Microbial Sinus Dynamics In Cystic Fibrosis Lung Transplant Patients

The upper airways in individuals with cystic fibrosis (PwCF) are constantly exposed to inhaled microbes. The sinonasal cavity is identified as the initial site colonized by pathogenic microbes with the potential to impact the lower respiratory tract. Chronic rhinosinusitis (C.R.S.), a prevalent inflammatory condition in PwCF, is linked to diminished quality of life and negative outcomes, including pulmonary exacerbations. Microbiome studies reveal a correlation between sinus and lower respiratory tract microbial communities in PwCF, while those who undergo lung transplantation exhibit persistent sinus involvement post-transplant. The study aims to characterize the microbial communities in the sputum and paranasal sinuses of PwCF and post-lung transplant individuals. It hypothesizes similar upper and lower airway microbial populations with variations in diversity between pre- and post-transplant settings. This research sheds light on the sinus microbial milieu’s role in the respiratory health of individuals with cystic fibrosis.

 

THE BACKGROUND OF THE STUDY

Cystic fibrosis (C.F.) is a genetic disorder that profoundly affects the respiratory system, leading to persistent lung infections and compromised respiratory function. The upper airways of individuals with C.F. face continuous exposure to inhaled microbes from the environment, particularly within the sinonasal cavity, considered the primary site for the initial colonization by pathogenic microbes with the potential to seed the lower respiratory tract [1]. This interconnectedness between the upper and lower airways is encapsulated by the “unified airway hypothesis,” emphasizing the importance of addressing upper respiratory tract symptoms to enhance lower respiratory tract health and vice versa [1]. Chronic rhinosinusitis (C.R.S.), an inflammatory disease impacting the nasal and paranasal sinus mucosa, is a defining feature in individuals with C.F., with prevalence reaching nearly 100% [2-4]. C.R.S. has been associated with a significant negative impact on the quality of life in pediatric and adult populations with C.F. [5].

Microbiome studies utilizing culture-independent methods have played a pivotal role in unraveling the dynamics of microbial communities in the sinuses and lower respiratory tract of individuals with C.F. These studies have demonstrated polymicrobial communities in the sinuses that progressively become dominated by classical C.F. pathogens with advancing disease [8-12]. Notably, individuals with C.F. who have undergone lung transplantation constitute a unique subgroup with less understood airway microbiomes. Concordance between pre- and post-transplant sputum microbiomes suggests persistent sinus involvement in airway infections, signifying the sinuses as a persistent nidus for infection [13]. Moreover, microbiome studies in post-transplant individuals with C.F. indicate distinct communities with reduced diversity compared to other chronic lung diseases, and aberrant microbial flora may contribute to graft injury post-transplant, including the development of bronchiolitis obliterans syndrome (B.O.S.) [14].

Given the increasing recognition of the link between sinuses in C.F. and respiratory health, understanding the role of the sinus microbial milieu becomes essential. This study aims to identify microbial communities in the sputum and paranasal sinuses of individuals with C.F. and post-lung transplant individuals with C.F., exploring associations with chronic rhinosinusitis during stability and illness. The hypothesis posits that similar microbial populations will be present in the upper and lower airways, with differences in diversity between pre- and post-transplant settings. This research holds promise for providing valuable insights into the role of the sinus microbial milieu in the respiratory health of individuals with cystic fibrosis [1, 13]. 

 

THE STUDY METHOD

The study employed a prospective, matched cohort design involving 31 adult individuals with cystic fibrosis (PwCF) and post-lung transplant individuals with cystic fibrosis (pTxPwCF). The cohorts were carefully matched for sex and age (±2 years) with C.F. and symptomatic chronic rhinosinusitis (C.R.S.) between July 2015 and December 2016. Sample size calculations were based on 80% power to detect differences in microbial richness in pre- and post-transplant cohorts, requiring a total sample size of 30 patients (15 PwCF, 15 pTxPwCF). Participants meeting specific criteria, including a confirmed diagnosis of C.F., age ≥18 years, and specific CFTR mutations, were enrolled. Exclusions comprised individuals with a percent predicted forced expiratory volume in 1 second (ppFEV1) <30% at study initiation, recent sinus surgery, or planned surgery during the study period.

Data collection involved routine quarterly clinic visits and unscheduled visits during exacerbation periods, with at least one sinus swab and expected sputum collected as paired samples. Sinonasal samples were obtained through nasal swabs directed at the middle meatus and administered by trained investigators. A minimum of two samples per enrolled subject was required for inclusion in the analysis. Demographic and clinical data, including age, sex, pancreatic status, CF-genotype, and ppFEV1, were collected through chart review. Participants completed a validated sinus symptom score at each visit, the Sinonasal Outcome Test (SNOT-22). The Lund-Mackay (L.M.) score was used to assess radiologic severity for those who underwent computed tomography of the sinuses.

The D.N.A. extraction and 16S ribosomal R.N.A. (rRNA) gene amplicon sequencing processes followed established methods. Briefly, frozen sputum or sinus samples were thawed, homogenized, mechanically lysed, and enzymatically processed, and D.N.A. was extracted using phenol-chloroform and purified using Zymo Clean and Concentrator-25 columns. The V3 region of the 16S ribosomal D.N.A. gene was amplified and sequenced using Illumina MiSeq. Reagent blanks were run for each set of D.N.A. extractions, and samples were excluded if controls were positive for polymerase chain reaction products, with D.N.A. extractions repeated as necessary. The University of Calgary’s Conjoint Health Research Ethics Board approved the study.

 

ANALYSIS

Microbial community analysis was performed using R v.4.1.2 with phyloseq, ggplot2, and vegan packages. All samples were rarefied to the lowest read count, and taxon relative abundance was calculated. Operational taxonomic unit (O.T.U.) tables enabled richness and diversity indices computation, including the Shannon Diversity Index. The principal component analysis assessed β-diversity. Bacterial evenness within samples was evaluated with the Shannon Evenness Index. Paired group comparisons utilized t-tests or semiparametric methods, and multivariate parametric calculations employed PERMANOVA with Dirichlet-Multinomial distribution. Numbers and frequencies presented categorical variables, while continuous variables were mean ± standard deviation or median (IQR, Interquartile Range). Microbial measures correlated with demographics, microbiologic and clinical parameters, sinus symptoms, and radiographic scores, providing insights into microbial community dynamics and their associations with clinical factors.

 

RESULTS

1. Cohort Demographics

• Thirty-one participants (16 PwCF and 15 pTxPwCF) matched by sex and age were included.
• Baseline demographics were comparable between cohorts.
• The median time from lung transplantation to the first study visit for transplant recipients was 5.2 years (IQR, 3.3‐7.8).
• 94% of subjects completed all three visits.
• Forty-seven (47) sputum (40 pre-lung transplants and seven pTx) and ninety (90) sinus (46 PwCF and 44 pTxPwCF) samples were collected.

2. Microbial Community Structure

• D.N.A. extraction was performed on 137 samples, with 16S rRNA amplicon sequencing obtained from 107 samples.
• Pseudomonas (44.6%), Haemophilus (14.6%), and Staphylococcus (12%) were dominant in community composition.
• Dominant O.T.U. (Operational Taxonomic Unit) did not differ significantly between sinus and sputum samples or between the two patient cohorts.
• No specific associations in microbial community structure during exacerbation were observed.

3. Microbial Diversity Composition at First Visit

• Sinus microbial diversity, measured by S.D.I. (Shannon Diversity Index), was significantly greater in pTxPwCF compared to PwCF (P= .04).
• No differences in diversity by transplant status were observed in sputum samples.
• β‐diversity assessed by sample type showed significant differences between patient cohorts in sputum but not sinus samples.

4. Microbial Composition and C.R.S. Symptom Scores

• No significant differences in microbial composition were observed based on SNOT‐22 (Sinonasal Outcome Test-22) scores using the established cut‐off of 21.
• A statistically significant interaction between SNOT‐22 scores and lung transplant status was observed when all time points were included.

5. Microbial Composition in Subjects with Paired Sinus and Sputum Samples

• In individuals with paired samples, there was a significant difference in α‐diversity between sinus and sputum samples in the pre-transplant group.
• β‐diversity of microbiome composition between sample types was significantly different in the PwCF cohort but not statistically significant in the pTxPwCF group.

These findings suggest significant differences in microbial community structure, diversity, and composition between individuals with cystic fibrosis and those post-lung transplant, particularly in sinus samples. The study also highlights the association between microbial composition and sinus symptoms, providing valuable insights into the respiratory health dynamics in these populations.

 

DISCUSSION

The conducted study emerges as one of the pioneering prospective matched cohort investigations into microbial communities within the paranasal sinuses of individuals with cystic fibrosis (PwCF), encompassing both non-transplant and transplant scenarios [1]. Exploring associations between these microbial communities and clinical disease in C.F. contributes significant insights to the field.

Differences in the sinus and airway microbiome based on transplant status in PwCF were unveiled, emphasizing the dynamic nature of microbial compositions across diverse clinical contexts [1]. While diversity exhibited variations across sinus and airway microbiomes among different patient groups, the overall changes in community structure remained modest, with consistent, prevalent organisms persisting [1]. The prevalence of specific taxa, identified through culture-independent analysis and traditional culture-dependent growth, remained constant across different sample types, affirming prior observations of a potential pathogenic reservoir in transplant recipients [1].

The study uniquely associated sinus microbiome compositional structure with sinonasal clinical outcomes by transplant status in PwCF, as evidenced by patient-reported questionnaires [1]. The microbial diversity was notably linked to improved symptom scores, corroborating earlier findings [1]. However, a significant association with Lund-Mackay scores was not observed, potentially due to limitations in sample size, mirroring challenges faced in other studies [1, 26, 27].

The findings of this study underscore the sinonasal cavity’s role as an initial site of bacterial colonization in PwCF, with implications for subsequent seeding of the lungs [1, 28]. The persistence of Pseudomonas aeruginosa as the most prevalent taxa, identified through molecular and clinical culture techniques, further emphasizes the presence of a latent reservoir in both pre-and post-transplant scenarios [1]. Concordance between sputum and sinus microbiota suggests preserving unique microbial communities within individuals, providing novel insights, particularly in the post-lung transplant population [1].

Therapeutically, the study suggests a potential role for interventions aiming to attenuate future reinfection and mitigate the risk of graft rejection through early therapeutic measures [1]. This aligns with the findings of previous studies, such as one that performed endoscopic sinus surgery post-lung transplantation, indicating improved survival and reduced bronchiolitis obliterans syndrome incidence in those who achieved clearance of P. aeruginosa airway colonization [1].

With the advent of highly effective modulator therapy (H.E.M.T.), questions have arisen regarding its impact on the sinus microbiome and its relation to lower respiratory tract infections in PwCF [1]. The upcoming PROMISE (Prospective Observational Multicenter Investigation of the Safety and Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis) study, a significant U.S. multidisciplinary prospective endeavor, aims to address these queries by evaluating both culture-dependent and independent measures of pathogen/microbiome-constituent abundance in the post-modulator era [1].

In summary, the study contributes nuanced insights into microbial dynamics in the sinuses of PwCF, shedding light on the persistence of pathogens, therapeutic considerations, and potential ramifications of modulator therapy [1].

 

LIMITATIONS OF THE STUDY

1. Homogeneous Cohorts: Both non-transplanted and transplanted cohorts comprised individuals with cystic fibrosis (C.F.), potentially limiting the generalizability of findings, as they share CF-related sinus disease and altered microbiota.
2. Single-Center Study: The study’s single-center design may influence the broader applicability of results; however, efforts to enroll a matched cohort with a high completion rate (94%) enhance internal validity.
3. Sputum Sample Discrepancy: The lack of sputum samples in the post-lung transplant persons with cystic fibrosis (pTxPwCF) group, attributed to their inability to expectorate similarly to persons with C.F. (PwCF), restricts the scope of comparative analyses.
4. Limited Power for Subgroup Analysis: Despite collecting comprehensive clinical data and having the power to discern microbial composition differences, the study’s limited power hampers in-depth subgroup analyses.
5. Potential Confounding Factors: While age and sex were matched, the potential for other confounding variables remains, introducing uncertainty in the observed associations.
6. Observational Nature: As with many observational studies, associations identified do not necessarily imply causation, necessitating validation in larger cohorts or controlled experiments.
7. Absence of CFTR Modulator Therapy: None of the study subjects received cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, limiting insights into potential confounding effects on the microbiome and symptoms.
8. Preceding Introduction of E.T.I.: The study predates the introduction of highly effective modulator therapy (E.T.I.) in 2019, potentially leaving the relative sinus microbial restructuring associated with this therapeutic advancement unexplored.

These limitations underscore the need for cautious interpretation and consideration of potential confounding factors in understanding the observed microbial dynamics in C.F. sinuses.

 

CONCLUSION

In conclusion, the study on individuals with cystic fibrosis (PwCF) and post-lung transplant (pTxPwCF) revealed subtle variations in the microbiome of sinuses and lower airways. Despite these differences, the consistency of prevalent organisms in both groups suggests that sinuses may serve as potential post-transplant reservoirs for pathogens, carrying significant implications for infection management. The observed correlation between Sinonasal Outcome Test-22 (SNOT-22) scores and microbiome structure indicates the potential utility of SNOT-22 as a longitudinal metric in PwCF care. As the healthcare landscape transitions to the highly effective modulator therapy (H.E.M.T.) era, monitoring sinuses gains importance for surveillance of lower airway infections, emphasizing further investigation.

 

References

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  • Cholesterol Screening To Aid In Glaucoma Detection
  • Hearing Screening After Chemotherapy: A Study On Childhood Cancer Survivors
  • Olfactory Dysfunction and Screening For Depression: A QOL Study
  • Cancer Diagnosis And Mental Health
  • Mental Health Screening In Psoriatic Arthritis Patients
  • Prostate Cancer: A New Biopsy Risk Calculator Using MRI
  • Mental Health Study in Cancer Survivors
  • Mental Health Screening In The Community
  • Bone Mineral Density Screening Combined With Mammography
  • Bone Mineral Density In Type 1 Diabetes Mellitus
  • Cochlear Implants and Vestibular Screening
  • Aprocitentan In Resistant Hypertension
  • Predicting Cardiovascular Disease With Body Mass Index
  • Obesity Screening To Predict Hot Flashes
  • Hypertension Screening For Cardiovascular Health
  • Dental Screening For Cardiovascular Disease Risk
  • Blood Pressure and CVD Risk Reduction
  • Lifestyle Changes For Hypoglycemia Prevention
  • Ovarian Adenocarcinoma With Glaucoma: A Case Report
  • Community Hypertension and Atherosclerosis Risk
  • Thyroid Malignancy and Serum Calcitonin
  • Rare Schwannoma In Lateral Nasal Wall
  • Pyrotinib Therapy In HER2+ Breast Cancer
  • Osteopenia Predicts Outcomes in Pancreatic Cancer
  • Outcomes of Physical Exercise Regimens in Advanced Cancer
  • Penile Squamous Cell Carcinoma And HPV
  • Radiation Therapy And VTE Risk
  • Pseudouveitis With Pancreatic Carcinoma: A Case Study
  • Cancer Prevention In Rural Communities
  • Skeletal Muscle Mass and Cancer Patient Quality of Life: A Meta-Analysis
  • Incidence of Secondary Cancers After CIRT VS RT
  • Filanesib Combination Therapy in Multiple Myeloma
  • Pediatric Leukemia Patients Utilizing Levofloxacin
  • Breast Cancer And An Analysis Of Cardiovascular Events
  • Monotherapy Or Chemotherapy Adjunct: Pembrolizumab in Advanced NSCLC
  • Advanced Gastric Cancer: Prognosis with Nivolumab Monotherapy
  • Sinonasal B‐Cell Lymphomas A Cohort Study On Progression And Recurrence
  • Platinum Resistant Recurrent Ovarian Cancer Treatment+/-Bevacizumab
  • Metastatic Melanoma and Follow-Up MRI Scans
  • Isatuximab Treatment in Refractory T-Acute Lymphoblastic Leukemia
  • Ocular Melanoma and Treatment with Metformin
  • Gastric Neuroendocrine Neoplasms
  • Lung Cancer with Brain Metastasis After Late-Onset Bipolar Disorder: Case Report
  • Anlotinib with Camrelizumab in Lung Cancer Treatment
  • Sebaceous Carcinoma Treatment Outcomes: A Multicenter Study
  • Diffuse-Type Tenosynovial Giant Cell Tumors: Treatment and Progression
  • Lung Spindle Cell Carcinoma Responsive to Pembrolizumab: A Rare Case Report
  • DNA Methylation Profiling in Sarcoma Classification
  • Breast Tomosynthesis Simulator For Virtual Clinical Trials
  • Renal Cell Carcinoma-Prognosis Via Albumin Levels
  • Diagnostic Error Causing Cases of Cytopenia
  • Hodgkin’s Lymphoma: A Case Study With Nystagmus and Diplopia
  • Brugada Syndrome Treated with Lenalidomide: A Case Study
  • Koolen-de Vries Case Study
  • Suicidal Ideation and Somatic Treatments
  • Study on Pavlovian Fear Conditioning and Fear Reversal in OCD
  • Anxiety Scales in Lewy Body Disease
  • Inoperable Locally Advanced Non-Small Cell Lung Cancer: Survival Rates of Endostar, CCRT
  • Physician Practice Management and Private Equity
  • Physician Spending And Its Association With Patient Outcomes
  • Physician Burnout: Causes and Prevention
  • LEAP-MS: Adaptations for Advanced Stages
  • MS: Exercise Impacts on MRI
  • The Role of Preretirement Job Complexity in Cognitive Performance
  • Extrapontine Myelinolysis and PTA in Pregnancy
  • Verbal Communication and Masks
  • Sugammadex Versus Neostigmine in Thyroidectomy
  • SGLT Inhibitors on Weight and Lipid Metabolism in Diabetes
  • Saxagliptin: Obese Patients with Impaired Glucose Tolerance
  • Levothyroxine Therapy and Depression
  • Grave’s Disease and Risk of Systemic Lupus Erythematosus
  • Benign Thyroid Removal and Patient Satisfaction
  • MF- Biology, Management, and a Case Study of Ocular Manifestation
  • Quality Of Life In Adolescent Cancer Survivors
  • Cancer Opioid Risk Score
  • Oncology-Specific Opioid Risk Calculator In Cancer Survivors
  • 3D MRI for Non-invasive Ocular Proton Therapy of Uveal Melanomas
  • Sexual Dysfunction in Prostate Cancer Patients 
  • 3-Day Surprise Question To Predict Survival Rates in Advanced Cancer Patients

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