Abstract
CF is associated with multiple risk factors for caries and gingivitis, which in turn are potential risk factors for poor lung health, mediated through aspiration of dysbiotic oral microbiota. Nonetheless, the association between dental diseases and respiratory outcomes in CF has not previously been evaluated. Here, we report the baseline cross-sectional associations between dental diseases (caries and gingivitis) and respiratory outcomes (FEV1 and the respiratory domain of the CFQ-R) modeled using linear regression with adjustment for appropriate covariates from an ongoing multicenter, prospective cohort study enrolling people with CF ages 12 to 30. Among 203 participants (mean (SD) age at enrollment of 18.7 (5.0) years, 86% on elexacftor-tezacaftor-ivacaftor or ivacaftor)), we found that ≥3 surfaces with untreated caries was associated with a mean decrement of −0.88 (95% CI −1.61, −0.16, p=0.02) in FEV1 z score compared to no untreated caries, and a mean decrement of −11.7 (95% CI −20.7, −2.7, p=0.01) in the CFQ-R respiratory domain. We did not observe an association between gingivitis and respiratory outcomes. Our results suggest that poor oral health could be a modifiable risk factor for worse lung health in CF, and that prevention and treatment of dental caries could potentially improve respiratory health in adolescents and young adults with CF, even in the post-modulator era.
1. Introduction
CF is associated with multiple risk factors for dental diseases and poor oral health, including frequent high-calorie food intake to maintain weight, high intraoral Streptococcus mutans levels, and altered saliva characteristics, all of which may contribute to an acidic intraoral pH and a cariogenic environment1,2. In addition, dental caries and gingivitis are potential risk factors for poor lung health, mediated through aspiration of dysbiotic oral microbiota3. Nonetheless, the association between dental diseases and respiratory outcomes in CF has not previously been evaluated. We hypothesized that poorer dental health is associated with lower FEV1, poorer respiratory health-related quality of life and more pulmonary exacerbations.
2. Methods
2.1. Study design and eligibility criteria:
We conducted a prospective, observational cohort study in adolescents and young adults (AYAs) with CF at three U.S. centers: Seattle Children’s Hospital/University of Washington, Seattle, WA; University of North Carolina at Chapel Hill, NC; University of Alabama at Birmingham, AL. Eligibility criteria included a confirmed diagnosis of CF, age 12 to 30 years at enrollment, no history of solid organ transplant, and no acute course of oral antibiotics for a respiratory indication at enrollment or within one month prior. Participants underwent three annual study visits including a dental exam (visits 1 and 3), spirometry, participant surveys, health record review and collection of sputum and saliva. Dental exams were conducted by a trained and calibrated dental examiner, according to published protocols4. Dental caries were assessed using modified EC4 Criteria5. Gingivitis was assessed by bleeding on probing on six surfaces of each fully erupted permanent tooth6. Study visits are ongoing. Here, we report cross-sectional results from the baseline study visit. IRB approval was obtained from the University of Washington and written informed consent was provided by each participant or parent/guardian.
2.2. Predictor Variables:
The two dental disease predictors were: 1) untreated caries, defined as 0, 1 to 2, or 3 or more surfaces with a cavitated lesion into enamel or dentin; and 2) gingivitis, classified by percentage of visible and erupted buccal and lingual sites with bleeding on probing: healthy: <10%, localized gingivitis: 10 to 30%, generalized gingivitis: >30%.
2.3. Outcomes:
At the baseline visit, spirometry indices from measurements performed according to American Thoracic Society-European Respiratory Society criteria7 at each clinic visit over the year before enrollment were abstracted from the medical record. The CFQ-R respiratory domain (CFQ-R RD) was administered at each study visit8. For this analysis, there were two outcomes: a) the mean of the two highest FEV1 z scores (based on GLI 2022 reference equations9) in the 12 months before and including the enrollment visit and b) the enrollment CFQ-R RD. Pulmonary exacerbations requiring IV antibiotics in the year before enrollment only occurred in 15 participants, so we had very limited power to estimate the association between dental diseases and these exacerbations. We did not capture oral antibiotic-treated exacerbations in the year before enrollment.
2.4. Statistical analysis:
Baseline participant characteristics were summarized using descriptive statistics. The associations of caries and gingivitis with FEV1 z score and CFQ-R RD were estimated (in separate models) using linear regression, adjusted for age, sex, race, health insurance, use of the highly effective CFTR modulators elexacaftor-tezacaftor-ivacaftor or ivacaftor and pancreatic enzyme use, employing heteroscedasticity-consistent standard errors10. We also tested for an interaction between highly effective modulator use and these associations. Analyses were 2 sided, and P <.05 was considered significant. Analyses were performed using R (version 4.5.2; The R Foundation for Statistical Computing 2025).
Sample size calculation: Based on our preliminary data11, we expected 20–30% of participants to have untreated caries and 40–70% to have gingivitis at Visit 1. A sample size of 210 provides >80% power to detect an odds ratio ≥1.6 for the association between continuous variables and untreated caries, and ≥1.5 for gingivitis, at Visit 1, with a 2-sided alpha = 0.05. For categorical risk factors, the power is >80% with N=210 individuals to detect an odds ratio of 2.2–3.0, depending on the prevalence of the risk factor and of caries or gingivitis.
3. Results
Two hundred and three participants were enrolled between March 2022 and December 2024 (Table 1). The mean (SD) age at enrollment was 18.7 (5.0) years. 55.7% were female, and 87% were non-Hispanic white. 85% of the subjects were on a highly effective modulator. Mean (SD) FEV1 z-score at enrollment was 0.1 (1.4) and mean CFQ-R RD score was 86.9 (16.1); 28% of participants had any untreated dental caries, and 12% had ≥3 surfaces of untreated dental caries. Two-thirds had either localized (40%) or generalized (26%) gingivitis.
Table 1:
Baseline characteristics of multicenter study cohort of 203 adolescents and young adults with CF (N (%) or mean (SD))
| Characteristic | All participants (N = 203) |
|---|---|
| Age, years (mean (SD)) | 18.7 (5.0) |
| Age category | |
| 12–17 | 98 (48.3%) |
| 18–30 | 105 (51.7%) |
| Female sex | 113 (55.7%) |
| Race | |
| White | 188 (92.6%) |
| Black | 7 (3.4%) |
| Other or >1 race | 8 (3.9%) |
| Hispanic ethnicity | 12 (5.9%) |
| Highly Effective Modulator Use1 | 175 (86.2%) |
| CF genotype | |
| F508del homozygous | 116 (57.1%) |
| F508del heterozygous | 70 (34.5%) |
| Taking pancreatic enzymes | 141 (69.5%) |
| CF-related diabetes2 | 26 (12.8%) |
| Untreated caries surfaces3 | |
| 0 | 146 (71.9%) |
| 1–2 | 32 (15.8%) |
| 3 or more | 25 (12.3%) |
| Gingivitis4 | |
| Healthy | 70 (34.7%) |
| Localized | 80 (39.6%) |
| Generalized | 52 (25.7%) |
| CFQ-R respiratory scale (mean (SD)) | 86.9 (16.1) |
| FEV1 z score (mean, (SD)) | 0.1 (1.4) |
| FEV1 % predicted (mean (SD)) | 101.3 (19.2) |
| Health insurance | |
| Public | 82 (40.4%) |
| Private | 120 (59.1%) |
| None | 1 (0.4%) |
| Dental insurance | |
| Public | 76 (39.0%) |
| Private | 111 (56.9%) |
| None | 8 (4.1%) |
| Unknown | 8 |
Elexacaftor/Tezacaftor/Ivacaftor (N=173) or Ivacaftor (N=2)
17 on insulin and 9 not on insulin.
Number of surfaces with a carious lesion into the enamel or dentin.
Based on % of buccal and lingual sites with bleeding on probing: healthy <10%, localized: 10 to 30%, generalized: >30%.
Untreated dental caries were associated with significantly worse FEV1 z-score and CFQ-R RD (Table 2). Specifically, ≥3 surfaces with untreated caries was associated with a mean decrement of −0.88 (95% CI −1.61, −0.16, p=0.02) in FEV1 z score compared to no untreated caries, and a mean decrement of −11.7 (95% CI −20.7, −2.7, p=0.01) in the CFQ-R respiratory domain. (The minimal clinically important difference for the CFQ-R RD is 412.) Gingivitis was not a significant predictor of FEV1 or CFQ-R RD (Table 3). There was no significant interaction between highly effective modulator use and the association of untreated caries or gingivitis with either outcome.
4. Discussion
In a multicenter cohort of AYA with CF ages 12 to 30 years, we found that untreated dental caries predicted clinically and statistically significant worse lung function and respiratory healthrelated quality of life at enrollment. We did not detect an association between gingivitis and these outcomes. Results were similar among those on or off highly effective modulators, though our power to detect a difference was limited by the small size of the non-modulator group (N=28). This is the first study to evaluate the association of oral diseases and lung health in CF.
In our cohort, the prevalence of untreated dental caries was 28% and of gingivitis was 66%. While we did not include a contemporary control group, the prevalence of these conditions was higher in our CF cohort than among participants ages 12–30 years in the National Health and Nutrition Examination Survey (NHANES (2017–2020 for caries; 2003–2004 for gingivitis): 16.4% and 25.8%, respectively17,18. Prior literature has yielded conflicting results2,11,13, with some studies describing a lower prevalence of caries in CF than in the general population14, while others report a similar or higher prevalence, particularly among AYAs and adults6,15,16.
Evidence suggests that the lower airways are continuously exposed to oral microbiota through microaspiration, with oral flora serving as persistent reservoirs that modulate both pulmonary immunity and susceptibility to infection19,20. It is not clear why the observed association between caries and pulmonary outcomes was not replicated with gingivitis. Perhaps the larger bacterial load associated with untreated caries lesions serve as a constant reservoir for virulent/pathogenic microorganisms that can be aspirated, while gingivitis is more reversible and has a more variable bacterial load (for example, that can be decreased with toothbrushing).
Our results suggest that poor oral health could be a modifiable risk factor for worse lung health in CF, likely mediated through oral dysbiosis, and that prevention and treatment of dental caries, for example, with regular toothbrushing with flouride toothpastes, could potentially improve respiratory health in AYAs with CF, even in the post-modulator era.
Our study has key strengths, including enrollment of a large, multicenter cohort; rigorous, standardized dental exams; and a longitudinal design. The current baseline analysis is limited by its cross sectional design, and the observed associations do not infer causality. We were unable to evaluate the association between oral diseases and pulmonary exacerbations because IV antibiotic-treated were rare and we did not collect data on oral antibiotics before enrollment. Prospectively, we are tracking oral- and IV-treated exacerbations. Future analyses at study completion will describe the incidence of dental diseases in this cohort over 3 years and associated risk factors, evaluate longitudinal associations between oral diseases and respiratory outcomes, and explore microbiome pathways linking the oral (plaque and salivary) microbiome, the sputum microbiome, and respiratory health.
Table 2:
Cross-sectional association of untreated dental caries surfaces with CFQ-RD (first column) and FEV1 z score (second column) in a multicenter cohort of 203 adolescents and young adults with CF, from multivariable linear regression adjusted for relevant covariates*
| CFQ-RD | FEV1 z score | |||
|---|---|---|---|---|
| Coefficient (95% CI) | P Value | Coefficient (95% CI) | P Value | |
| Untreated dental caries surfaces | 0.01 | 0.02 | ||
| 1–2 (N=57) (vs 0) | −5.7 (−11.4, 0.004) | 0.05 | 0.21 (−0.22, 0.64) | 0.33 |
| 3+ (N=25) (vs 0) | −11.7 (−20.7, −2.7) | 0.01 | −0.88 (−1.61, −0.16) | 0.02 |
age, sex, race/ethnicity (non-Hispanic white vs Hispanic white, Black, Other or >1 race), health insurance (private vs public), highly effective modulator use (yes vs no), and pancreatic enzyme use (yes vs no).
Table 3:
Cross-sectional association of gingivitis with CFQ-RD (first column) and FEV1 z score (second column) in a multicenter cohort of 203 adolescents and young adults with CF, from multivariable linear regression adjusted for relevant covariates*
| CFQ-RD | FEV1 z score | |||
|---|---|---|---|---|
| Coefficient (95% CI) | P Value | Coefficient (95% CI) | P Value | |
| Gingivitis | 0.59 | 0.12 | ||
| Localized (N=80) (vs Healthy) | 2.6 (−2.4, 7.6) | 0.31 | 0.33 (−0.07, 0.72) | 0.11 |
| Generalized (N=52) (vs Healthy) | 1.3 (−5.3, 7.8) | 0.71 | −0.08 (−0.58, 0.43) | 0.77 |
age, sex, race/ethnicity (non-Hispanic white vs Hispanic white, Black, Other or >1 race), health insurance (private vs public), highly effective modulator use (yes vs no), and pancreatic enzyme use (yes vs no).
Highlights.
We evaluated the cross-sectional association of oral diseases with respiratory outcomes in CF
Untreated caries were associated with lower FEV1 and higher (worse) CFQ-R respiratory domain score
We did not detect an association between gingivitis and respiratory outcomes
Poor oral health could be a modifiable risk factor for worse lung health, even in the postmodulator era
Acknowledgements:
The authors would like to thank the participants and their families for making this research possible.
Funding source:
This study was funded by the U.S. National Institute of Health (5U01DE030418). The sponsor reviewed and approved the protocol. It had no role in collection, analysis or interpretation of data, in the writing of this report or the decision to submit for publication.
Footnotes
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Conflict of Interest Statement: All authors declare that they have no financial or personal relationships with other people or organisations that could inappropriately influence or bias their work.
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