recent 16S rRNA studies (Abreu et al., 2012 and Aurora et al., 2013, respectively). 

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Published on 8 Comments on Antibiotic Use Increases Risk of Developing Chronic Sinusitis

Image result for antibiotics Yes, of course this makes sense!.... Many rounds of antibiotics have an effect not just in one area of the body, but kill off both good and bad bacteria in many areas of the human body. The researchers in this study found that taking antibiotics for a reason OTHER THAN SINUSITIS was associated with an increased risk of developing chronic sinusitis (as compared to those people not receiving antibiotics).

Use of antibiotics more than doubles the odds of developing chronic sinusitis without nasal polyps. And this effect lasted for at least 2 years.

Other research has already associated antibiotic use with "decreased microbial diversity" in our microbiome  and with "opportunistic infections" such as Candida albicans and Clostridium difficile. Diseases such as Crohn's disease and diabetes are also linked to antibiotic use. In other words, when there is a disturbance in the microbiome (e.g.from antibiotics) and the community of microbes becomes "out of whack", then pathogenic bacteria are "enriched" (increase) and can dominate.

This study lumped together chronic sinusitis without nasal polyps (CRSsNP) and chronic sinusitis with nasal polyps (CRSwNP), but when the 2 groups are separated out, then antibiotic use was mainly associated with chronic sinusitis without polyps. It appeared that antibiotic exposure did not significantly impact the odds of developing chronic sinusitis with nasal polyps.

The researchers write: "This effect was primarily driven by the CRSsNP subgroup, which also supports the evolving concept of CRSwNP (chronic sinusitis with nasal polyps) as a disease of primary inflammation rather than infection. Despite this, we elected to analyze the CRS (chronic rhinosinusitis) group as a whole because the precise relationship between CRS with and without nasal polyps remains incompletely understood, and it is possible that a proportion of the CRSsNP patients could go on to develop nasal polyps over time."

Which makes me wonder, will giving beneficial bacteria (such as Lactobacillus sakei) to those who have chronic sinusitis with nasal polyps show the same improvement in symptoms as those people without nasal polyps? Or do 2 treatments have to occur at once: something to lower the inflammation (which may be the reason for the nasal polyps) and also beneficial microbes to treat the bacterial imbalance of sinusitis? We just don't know yet. Note that CRS = chronic rhinosinusitis (commonly called chronic sinusitis). Research by A.Z. Maxfield et al from The Laryngoscope :

General antibiotic exposure is associated with increased risk of developing chronic rhinosinusitis 

Antibiotic use and chronic rhinosinusitis (CRS) have been independently associated with microbiome diversity depletion and opportunistic infections. This study was undertaken to investigate whether antibiotic use may be an unrecognized risk factor for developing CRS. Case-control study of 1,162 patients referred to a tertiary sinus center for a range of sinonasal disorders.

Patients diagnosed with CRS according to established consensus criteria (n = 410) were assigned to the case group (273 without nasal polyps [CRSsNP], 137 with nasal polyps [CRSwNP]). Patients with all other diagnoses (n = 752) were assigned to the control group. Chronic rhinosinusitis disease severity was determined using a validated quality of life (QOL) instrument. The class, diagnosis, and timing of previous nonsinusitis-related antibiotic exposures were recorded.

Antibiotic use significantly increased the odds of developing CRSsNP  as compared to nonusers. Antibiotic exposure was significantly associated with worse CRS QOL {Quality of Life} scores over at least the subsequent 2 years. These findings were confirmed by the administrative data review. Use of antibiotics more than doubles the odds of developing CRSsNP and is associated with a worse QOL for at least 2 years following exposure. These findings expose an unrecognized and concerning consequence of general antibiotic use.

Antibiotic use and chronic rhinosinusitis (CRS) have been independently associated with microbiome diversity depletion and opportunistic infections. This study was undertaken to investigate whether antibiotic use may be an unrecognized risk factor for developing CRS.....Antibiotics have also been associated with significant adverse side effects. It has long been recognized that antibiotic use may lead to increased susceptibility to secondary mucosal infections from pathogens including Candida albicans and Clostridium difficile.  Recent studies on the concept of mucosal microbial dysbiosis have suggested that these infections arise as a result of antibiotic induced depletion of the diverse commensal microbial assemblage, which enables the proliferation of pathogenic species.

Chronic rhinosinusitis (CRS) is defined....as having greater than 12 weeks of sinonasal symptoms, along with at least one objective measure of infection or inflammation by nasal endoscopy or radiographic imaging....However the distinct lack of long-term disease resolution following antimicrobial therapy and in some cases surgery, suggests that additional factors are likely involved. Through these studies, CRS with nasal polyps (CRSwNP) has been recognized as an inflammatory subtype characterized by eosinophilic inflammation and a T-helper cell type 2 immunologic profile. Although CRSwNP lacks the features of a classic infectious process, the precise role of bacteria and their byproducts in the promotion of nasal polyp-related inflammation remains unclear.

Recent findings from culture independent investigations of the sinonasal microbiome have offered new insights into the pathogenesis of CRS. These studies have suggested that a decreased microbial diversity exists in CRS patients as compared to healthy controls with a selective enrichment of pathogenic species. Furthermore, some studies have shown that antibiotic exposure may be a risk factor associated with this loss of biodiversity,  echoing the findings seen in postantibiotic C. difficile infections.  Although systemic antibiotics have long been a mainstay of therapy for CRS, these findings lead inexorably to the paradoxical hypothesis that antibiotic exposure may, in fact, promote its onset.

We performed a....case control study of 1,574 patients referred to the Massachusetts Eye and Ear Infirmary Sinus Center in 2014 with symptoms of presumed sinonasal disease.... Inclusion criteria included all antibotic naive patients, and all antibiotic exposed patients for whom antibiotic use was for nonsinonasal-related infections. Among the antibiotic exposed group, only patients who used antibiotics for nonsinonasal-related infections prior to the onset of symptoms of CRS (within the case group) were enrolled in the study.....The case group was further substratified into CRS patients without nasal polyps (CRSsNP, n =273) and with nasal polyps (CRSwNP, n =137) based on the presence of nasal polyps on sinonasal endoscopy.

Among the case patients, 56.34% reported a previous nonsinus-related antibiotic exposure as compared to 42.02% of control patients. Antibiotic use significantly increased the odds of developing both CRSsNP and any form of CRS as compared to nonusers. This odds ratio was similar even when excluding patients who were treated for upper aerodigestive infections. In contrast, antibiotic exposure did not significantly impact the odds of developing CRSwNP. The percent of patients with any form of CRS and CRSsNP only, which was attributable to a previous exposure to antibiotics, was 24.69%  and 33.70%, respectively. In both the case and control groups, the most common class of antibiotic patients received was a penicillin (52.63% vs. 45.77%), and the most common reported reason for antibiotic prescription was the diagnosis of pharyngitis(18.06% vs. 16.67%).

Among the CRS patients (i.e., case group), the use of antibiotics was significantly associated with worse QOL scores as compared to antibiotic-naıve CRS patients. The effect on QOL was enduring because patients who used antibiotics at least 2 years prior to the development of CRS (36.81%) had similar disease severity scores as compared to those with more recent exposures. There was no significant difference in QOL score among patients using different antibiotic classes and among patients with different underlying reasons for antibiotic use.

The human microbiome project has provided new insights into the distribution and abundance of bacterial species in both health and disease. Opportunistic pathogens, as defined by the pathosystems resource integration center, were found nearly ubiquitously in the nares of healthy subjects, albeit at relatively low abundance. Additional studies of the normal nasal cavity found an inverse correlation between the prevalence of Firmicutes such as S. aureus and benign commensal organisms, suggesting a homestatic antagonism between potential pathogens and the remainder of the healthy microbial assemblage. Extrapolation of this concept would therefore predict that events resulting in a perturbation or loss of the commensal microbial community would enable proliferation of pathogenic species, resulting in the disease phenotype. This prediction has borne out in several studies of the sinonasal microbiome in patients with CRS. Feazel et al. found a decreased number of bacterial types and an overabundance of S. aureus among CRS patients as compared to controls. Antibiotic exposure was one of the most significant clinical factors driving this effect. Similar findings were published by Choi et al. and Abreu et al.... Although literature regarding the sinonasal microbiome in health and disease remains nascent, it has provided some limited clues that antibiotics may lead to a reduction of sinonasal microbial biodiversity, which in turn may be a significant feature of CRS.

Our results demonstrate that exposure to antibiotics is a significant risk factor for the development of CRS and accounts for approximately 25% of the disease burden in our study population. These findings harmonize with the predictions of the nascent literature on the sinonasal microbiome. This effect was primarily driven by the CRSsNP subgroup, which also supports the evolving concept of CRSwNP as a disease of primary inflammation rather than infection. Despite this, we elected to analyze the CRS group as a whole because the precise relationship between CRS with and without nasal polyps remains incompletely understood, and it is possible that a proportion of the CRSsNP patients could go on to develop nasal polyps over time.....

One unexpected outcome of our study was that a large percentage of exposures preceeded the onset of the diagnosis of sinusitis by more than 2 years. This indicates that, regardless of the mechanism, the sequelae of antibiotic use may endure much longer then previously thought....The impact of antibiotics on promoting bacterial resistance, and the development of mucosal infections from pathogens such as C. difficile and C. albicans, has been well established. This study demonstrates that antibiotics also significantly increase the risk of developing CRS, an effect that is driven primarily by CRS patients who do not have nasal polyps. Furthermore, premorbid antibiotic use could account for approximately 25% of our patients who developed CRS, and exposure conferred a worse disease-specific quality of life.

Published on Leave a comment on Bacterial Communities Vary Between the Sinuses In People With Chronic Sinusitis

New research that found that microbial communities vary between the sinuses in a person with chronic sinusitis. This is a result that many sinusitis sufferers already suspect based on their sinusitis symptoms. The researchers also found that bacterial communities in the sinuses vary between people with chronic sinusitis. It is frustrating though for me to read study after study where the researchers focus on describing the types of bacteria found in chronic sinusitis sufferers (and then just saying that the sinus microbiomes or community of microbes vary from person to person) rather than studies comparing the sinus microbiomes (bacteria and other microbes, such as fungi) between healthy individuals and sinusitis sufferers.

Since research finds that sinusitis sufferers have altered sinus microbiomes, then what would be really helpful now is finding more beneficial or keystone species (besides Lactobacillus sakei) that are needed for healthy sinus microbiomes. This would be an important step towards then adding (perhaps using a nasal spray) these missing microbes to the sinus microbiome. From Frontiers in Microbiology:

Bacterial communities vary between sinuses in chronic rhinosinusitis patients

ABSTRACT: Chronic rhinosinusitis (CRS) is a common and potentially debilitating disease characterized by inflammation of the sinus mucosa for longer than 12 weeks. Bacterial colonization of the sinuses and its role in the pathogenesis of this disease is an ongoing area of research. Recent advances in culture-independent molecular techniques for bacterial identification have the potential to provide a more accurate and complete assessment of the sinus microbiome, however there is little concordance in results between studies, possibly due to differences in the sampling location and techniques. This study aimed to determine whether the microbial communities from one sinus could be considered representative of all sinuses, and examine differences between two commonly used methods for sample collection, swabs and tissue biopsies. High-throughput DNA sequencing of the bacterial 16S rRNA gene was applied to both swab and tissue samples from multiple sinuses of 19 patients undergoing surgery for treatment of CRS. Results from swabs and tissue biopsies showed a high degree of similarity, indicating that swabbing is sufficient to recover the microbial community from the sinuses. Microbial communities from different sinuses within individual patients differed to varying degrees, demonstrating that it is possible for distinct microbiomes to exist simultaneously in different sinuses of the same patient. The sequencing results correlated well with culture-based pathogen identification conducted in parallel, although the culturing missed many species detected by sequencing. This finding has implications for future research into the sinus microbiome, which should take this heterogeneity into account by sampling patients from more than one sinus. It may also be of clinical importance, as determination of antibiotic sensitivities using culture of a swab from a single sinus could miss relevant pathogens that are localized to another sinus.

CRS can be a debilitating condition that is recalcitrant to treatment. Bacterial colonization of the sinuses is likely to play an important role in the pathogenesis and perpetuation of the disease; however different studies have yielded contrasting results with respect to which bacterial taxa are characteristic of the disease (ref). We observed bacterial communities dominated by different taxa in CRS patients; for example some have sinuses colonized primarily with Haemophilus, while others are dominated by Corynebacterium and Staphylococcus, or Pseudomonas. Some patients’ sinuses contain anaerobic bacteria such as Anaerococcus, Finegoldia, and Peptoniphilus, while these were absent from others. Indeed, our results have shown, for the first time, that it is possible for a patient to simultaneously have different bacterial communities in different sinuses, pointing to distinct, localized microbiomes within the same patient. Understanding this variation in the sinus microbiome could prove critical to the appropriate selection of treatments for CRS in the future.

The weighted unifrac distances between samples within patients (Figure 1) demonstrate that at least some CRS patients have substantial variation of bacterial communities between sinuses, although it is significantly smaller than the variation observed between different individuals. While this variation was related to abundance rather than the presence or absence of dominant community members, some of these variations were large: for example Corynebacterium sequences dominating the right sinuses of patient 003 (60.7 and 41.7% of all sequences), while the left sinuses had much smaller abundances (9.8 and 6.2%) and were dominated by the anaerobic bacteria Anaerococcus, Finegoldia  and Peptinophillus.