Risk of ankylosing spondylitis following chronic tonsillitis and adenoiditis: a retrospective cohort study utilizing TriNetX global collaborative network

Risk of ankylosing spondylitis following chronic tonsillitis and adenoiditis: a retrospective cohort study utilizing TriNetX global collaborative network | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk of ankylosing spondylitis following chronic tonsillitis and adenoiditis: a retrospective cohort study utilizing TriNetX global collaborative network Xiuwen Wang, Zhi Ye, Yu Wang, Shuai jie Ding, Yu-Hsun Wang, James Cheng-Chung Wei, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8106028/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Objective: To assess the incidence rate and risk of ankylosing spondylitis (AS) in patients with chronic tonsillitis and adenoiditis compared with those without chronic tonsillitis and adenoiditis. Methods: All patients with chronic tonsillitis and adenoiditis (n = 104,956) in the TriNetX (2016–2023) were individually matched up with control subjects without chronic tonsillitis and adenoiditis by age and sex (n = 104,956). All of the patients were tracked until an AS event was noted. Cox proportional hazards regression was used to calculate the HRs for the development of AS, adjusting for age, sex, urbanization, lifestyle, medications, and comorbidities. The Kaplan-Meier method was used to plot the cumulative incidence curves. Subgroup analyses examined the association between chronic tonsillitis and adenoiditis and AS in subgroups stratified by age, sex, and, race. To ensure the robustness of the findings, in this sensitivity analysis, this study incorporated five different negative outcome controls. Results: The chronic cohort had a 1.41(95%C.I. = 1.11–1.80) times higher risk of AS than that of the non-chronic tonsillitis and adenoiditis cohort after adjusting for age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medications. Moreover, the cumulative incidence curves plotted by the Kaplan-Meier method revealed that after 7 follow-up years, the chronic tonsillitis and adenoiditis cohort displayed a higher cumulative incidence of AS than that of the non-chronic tonsillitis and adenoiditis cohort (Log-rank test p = 0.005). Additionally, subgroup analyses indicated stronger associations in females (HR = 1.36, 95% CI: 1.02–1.80) and individuals aged 18–64 years (HR = 1.39, 95% CI: 1.08–1.78). Sensitivity analyses using negative outcome controls (e.g., burns, cancer) confirmed specificity of the association. Conclusions: Our study revealed that patients with chronic tonsillitis and adenoiditis had a higher risk of developing AS compared with non-chronic tonsillitis and adenoiditis patients, especially in females and those below 65 years old. These findings highlight the potential role of chronic upper airway inflammation in AS pathogenesis and warrant further investigations. Chronic tonsillitis and adenoiditis Ankylosing spondylitis Cohort Figures Figure 1 Figure 2 Figure 3 Introduction Ankylosing spondylitis (AS), an immune-mediated arthritis that has long been regarded as the archetypal condition within the spectrum of spondyloarthritis[ 1 ].It was estimated that the global prevalence of AS is estimated to range from 0.1% to 1.4%. The first clinical manifestations typically emerge between ages 26 and 45 years, with a male-to-female predominance of 2:1 to 3:1 as established through clinical epidemiology study[ 2 ]. The main clinical feature of AS is chronic back pain, which can lead to aberrant bone remodeling and ankylosis, the following structural and functional impairments have a negative impact on the quality of life[ 3 ]. The reasons for the occurrence of AS are believed to be genetic and environmental factors. Genetic epidemiology identifies HLA-B27 as the most significant susceptibility allele for AS, with its pathogenic role mediated through distinct molecular aberrations[ 4 ]. The allele's propensity to form B27 dimers via aberrant protein folding, disrupting canonical antigen presentation. This structural alteration activates the proinflammatory IL-23/IL-17 axis, a key pathway implicated in AS immunopathogenesis[ 5 ]. Beyond established genetic contributors, accumulating evidence highlights the critical role of infections in AS, which are implicated in activating adaptive immune responses that may drive autoimmunity through molecular mimicry or epitope spreading mechanisms[ 6 , 7 ]. The tonsillar apparatus serves as the primary immune barrier at the junction of the digestive and respiratory tracts, defending against ingested pathogens and inhaled allergens. As a lymphoid organ complex, it comprises four distinct anatomical regions: the paired palatine tonsils, the nasopharyngeal or adenoid tonsil, the paired tubal tonsils, and the lingual tonsil[ 8 ]. Tonsils and adenoids, as the secondary lymphoid organs, are crucial for the immune system’s first line of defense, particularly in the recognition of pathogens and the initiation of immune responses by producing secretory IgA and fostering T-cell differentiation[ 9 , 10 ]. Chronic inflammation in these tissues—frequently triggered by recurrent bacterial (e.g., Group A streptococcal) or viral infections—are associated with biofilm formation, tissue remodeling, and aberrant adaptive immune responses[ 11 ]. Associations were observed between recurrent tonsillitis and various autoimmune diseases, such as rheumatic fever, rheumatic heart disease, psoriasis and palmar plantar pustulosis. And it is hypothesized that these conditions may arise from a disruption of immune tolerance mechanisms toward resident microorganisms in the tonsils[ 12 – 14 ]. Tonsillectomy may be a potential option for patients with recalcitrant autoimmune diseases, and has been proven to effectively reduce disease activity of psoriasis[ 11 ], palmoplantar pustulosis and pustulotic arthro-osteitis[ 15 ] and pediatric autoimmune neuropsychiatric disorder associated with streptococcus[ 16 ]. Study on the role of chronic tonsillitis and adenoiditis in the development of AS is limited. Previous researches have revealed that tonsillitis may be a risk factor for AS[ 17 , 18 ], while the potential causal relationship between chronic tonsillitis and AS remains unclear. To this end, we performed this long-term population-based study to elucidate the relationship between chronic tonsillitis and adenoiditis in adults and the risk of new-onset AS using data derived from the de-identified electronic health records from TriNetX, a U.S.-based collaborative network. Methods Data source This retrospective cohort study utilized de-identified electronic health records from TriNetX, a U.S.-based collaborative network encompassing data on approximately 116 million patients. The dataset includes information from various healthcare environments, such as hospitals, primary care facilities, and specialty clinics, and contains anonymized patient records. Key data components include demographic information, diagnoses coded using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), medications classified by the Anatomical Therapeutic Chemical (ATC) system and standardized via RxNorm, procedures recorded with ICD-10-PCS, Current Procedural Terminology, and Systematized Nomenclature of Medicine, as well as laboratory test results coded with Logical Observation Identifier Names and Codes. TriNetX serves as a global federated platform for real-world data integration and analysis, supporting diverse research initiatives (Palchuk et al., 2023). This study was exempted from informed consent requirements under Section § 164.514(a) of the HIPAA Privacy Rule due to its reliance on anonymized secondary data without direct interaction with human subjects. The de-identification process adhered to Section § 164.514(b)(1) of the HIPAA Privacy Rule, verified by a qualified expert. Ethical approval was granted by the Institutional Review Board of Chung Shan Medical University Hospital (IRB No.: CS2-21176). Study design Figure 1 illustrates the flowchart for cohort construction. The exposure population included individuals aged 18 or older who were diagnosed with chronic tonsillitis and adenoiditis (ICD-10-CM: J35.0) between 2016 and 2023. The comparison group consisted of individuals aged 18 or older who had an encounter for a general adult medical examination (ICD-10-CM: Z00.0) between 2006 and 2023. The index date was defined as the date of the first diagnosis of chronic tonsillitis and adenoiditis or the first visit for a general adult medical examination. Both cohorts excluded individuals diagnosed with ankylosing spondylitis (ICD-10-CM: M45) or juvenile ankylosing spondylitis (ICD-10-CM: M08.1) before the index date. Baseline data, including age, sex, race, body mass index (BMI), socioeconomic status, lifestyle, medical utilization, comorbid conditions, and medication use were collected from medical records covering the year preceding the index date. Medical utilization included ambulatory care visits, emergency department visits, and inpatient admissions. Comorbidities assessed included overweight and obesity, hypertension, hyperlipidemia, diabetes mellitus, asthma, allergic rhinitis, chronic sinusitis, acute sinusitis, atopic dermatitis, obstructive sleep apnea, rheumatoid arthritis, and Sjögren syndrome. Medication data focused on corticosteroids for systemic use, anti-inflammatory and antirheumatic products (non-steroids), and antihistamines for systemic use. Detailed codes are provided in Supplementary Table 1 . Propensity score matching (PSM) was implemented to address baseline differences and control for confounding factors. A 1:1 matching ratio was applied using the TriNetX platform, considering variables such as age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medication. A greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard deviations was employed. The primary goal was to assess the risk of ankylosing spondylitis (ICD-10-CM: M45) in the exposure and comparison cohorts. Participants were followed until the first occurrence of ankylosing spondylitis or their last recorded medical event within the US collaborative network. Statistical analysis Statistical analyses were performed using the TriNetX platform. Balance between matched cohorts was evaluated using standardized mean differences (SMD), with values below 0.1 indicating sufficient balance. Kaplan-Meier survival analysis was used to compare the cumulative incidence of ankylosing spondylitis between the cohorts, with statistical significance assessed via the log-rank test. Cox proportional hazards models were utilized to estimate the relationship between cohort assignment and the risk of ankylosing spondylitis, presenting hazard ratios (HRs) with 95% confidence intervals. Subgroup analyses examined the association between chronic tonsillitis and adenoiditis and ankylosing spondylitis in subgroups stratified by age, sex, and, race. To ensure the robustness of the findings, in this sensitivity analysis, this study incorporated five different negative outcome controls. These included burns (ICD-10-CM: T20-T25), exposure to smoke, fire, and flames (ICD-10-CM: X00-X08), gout (ICD-10-CM: M10), cancer (ICD-10-CM: C00-C96), and cerebrovascular diseases (ICD-10-CM: I60-I69). These negative control outcomes were selected to strengthen the reliability of the study conclusions. All statistical procedures were conducted on the TriNetX platform, which integrates R 4.0.2 for advanced analyses. Results Baseline demographics and clinical characteristics After performing propensity score matching, the study included 104,956 individuals in both the exposure group (chronic tonsillitis and adenoiditis) and the matched comparison group. Table 1 summarizes the demographic and clinical characteristics before and after PSM. Before PSM, there were significant differences in age (Mean ± SD: 30.80 ± 12.35 in the exposure group vs. 46.95 ± 17.59 in the comparison group, SMD = 1.063), sex, medical utilization, hypertension, hyperlipidemia, diabetes mellitus, asthma, allergic rhinitis, chronic sinusitis, acute sinusitis, obstructive sleep apnea, and medication distribution. Following PSM, the groups were well-balanced with minimal differences across key variables, including age, sex, and medical utilization. Other covariates such as comorbidities, and medications were similarly balanced after PSM, ensuring comparability between the exposure and the comparison cohorts. Table 1 Demographic characteristics of exposure group and comparison group Before PSM After PSM Exposure group N = 104966 Comparison group N = 11696620 SMD Exposure group N = 104956 Comparison group N = 104956 SMD Age, Mean ± SD 30.80 ± 12.35 46.95 ± 17.59 1.063 30.80 ± 12.35 30.80 ± 12.35 < 0.001 Sex Female 71995 (68.59) 6293629 (53.81) 0.307 71986 (68.59) 70008 (66.70) 0.040 Male 29108 (27.73) 4754807 (40.65) 0.275 29108 (27.73) 29093 (27.72) < 0.001 Unknown Gender 3863 (3.68) 648184 (5.54) 0.089 3862 (3.68) 5855 (5.58) 0.090 Race White 66807 (63.65) 7320262 (62.58) 0.022 66806 (63.65) 61701 (58.79) 0.100 Black or African American 12927 (12.32) 1572854 (13.45) 0.034 12923 (12.31) 16097 (15.34) 0.088 Asian characteristic(s) 3964 (3.78) 538330 (4.60) 0.041 3963 (3.78) 5187 (4.94) 0.057 Native Hawaiian or Other Pacific Islander 814 (0.78) 80027 (0.68) 0.011 814 (0.78) 514 (0.49) 0.036 American Indian or Alaska Native 411 (0.39) 33772 (0.29) 0.018 411 (0.39) 338 (0.32) 0.012 Other Race 5028 (4.79) 480698 (4.11) 0.033 5027 (4.79) 5208 (4.96) 0.008 Unknown Race 15015 (14.31) 1670677 (14.28) 0.001 15012 (14.30) 15911 (15.16) 0.024 BMI, Mean ± SD 29.14 ± 7.76 29.43 ± 7.24 0.039 29.14 ± 7.76 28.96 ± 8.14 0.023 Social economic status Persons with potential health hazards related to socioeconomic and psychosocial circumstances 785 (0.75) 82145 (0.70) 0.005 783 (0.75) 1107 (1.06) 0.033 Housing/economic circumstances problem 129 (0.12) 23636 (0.20) 0.020 129 (0.12) 261 (0.25) 0.029 Problems related to education and literacy 29 (0.03) 3300 (0.03) < 0.001 29 (0.03) 58 (0.06) 0.014 Employment or unemployment problems 66 (0.06) 8382 (0.07) 0.003 66 (0.06) 124 (0.12) 0.018 Occupational exposure to risk factors 58 (0.06) 4840 (0.04) 0.006 58 (0.06) 81 (0.08) 0.009 Lifestyle Personal history of nicotine dependence 1908 (1.82) 310858 (2.66) 0.057 1907 (1.82) 2018 (1.92) 0.008 Nicotine dependence 3968 (3.78) 384535 (3.29) 0.027 3967 (3.78) 3612 (3.44) 0.018 Alcohol related disorders 573 (0.55) 105040 (0.90) 0.042 573 (0.55) 834 (0.80) 0.030 Medical utilization Ambulatory 68448 (65.21) 6523681 (55.77) 0.194 68438 (65.21) 68452 (65.22) < 0.001 Emergency 18138 (17.28) 1025052 (8.76) 0.255 18135 (17.28) 14102 (13.44) 0.107 Inpatient Encounter 6483 (6.18) 810977 (6.93) 0.031 6482 (6.18) 8871 (8.45) 0.088 Comorbidities Overweight and obesity 7576 (7.22) 679654 (5.81) 0.057 7570 (7.21) 7491 (7.14) 0.003 Hypertension 7078 (6.74) 2023378 (17.30) 0.329 7077 (6.74) 7066 (6.73) < 0.001 Hyperlipidemia 3733 (3.56) 1108250 (9.48) 0.242 3733 (3.56) 3625 (3.45) 0.006 Diabetes mellitus 2802 (2.67) 878996 (7.52) 0.222 2802 (2.67) 3639 (3.47) 0.046 Asthma 6735 (6.42) 403966 (3.45) 0.137 6728 (6.41) 6171 (5.88) 0.022 Allergic rhinitis 5009 (4.77) 235943 (2.02) 0.153 5007 (4.77) 3097 (2.95) 0.095 Chronic sinusitis 4926 (4.69) 153569 (1.31) 0.199 4916 (4.68) 4898 (4.67) 0.001 Acute sinusitis 4789 (4.56) 250021 (2.14) 0.135 4786 (4.56) 3344 (3.19) 0.071 Atopic dermatitis 419 (0.40) 25655 (0.22) 0.032 419 (0.40) 542 (0.52) 0.017 Obstructive sleep apnea 4884 (4.65) 266485 (2.28) 0.130 4874 (4.64) 4862 (4.63) 0.001 Rheumatoid arthritis 402 (0.38) 70654 (0.60) 0.032 402 (0.38) 428 (0.41) 0.004 Sjögren syndrome 162 (0.15) 18280 (0.16) < 0.001 162 (0.15) 147 (0.14) 0.004 Medications Corticosteroids for systemic use 25000 (23.82) 1449501 (12.39) 0.300 24992 (23.81) 25016 (23.84) 0.001 Anti-inflammatory and antirheumatic products, non-steroids 19230 (18.32) 1272758 (10.88) 0.212 19226 (18.32) 17189 (16.38) 0.051 Antihistamines for systemic use 14906 (14.20) 968100 (8.28) 0.188 14900 (14.20) 14094 (13.43) 0.022 PSM: Propensity score matching. BMI: Body mass index. SMD: standardized mean difference. Association between chronic tonsillitis and adenoiditis and the risk of ankylosing spondylitis Table 2 presents the primary analysis evaluating the risk of ankylosing spondylitis in the exposure group (chronic tonsillitis and adenoiditis) versus comparison groups. The study results were divided into three models. Model 1 used propensity score matching by age, sex, and race. Model 2 used propensity score matching by age, sex, race, BMI, socioeconomic status, and lifestyle. Model 3 used propensity score matching by age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medications. The study showed that the hazard ratios for the exposure group compared to the comparison group were HR = 1.85 (95% C.I. = 1.42–2.40), HR = 1.69 (95% C.I. = 1.31–2.18), and HR = 1.41 (95% C.I. = 1.11–1.80), respectively. The Kaplan-Meier survival curve (Fig. 2 ) further illustrates a consistent association with the risk of ankylosing spondylitis over the follow-up period for the exposure group (Log-rank, p = 0.005). Table 2 Risk of Ankylosing Spondylitis exposed to exposure group compared to comparison group Model 1 Model 2 Model 3 N 104966 104966 104956 No. of event Comparison group 86 94 112 Exposure group 162 162 162 HR (95% C.I.) 1.85 (1.42–2.40) 1.69 (1.31–2.18) 1.41 (1.11–1.80) Model 1: Propensity score matching by age, sex, and race. Model 2: Propensity score matching by age, sex, race, BMI, social economic status, and lifestyle. Model 3: Propensity score matching by age, sex, race, BMI, social economic status, lifestyle, medical utility, comorbidities, and medications. Subgroup analyses Figure 3 shows the results of the subgroup analysis for the risk of ankylosing spondylitis in the exposure group (chronic tonsillitis and adenoiditis) compared to the comparison group. In the age group of 18 to 64 years and the female subgroup, the exposure group had a significantly higher risk of developing ankylosing spondylitis compared to the comparison group. The hazard ratios were 1.39 (95% C.I. = 1.08–1.78) and 1.36 (95% C.I. = 1.02–1.80), respectively. Sensitivity analysis Table 3 demonstrates the findings from various sensitivity analyses for negative outcome control. No significant association was found between exposure group (chronic tonsillitis and adenoiditis) and outcomes such as burns (HR = 1.09; 95% C.I. = 0.98–1.21), exposure to smoke, fire, and flames (HR = 1.12; 95% CI: 0.76–1.65), gout (HR = 0.99; 95% C.I. = 0.89–1.11), cancer (HR = 0.98; 95% C.I. = 0.93–1.04), and Cerebrovascular diseases (HR = 0.98; 95% CI = 0.91–1.05). These findings support the specificity of the association between the exposure and the risk of ankylosing spondylitis. Table 3 Sensitivity analysis for negative outcome control Exposure group Comparison group N No. of event N No. of event HR (95% C.I.) Negative outcome control Burn 104365 724 104365 655 1.09 (0.98–1.21) Exposure to smoke, fire, and flames 105022 55 105022 49 1.12 (0.76–1.65) Gout 99075 598 99075 584 0.99 (0.89–1.11) Cancer 96587 2381 96587 2333 0.98 (0.93–1.04) Cerebrovascular diseases 98374 1606 98374 1556 0.98 (0.91–1.05) Discussion We performed a nationwide population-based cohort study of 104,966 patients with chronic tonsillitis and adenoiditis, and 104,966 controls without chronic tonsillitis and adenoiditis, and observed a 1.41-fold (95% C.I. = 1.11–1.80) higher incidence of AS in the study group with chronic tonsillitis and adenoiditis compared with controls with no chronic tonsillitis and adenoiditis. In addition, the subgroup analysis has revealed that females and those individuals aged below 65 are at higher risk of developing AS (95% C.I. = 1.08–1.78 and 95% C.I. = 1.02–1.80, respectively). A diverse range of sensitivity analyses reaffirmed the strength and reliability of our main findings. Several evidence have shown that infection, including bacterial, viral, fungal and other microorganisms, may lead to the development of autoimmune diseases. [19–22] In this study, we revealed the relationship between chronic tonsillitis and adenoiditis and the development of AS, further confirming the pathogenic role of infection in AS pathogenesis. Chronic mucosal infections, have been implicated in AS development, likely through mechanisms involving molecular mimicry, bystander activation, or persistent antigenic stimulation[ 23 ]. Chronic tonsillitis leads to dysregulation of immune tolerance, thereby potentially triggering AS. What’s more, Streptococcus pyogenes group A, whose cell wall shares common antigens with human kidneys, hearts, and joints, induces recurrent inflammatory episodes. This cross-reactive immune response may explain the heightened susceptibility to AS observed in patients with chronic tonsillitis and adenoiditis[ 24 ]. In AS patients, the persistent activation of the IL-17/IL-23 axis mediates the chronic inflammatory milieu observed in affected joints[ 25 , 26 ]. As demonstrated by research, Group A streptococcal infection induces TGF-β1 production and subsequent TGF-β1-dependent T helper cell 17 (Th17) differentiation, thus, recurrent tonsillitis may cause the persistence of Th17 cells in the tonsils and the upregulated level of IL-17A[ 27 ], which linked to the development of AS. Also, patients with chronic tonsillitis also exhibit elevated levels of pro-inflammatory cytokines in both peripheral blood and tonsillar tissue, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which share overlapping immune pathways with AS[ 28 ]. These cumulative findings may underlie the heightened AS susceptibility observed in chronic tonsillitis and adenoiditis patients. The tonsils harbor a diverse array of microorganisms that interact closely with the host immune system. A recent study conducted by Li., et al. has identified significant dysbiosis in the tonsillar microbiome of RA patients, particularly manifested as enrichment of pathogenic Streptococcus species, which significantly exacerbates arthritis severity and amplifies autoimmune responses in collagen-induced arthritis[ 29 ]. In addition, emerging evidence suggests that the gut microbiota may modulate AS pathogenesis through complex interactions with host immune system[ 30 ]. Given the critical role of microbial pathogenesis and immunomodulatory mechanisms, future studies are necessary to evaluate the impact of tonsillar microbiome on AS development. In subgroup analyses, females with chronic tonsillitis and adenoiditis demonstrated a stronger association with AS development (HR = 1.36), potentially reflecting sex-specific hormonal modulation of immune responses. Estrogen is well-established to enhance immune reactivity by promoting B-cell and T-cell activation, increasing autoantibody production, and consequently elevating the risk of autoimmune diseases. Furthermore, women exhibit stronger immune responses to infections, characterized by more pronounced release of inflammatory cytokines including IL-17, TNF-α, and IL-6 – all of, which are involved in the pathogenesis of AS[ 31 , 32 ]. Additionally, in our study, the highest risk was observed in adults aged 18–64 years (HR = 1.39), with no significant association in individuals ≥ 65 years (HR = 1.05). Normally, the peak ages for the onset of AS are below 65 years old, while streptococcal tonsillitis usually occurs in school-age children[ 3 ]. The result of our study could be explained by the nature and prevalence of streptococcal tonsillitis and AS development. Furthermore, this pattern aligns with active immune response in youngers and immunosenescence-related immune dampening in older populations as young individuals exhibit a more robust immune response to pathogens, potentially leading to excessive release of inflammatory cytokines for which engaged in the pathogenesis of AS[ 31 ]. Importantly, in this research, no significant associations were found between exposure and non-immune outcomes (e.g., burns, cancer), reinforcing the specificity of the AS link. The strength of this investigation is underscored by its utilization of a vast healthcare claims database, which possesses the theoretical potential to longitudinally track medical records for the entire population cohort under study. The large sample size enabled us select a large sample of patients with an accurate diagnosis of chronic tonsillitis and adenoiditis and AS. Furthermore, compared with non-chronic tonsillitis and adenoiditis controls, subjects with chronic tonsillitis and adenoiditis exhibited a significantly elevated hazard ratio of HRs across all three analytical models. Notably, the magnitude of this association remained statistically significant after sequential adjustment for key confounding variables, demonstrating consistent evidence of the association between chronic tonsillitis and adenoiditis and AS. In addition, we perform a multitude of sensitivity analyses, thereby we confirmed the robustness of our core findings. However, the present study has several limitations. Firstly, despite conducting multivariable analyses, we did not account for all potential confounding factors. For example, information regarding the family history of HLA-B27, an established risk factor contributing to the notably high heritability of AS was not included in the adjustments. Secondly, the comorbid conditions obtained from medical records remain to be further comprehensively collected. A piece of evidence has shown that many viral infections, including SARS-CoV-2, EBV and HPV are likely to be related with a substantial risk for autoimmune and autoinflammatory connective tissue disorders[ 20 , 33 , 34 ]. Further research is needed to exclude the impact of viral infection on the risk of AS in chronic tonsillitis and adenoiditis. What’s more, data on the primary pathogens of chronic tonsillitis, indicators associated with the precise severity of chronic tonsillitis, such as C-reactive protein and erythrocyte sedimentation rate and prior antibiotic and antiviral medication use for its treatment was insufficiency. Additionally, we lack of data on the time interval between the diagnosis dates of chronic tonsillitis and AS, thereby preventing us from investigating investigate the impact of cumulative tonsillitis duration on AS risk. Conclusion This large-scale cohort study revealed that chronic tonsillitis and adenoiditis was associated with increased risk of AS after adjusting for confounders and demographics. Further investigation is needed to clarify the basic mechanism of the association. Prospective studies are warranted to identify the necessity of regular follow-ups and patient education of AS for those patients who had diagnosed with chronic tonsillitis and adenoiditis with potential long-term immune-related complications. Abbreviations AS Ankylosing spondylitis PSM Propensity score matching BMI Body mass index SMD Standardized mean differences HR Hazard ratio Th17 T helper cell 17 TNF-α Tumor necrosis factor-alpha IL-6 Interleukin-6 Declarations Acknowledgements We thank all the researchers who contributed in this study. Author contributions X.W.W., J.C.C.W. and Z.H.Y. were involved in the design of the study, writing of the manuscript, and discussion of mechanism. Y.H.W conducted the data analysis and interpretation. X.W.W. and Y.Z. drafted the manuscript. Y.W. and S.J.D. provided critical feedback and helped shape the interpretation of the results. Z.H.Y. and J.C.C.W. were involved in the supervision and revision of the manuscript. All authors read and approved the final manuscript. Funding This work was supported by The Key Laboratory of Traditional Chinese Medicine Arthritis Diagnosis and Treatment Research in Zhejiang Zhejiang Province (grant number A-2023-W2008). Availability of data and materials The de-identified data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate All participants gave informed consent to participate. This study was approved by the Institutional Review Board for Ethics of Chung Shan Medical University Hospital (IRB number: CS2-21176) and performed in accordance with the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Sharip, A. and J. Kunz, Understanding the Pathogenesis of Spondyloarthritis. Biomolecules, 2020. 10 (10). Dean, L.E., et al., Global prevalence of ankylosing spondylitis. Rheumatology (Oxford), 2014. 53 (4): p. 650-7. Braun, J. and J. Sieper, Ankylosing spondylitis. Lancet, 2007. 369 (9570): p. 1379-1390. Sieper, J., et al., Axial spondyloarthritis. Nat Rev Dis Primers, 2015. 1 : p. 15013. Smith, J.A. and R.A. Colbert, Review: The interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond. Arthritis Rheumatol, 2014. 66 (2): p. 231-41. Mauro, D., et al., Ankylosing spondylitis: an autoimmune or autoinflammatory disease? Nat Rev Rheumatol, 2021. 17 (7): p. 387-404. Bilski, R., et al., Environmental and Genetic Determinants of Ankylosing Spondylitis. Int J Mol Sci, 2024. 25 (14). Lesmeister, M.J., M.R. Bothwell, and M.L. Misfeldt, Toll-like receptor expression in the human nasopharyngeal tonsil (adenoid) and palantine tonsils: a preliminary report. Int J Pediatr Otorhinolaryngol, 2006. 70 (6): p. 987-92. Surján, L., Jr., Tonsils and lympho-epithelial structures in the pharynx as immuno-barriers. Acta Otolaryngol, 1987. 103 (5-6): p. 369-72. Hodson, A.H., Immunology of the tonsils. J R Soc Med, 1991. 84 (1): p. 58. Allen, H.B., et al., Psoriasis, chronic tonsillitis, and biofilms: Tonsillar pathologic findings supporting a microbial hypothesis. Ear Nose Throat J, 2018. 97 (3): p. 79-82. Cunningham, M.W., Pathogenesis of group A streptococcal infections and their sequelae. Adv Exp Med Biol, 2008. 609 : p. 29-42. Groot, J., et al., Presence of streptococci and frequent tonsillitis among adolescents with psoriasis. Br J Dermatol, 2021. 184 (4): p. 758-759. Harabuchi, Y. and M. Takahara, Pathogenic role of palatine tonsils in palmoplantar pustulosis: A review. J Dermatol, 2019. 46 (11): p. 931-939. Takahara, M., et al., Treatment outcome and prognostic factors of tonsillectomy for palmoplantar pustulosis and pustulotic arthro-osteitis: A retrospective subjective and objective quantitative analysis of 138 patients. J Dermatol, 2018. 45 (7): p. 812-823. Demesh, D., J.M. Virbalas, and J.P. Bent, The role of tonsillectomy in the treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). JAMA Otolaryngol Head Neck Surg, 2015. 141 (3): p. 272-5. Lindström, U., et al., Childhood hospitalisation with infections and later development of ankylosing spondylitis: a national case-control study. Arthritis Res Ther, 2016. 18 (1): p. 240. Chao, W.C., et al., Association between tonsillitis and newly diagnosed ankylosing spondylitis: A nationwide, population-based, case-control study. PLoS One, 2019. 14 (8): p. e0220721. Wei, J.C., et al., The association between Candida infection and ankylosing spondylitis: a population-based matched cohort study. Curr Med Res Opin, 2020. 36 (12): p. 2063-2069. Wei, C.Y., et al., Risk of ankylosing spondylitis following human papillomavirus infection: A nationwide, population-based, cohort study. J Autoimmun, 2020. 113 : p. 102482. Attaway, A.H., et al., Subacute Invasive Pulmonary Aspergillosis Associated with Ankylosing Spondylitis. Am J Respir Crit Care Med, 2016. 193 (5): p. 572-3. Smatti, M.K., et al., Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms. Viruses, 2019. 11 (8). Zhang, X., et al., Association Between Infections and Risk of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis. Front Immunol, 2021. 12 : p. 768741. Trier, N.H. and G. Houen, Antibody Cross-Reactivity in Auto-Immune Diseases. Int J Mol Sci, 2023. 24 (17). McGonagle, D.G., et al., The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann Rheum Dis, 2019. 78 (9): p. 1167-1178. Khan, M.A., S.B. Yong, and J.C. Wei, Ankylosing spondylitis: History, epidemiology, and HLA-B27. Int J Rheum Dis, 2023. 26 (3): p. 413-414. Wang, B., et al., Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection. Proc Natl Acad Sci U S A, 2010. 107 (13): p. 5937-42. Todorović, M.M. and E.Z. Zvrko, Immunoregulatory cytokines and chronic tonsillitis. Bosn J Basic Med Sci, 2013. 13 (4): p. 230-6. Li, J., et al., The aberrant tonsillar microbiota modulates autoimmune responses in rheumatoid arthritis. JCI Insight, 2024. 9 (18). Asquith, M., et al., HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome. Arthritis Rheumatol, 2019. 71 (10): p. 1642-1650. Giefing-Kröll, C., et al., How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell, 2015. 14 (3): p. 309-21. Goetzl, E.J., et al., Gender specificity of altered human immune cytokine profiles in aging. Faseb j, 2010. 24 (9): p. 3580-9. Lim, S.H., et al., Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19. JAMA Netw Open, 2023. 6 (10): p. e2336120. Robinson, W.H., et al., Epstein-Barr virus as a potentiator of autoimmune diseases. Nat Rev Rheumatol, 2024. 20 (11): p. 729-740. Additional Declarations No competing interests reported. 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Hangzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zhi","middleName":"","lastName":"Ye","suffix":""},{"id":594089250,"identity":"58ddf94e-ec6b-4c65-a310-d11969e88ff3","order_by":2,"name":"Yu Wang","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital, Hangzhou Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Wang","suffix":""},{"id":594089256,"identity":"1b03de3c-08c3-4fbf-9c8f-30e7e5698b37","order_by":3,"name":"Shuai jie Ding","email":"","orcid":"","institution":"Hangzhou Normal University","correspondingAuthor":false,"prefix":"","firstName":"Shuai","middleName":"jie","lastName":"Ding","suffix":""},{"id":594089257,"identity":"17c6fc9a-fa29-4810-b56c-0aeaea7f11a4","order_by":4,"name":"Yu-Hsun Wang","email":"","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu-Hsun","middleName":"","lastName":"Wang","suffix":""},{"id":594089262,"identity":"d161a03e-3216-4283-88de-7af2adfa7f4c","order_by":5,"name":"James Cheng-Chung Wei","email":"","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"Cheng-Chung","lastName":"Wei","suffix":""},{"id":594089263,"identity":"42b4bab2-6e0b-4db8-abd6-7f05b2c4651e","order_by":6,"name":"Zhenhua 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13:08:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8106028/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8106028/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103177407,"identity":"8265deb5-fe60-4073-95de-22bb84bb26a4","added_by":"auto","created_at":"2026-02-22 16:50:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41047,"visible":true,"origin":"","legend":"\u003cp\u003eFlow-chart of subject selection\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8106028/v1/98ecf3111836c048779d9c1e.png"},{"id":103177408,"identity":"caf0302c-0f96-4672-b7c7-496e15436dae","added_by":"auto","created_at":"2026-02-22 16:50:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":71302,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier plot for risk of Ankylosing Spondylitis\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8106028/v1/61f63587d1c03770ba571265.png"},{"id":103177409,"identity":"3539b4c4-e7c3-40a0-b270-e85d0b8904dc","added_by":"auto","created_at":"2026-02-22 16:50:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":113553,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for subgroup analysis of risk of Ankylosing Spondylitis\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8106028/v1/c0e0739170105f0788971813.png"},{"id":103505261,"identity":"760b9fa7-a17b-4d02-bc89-d2967dc7faac","added_by":"auto","created_at":"2026-02-26 13:29:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1357490,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8106028/v1/eea691d0-ef7e-447a-aafe-083ca5cabcc0.pdf"},{"id":103177410,"identity":"e88fa721-f5e3-49fe-969c-44c40bf1ecaf","added_by":"auto","created_at":"2026-02-22 16:50:56","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":12664,"visible":true,"origin":"","legend":"","description":"","filename":"SupTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-8106028/v1/ba38866b2c50a0c755aa7434.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk of ankylosing spondylitis following chronic tonsillitis and adenoiditis: a retrospective cohort study utilizing TriNetX global collaborative network","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnkylosing spondylitis (AS), an immune-mediated arthritis that has long been regarded as the archetypal condition within the spectrum of spondyloarthritis[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].It was estimated that the global prevalence of AS is estimated to range from 0.1% to 1.4%. The first clinical manifestations typically emerge between ages 26 and 45 years, with a male-to-female predominance of 2:1 to 3:1 as established through clinical epidemiology study[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The main clinical feature of AS is chronic back pain, which can lead to aberrant bone remodeling and ankylosis, the following structural and functional impairments have a negative impact on the quality of life[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The reasons for the occurrence of AS are believed to be genetic and environmental factors. Genetic epidemiology identifies HLA-B27 as the most significant susceptibility allele for AS, with its pathogenic role mediated through distinct molecular aberrations[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The allele's propensity to form B27 dimers via aberrant protein folding, disrupting canonical antigen presentation. This structural alteration activates the proinflammatory IL-23/IL-17 axis, a key pathway implicated in AS immunopathogenesis[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Beyond established genetic contributors, accumulating evidence highlights the critical role of infections in AS, which are implicated in activating adaptive immune responses that may drive autoimmunity through molecular mimicry or epitope spreading mechanisms[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe tonsillar apparatus serves as the primary immune barrier at the junction of the digestive and respiratory tracts, defending against ingested pathogens and inhaled allergens. As a lymphoid organ complex, it comprises four distinct anatomical regions: the paired palatine tonsils, the nasopharyngeal or adenoid tonsil, the paired tubal tonsils, and the lingual tonsil[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Tonsils and adenoids, as the secondary lymphoid organs, are crucial for the immune system\u0026rsquo;s first line of defense, particularly in the recognition of pathogens and the initiation of immune responses by producing secretory IgA and fostering T-cell differentiation[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Chronic inflammation in these tissues\u0026mdash;frequently triggered by recurrent bacterial (e.g., Group A streptococcal) or viral infections\u0026mdash;are associated with biofilm formation, tissue remodeling, and aberrant adaptive immune responses[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Associations were observed between recurrent tonsillitis and various autoimmune diseases, such as rheumatic fever, rheumatic heart disease, psoriasis and palmar plantar pustulosis. And it is hypothesized that these conditions may arise from a disruption of immune tolerance mechanisms toward resident microorganisms in the tonsils[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Tonsillectomy may be a potential option for patients with recalcitrant autoimmune diseases, and has been proven to effectively reduce disease activity of psoriasis[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], palmoplantar pustulosis and pustulotic arthro-osteitis[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and pediatric autoimmune neuropsychiatric disorder associated with streptococcus[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Study on the role of chronic tonsillitis and adenoiditis in the development of AS is limited. Previous researches have revealed that tonsillitis may be a risk factor for AS[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], while the potential causal relationship between chronic tonsillitis and AS remains unclear.\u003c/p\u003e \u003cp\u003eTo this end, we performed this long-term population-based study to elucidate the relationship between chronic tonsillitis and adenoiditis in adults and the risk of new-onset AS using data derived from the de-identified electronic health records from TriNetX, a U.S.-based collaborative network.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eData source\u003c/h2\u003e\n \u003cp\u003eThis retrospective cohort study utilized de-identified electronic health records from TriNetX, a U.S.-based collaborative network encompassing data on approximately 116\u0026nbsp;million patients. The dataset includes information from various healthcare environments, such as hospitals, primary care facilities, and specialty clinics, and contains anonymized patient records. Key data components include demographic information, diagnoses coded using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), medications classified by the Anatomical Therapeutic Chemical (ATC) system and standardized via RxNorm, procedures recorded with ICD-10-PCS, Current Procedural Terminology, and Systematized Nomenclature of Medicine, as well as laboratory test results coded with Logical Observation Identifier Names and Codes.\u003c/p\u003e\n \u003cp\u003eTriNetX serves as a global federated platform for real-world data integration and analysis, supporting diverse research initiatives (Palchuk et al., 2023). This study was exempted from informed consent requirements under Section §\u0026nbsp;164.514(a) of the HIPAA Privacy Rule due to its reliance on anonymized secondary data without direct interaction with human subjects. The de-identification process adhered to Section §\u0026nbsp;164.514(b)(1) of the HIPAA Privacy Rule, verified by a qualified expert. Ethical approval was granted by the Institutional Review Board of Chung Shan Medical University Hospital (IRB No.: CS2-21176).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eFigure 1 illustrates the flowchart for cohort construction. The exposure population included individuals aged 18 or older who were diagnosed with chronic tonsillitis and adenoiditis (ICD-10-CM: J35.0) between 2016 and 2023. The comparison group consisted of individuals aged 18 or older who had an encounter for a general adult medical examination (ICD-10-CM: Z00.0) between 2006 and 2023. The index date was defined as the date of the first diagnosis of chronic tonsillitis and adenoiditis or the first visit for a general adult medical examination. Both cohorts excluded individuals diagnosed with ankylosing spondylitis (ICD-10-CM: M45) or juvenile ankylosing spondylitis (ICD-10-CM: M08.1) before the index date.\u003c/p\u003e\n\u003cp\u003eBaseline data, including age, sex, race, body mass index (BMI), socioeconomic status, lifestyle, medical utilization, comorbid conditions, and medication use were collected from medical records covering the year preceding the index date. Medical utilization included ambulatory care visits, emergency department visits, and inpatient admissions. Comorbidities assessed included overweight and obesity, hypertension, hyperlipidemia, diabetes mellitus, asthma, allergic rhinitis, chronic sinusitis, acute sinusitis, atopic dermatitis, obstructive sleep apnea, rheumatoid arthritis, and Sjögren syndrome. Medication data focused on corticosteroids for systemic use, anti-inflammatory and antirheumatic products (non-steroids), and antihistamines for systemic use. Detailed codes are provided in \u003cstrong\u003eSupplementary Table\u0026nbsp;1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003ePropensity score matching (PSM) was implemented to address baseline differences and control for confounding factors. A 1:1 matching ratio was applied using the TriNetX platform, considering variables such as age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medication. A greedy nearest-neighbor algorithm with a caliper of 0.1 pooled standard deviations was employed. The primary goal was to assess the risk of ankylosing spondylitis (ICD-10-CM: M45) in the exposure and comparison cohorts. Participants were followed until the first occurrence of ankylosing spondylitis or their last recorded medical event within the US collaborative network.\u003c/p\u003e\n\u003cdiv id=\"Sec5\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analyses were performed using the TriNetX platform. Balance between matched cohorts was evaluated using standardized mean differences (SMD), with values below 0.1 indicating sufficient balance. Kaplan-Meier survival analysis was used to compare the cumulative incidence of ankylosing spondylitis between the cohorts, with statistical significance assessed via the log-rank test. Cox proportional hazards models were utilized to estimate the relationship between cohort assignment and the risk of ankylosing spondylitis, presenting hazard ratios (HRs) with 95% confidence intervals.\u003c/p\u003e\n \u003cp\u003eSubgroup analyses examined the association between chronic tonsillitis and adenoiditis and ankylosing spondylitis in subgroups stratified by age, sex, and, race. To ensure the robustness of the findings, in this sensitivity analysis, this study incorporated five different negative outcome controls. These included burns (ICD-10-CM: T20-T25), exposure to smoke, fire, and flames (ICD-10-CM: X00-X08), gout (ICD-10-CM: M10), cancer (ICD-10-CM: C00-C96), and cerebrovascular diseases (ICD-10-CM: I60-I69). These negative control outcomes were selected to strengthen the reliability of the study conclusions. All statistical procedures were conducted on the TriNetX platform, which integrates R 4.0.2 for advanced analyses.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBaseline demographics and clinical characteristics\u003c/h2\u003e \u003cp\u003eAfter performing propensity score matching, the study included 104,956 individuals in both the exposure group (chronic tonsillitis and adenoiditis) and the matched comparison group. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the demographic and clinical characteristics before and after PSM. Before PSM, there were significant differences in age (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 30.80\u0026thinsp;\u0026plusmn;\u0026thinsp;12.35 in the exposure group vs. 46.95\u0026thinsp;\u0026plusmn;\u0026thinsp;17.59 in the comparison group, SMD\u0026thinsp;=\u0026thinsp;1.063), sex, medical utilization, hypertension, hyperlipidemia, diabetes mellitus, asthma, allergic rhinitis, chronic sinusitis, acute sinusitis, obstructive sleep apnea, and medication distribution. Following PSM, the groups were well-balanced with minimal differences across key variables, including age, sex, and medical utilization. Other covariates such as comorbidities, and medications were similarly balanced after PSM, ensuring comparability between the exposure and the comparison cohorts.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of exposure group and comparison group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBefore PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eAfter PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExposure group N\u0026thinsp;=\u0026thinsp;104966\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComparison group\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11696620\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExposure group N\u0026thinsp;=\u0026thinsp;104956\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComparison group\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;104956\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.80\u0026thinsp;\u0026plusmn;\u0026thinsp;12.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46.95\u0026thinsp;\u0026plusmn;\u0026thinsp;17.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.063\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30.80\u0026thinsp;\u0026plusmn;\u0026thinsp;12.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.80\u0026thinsp;\u0026plusmn;\u0026thinsp;12.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71995 (68.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6293629 (53.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.307\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71986 (68.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e70008 (66.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29108 (27.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4754807 (40.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.275\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29108 (27.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29093 (27.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown Gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3863 (3.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e648184 (5.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3862 (3.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5855 (5.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.090\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRace\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66807 (63.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7320262 (62.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66806 (63.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e61701 (58.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack or African American\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12927 (12.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1572854 (13.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12923 (12.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16097 (15.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian characteristic(s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3964 (3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e538330 (4.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3963 (3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5187 (4.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNative Hawaiian or Other Pacific Islander\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e814 (0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80027 (0.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e814 (0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e514 (0.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmerican Indian or Alaska Native\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e411 (0.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33772 (0.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e411 (0.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e338 (0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther Race\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5028 (4.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e480698 (4.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5027 (4.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5208 (4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown Race\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15015 (14.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1670677 (14.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15012 (14.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15911 (15.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.14\u0026thinsp;\u0026plusmn;\u0026thinsp;7.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.43\u0026thinsp;\u0026plusmn;\u0026thinsp;7.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29.14\u0026thinsp;\u0026plusmn;\u0026thinsp;7.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.96\u0026thinsp;\u0026plusmn;\u0026thinsp;8.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSocial economic status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersons with potential health hazards related to\u003c/p\u003e \u003cp\u003esocioeconomic and psychosocial circumstances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e785 (0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82145 (0.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e783 (0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1107 (1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHousing/economic circumstances problem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23636 (0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e129 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e261 (0.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProblems related to education and literacy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3300 (0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmployment or unemployment problems\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8382 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e66 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e124 (0.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccupational exposure to risk factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4840 (0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58 (0.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81 (0.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLifestyle\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersonal history of nicotine dependence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1908 (1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e310858 (2.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1907 (1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2018 (1.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNicotine dependence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3968 (3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e384535 (3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3967 (3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3612 (3.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlcohol related disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e573 (0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105040 (0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e573 (0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e834 (0.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedical utilization\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmbulatory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68448 (65.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6523681 (55.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.194\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68438 (65.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e68452 (65.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmergency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18138 (17.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1025052 (8.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.255\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18135 (17.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14102 (13.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.107\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInpatient Encounter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6483 (6.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e810977 (6.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6482 (6.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8871 (8.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.088\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverweight and obesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7576 (7.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e679654 (5.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7570 (7.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7491 (7.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7078 (6.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2023378 (17.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.329\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7077 (6.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7066 (6.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3733 (3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1108250 (9.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.242\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3733 (3.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3625 (3.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2802 (2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e878996 (7.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.222\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2802 (2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3639 (3.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6735 (6.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e403966 (3.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.137\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6728 (6.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6171 (5.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllergic rhinitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5009 (4.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e235943 (2.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.153\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5007 (4.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3097 (2.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic sinusitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4926 (4.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e153569 (1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.199\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4916 (4.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4898 (4.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute sinusitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4789 (4.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e250021 (2.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.135\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4786 (4.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3344 (3.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtopic dermatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e419 (0.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25655 (0.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e419 (0.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e542 (0.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObstructive sleep apnea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4884 (4.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e266485 (2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.130\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4874 (4.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4862 (4.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e402 (0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70654 (0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e402 (0.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e428 (0.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSj\u0026ouml;gren syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162 (0.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18280 (0.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e162 (0.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e147 (0.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedications\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorticosteroids for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25000 (23.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1449501 (12.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.300\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24992 (23.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25016 (23.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-inflammatory and antirheumatic products,\u003c/p\u003e \u003cp\u003enon-steroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19230 (18.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1272758 (10.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.212\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19226 (18.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17189 (16.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntihistamines for systemic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14906 (14.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e968100 (8.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.188\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14900 (14.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14094 (13.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePSM: Propensity score matching. BMI: Body mass index. SMD: standardized mean difference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between chronic tonsillitis and adenoiditis and the risk of ankylosing spondylitis\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the primary analysis evaluating the risk of ankylosing spondylitis in the exposure group (chronic tonsillitis and adenoiditis) versus comparison groups. The study results were divided into three models. Model 1 used propensity score matching by age, sex, and race. Model 2 used propensity score matching by age, sex, race, BMI, socioeconomic status, and lifestyle. Model 3 used propensity score matching by age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medications. The study showed that the hazard ratios for the exposure group compared to the comparison group were HR\u0026thinsp;=\u0026thinsp;1.85 (95% C.I. = 1.42\u0026ndash;2.40), HR\u0026thinsp;=\u0026thinsp;1.69 (95% C.I. = 1.31\u0026ndash;2.18), and HR\u0026thinsp;=\u0026thinsp;1.41 (95% C.I. = 1.11\u0026ndash;1.80), respectively. The Kaplan-Meier survival curve (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) further illustrates a consistent association with the risk of ankylosing spondylitis over the follow-up period for the exposure group (Log-rank, p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk of Ankylosing Spondylitis exposed to exposure group compared to comparison group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModel 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eModel 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eModel 3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104966\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e104966\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104956\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of event\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComparison group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHR (95% C.I.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.85 (1.42\u0026ndash;2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.69 (1.31\u0026ndash;2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.41 (1.11\u0026ndash;1.80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eModel 1: Propensity score matching by age, sex, and race.\u003c/p\u003e \u003cp\u003eModel 2: Propensity score matching by age, sex, race, BMI, social economic status, and lifestyle.\u003c/p\u003e \u003cp\u003eModel 3: Propensity score matching by age, sex, race, BMI, social economic status, lifestyle, medical utility, comorbidities, and medications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSubgroup analyses\u003c/h3\u003e\n\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the results of the subgroup analysis for the risk of ankylosing spondylitis in the exposure group (chronic tonsillitis and adenoiditis) compared to the comparison group. In the age group of 18 to 64 years and the female subgroup, the exposure group had a significantly higher risk of developing ankylosing spondylitis compared to the comparison group. The hazard ratios were 1.39 (95% C.I. = 1.08\u0026ndash;1.78) and 1.36 (95% C.I. = 1.02\u0026ndash;1.80), respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSensitivity analysis\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e demonstrates the findings from various sensitivity analyses for negative outcome control. No significant association was found between exposure group (chronic tonsillitis and adenoiditis) and outcomes such as burns (HR\u0026thinsp;=\u0026thinsp;1.09; 95% C.I. = 0.98\u0026ndash;1.21), exposure to smoke, fire, and flames (HR\u0026thinsp;=\u0026thinsp;1.12; 95% CI: 0.76\u0026ndash;1.65), gout (HR\u0026thinsp;=\u0026thinsp;0.99; 95% C.I. = 0.89\u0026ndash;1.11), cancer (HR\u0026thinsp;=\u0026thinsp;0.98; 95% C.I. = 0.93\u0026ndash;1.04), and Cerebrovascular diseases (HR\u0026thinsp;=\u0026thinsp;0.98; 95% CI\u0026thinsp;=\u0026thinsp;0.91\u0026ndash;1.05). These findings support the specificity of the association between the exposure and the risk of ankylosing spondylitis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analysis for negative outcome control\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eExposure group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eComparison group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo. of event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo. of event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR (95% C.I.)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative outcome control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBurn\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e104365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e724\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e104365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e655\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.09 (0.98\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure to smoke, fire, and flames\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e105022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.12 (0.76\u0026ndash;1.65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGout\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e99075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e598\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e99075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e584\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.99 (0.89\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e96587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2381\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.98 (0.93\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebrovascular diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e98374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1606\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e98374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.98 (0.91\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe performed a nationwide population-based cohort study of 104,966 patients with chronic tonsillitis and adenoiditis, and 104,966 controls without chronic tonsillitis and adenoiditis, and observed a 1.41-fold (95% C.I. = 1.11\u0026ndash;1.80) higher incidence of AS in the study group with chronic tonsillitis and adenoiditis compared with controls with no chronic tonsillitis and adenoiditis. In addition, the subgroup analysis has revealed that females and those individuals aged below 65 are at higher risk of developing AS (95% C.I. = 1.08\u0026ndash;1.78 and 95% C.I. = 1.02\u0026ndash;1.80, respectively). A diverse range of sensitivity analyses reaffirmed the strength and reliability of our main findings.\u003c/p\u003e \u003cp\u003eSeveral evidence have shown that infection, including bacterial, viral, fungal and other microorganisms, may lead to the development of autoimmune diseases.\u003csup\u003e[19\u0026ndash;22]\u003c/sup\u003e In this study, we revealed the relationship between chronic tonsillitis and adenoiditis and the development of AS, further confirming the pathogenic role of infection in AS pathogenesis. Chronic mucosal infections, have been implicated in AS development, likely through mechanisms involving molecular mimicry, bystander activation, or persistent antigenic stimulation[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Chronic tonsillitis leads to dysregulation of immune tolerance, thereby potentially triggering AS. What\u0026rsquo;s more, Streptococcus pyogenes group A, whose cell wall shares common antigens with human kidneys, hearts, and joints, induces recurrent inflammatory episodes. This cross-reactive immune response may explain the heightened susceptibility to AS observed in patients with chronic tonsillitis and adenoiditis[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn AS patients, the persistent activation of the IL-17/IL-23 axis mediates the chronic inflammatory milieu observed in affected joints[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. As demonstrated by research, Group A streptococcal infection induces TGF-β1 production and subsequent TGF-β1-dependent T helper cell 17 (Th17) differentiation, thus, recurrent tonsillitis may cause the persistence of Th17 cells in the tonsils and the upregulated level of IL-17A[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], which linked to the development of AS. Also, patients with chronic tonsillitis also exhibit elevated levels of pro-inflammatory cytokines in both peripheral blood and tonsillar tissue, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which share overlapping immune pathways with AS[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These cumulative findings may underlie the heightened AS susceptibility observed in chronic tonsillitis and adenoiditis patients.\u003c/p\u003e \u003cp\u003eThe tonsils harbor a diverse array of microorganisms that interact closely with the host immune system. A recent study conducted by Li., et al. has identified significant dysbiosis in the tonsillar microbiome of RA patients, particularly manifested as enrichment of pathogenic Streptococcus species, which significantly exacerbates arthritis severity and amplifies autoimmune responses in collagen-induced arthritis[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In addition, emerging evidence suggests that the gut microbiota may modulate AS pathogenesis through complex interactions with host immune system[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Given the critical role of microbial pathogenesis and immunomodulatory mechanisms, future studies are necessary to evaluate the impact of tonsillar microbiome on AS development.\u003c/p\u003e \u003cp\u003eIn subgroup analyses, females with chronic tonsillitis and adenoiditis demonstrated a stronger association with AS development (HR\u0026thinsp;=\u0026thinsp;1.36), potentially reflecting sex-specific hormonal modulation of immune responses. Estrogen is well-established to enhance immune reactivity by promoting B-cell and T-cell activation, increasing autoantibody production, and consequently elevating the risk of autoimmune diseases. Furthermore, women exhibit stronger immune responses to infections, characterized by more pronounced release of inflammatory cytokines including IL-17, TNF-α, and IL-6 \u0026ndash; all of, which are involved in the pathogenesis of AS[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, in our study, the highest risk was observed in adults aged 18\u0026ndash;64 years (HR\u0026thinsp;=\u0026thinsp;1.39), with no significant association in individuals\u0026thinsp;\u0026ge;\u0026thinsp;65 years (HR\u0026thinsp;=\u0026thinsp;1.05). Normally, the peak ages for the onset of AS are below 65 years old, while streptococcal tonsillitis usually occurs in school-age children[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The result of our study could be explained by the nature and prevalence of streptococcal tonsillitis and AS development. Furthermore, this pattern aligns with active immune response in youngers and immunosenescence-related immune dampening in older populations as young individuals exhibit a more robust immune response to pathogens, potentially leading to excessive release of inflammatory cytokines for which engaged in the pathogenesis of AS[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Importantly, in this research, no significant associations were found between exposure and non-immune outcomes (e.g., burns, cancer), reinforcing the specificity of the AS link.\u003c/p\u003e \u003cp\u003eThe strength of this investigation is underscored by its utilization of a vast healthcare claims database, which possesses the theoretical potential to longitudinally track medical records for the entire population cohort under study. The large sample size enabled us select a large sample of patients with an accurate diagnosis of chronic tonsillitis and adenoiditis and AS. Furthermore, compared with non-chronic tonsillitis and adenoiditis controls, subjects with chronic tonsillitis and adenoiditis exhibited a significantly elevated hazard ratio of HRs across all three analytical models. Notably, the magnitude of this association remained statistically significant after sequential adjustment for key confounding variables, demonstrating consistent evidence of the association between chronic tonsillitis and adenoiditis and AS. In addition, we perform a multitude of sensitivity analyses, thereby we confirmed the robustness of our core findings.\u003c/p\u003e \u003cp\u003eHowever, the present study has several limitations. Firstly, despite conducting multivariable analyses, we did not account for all potential confounding factors. For example, information regarding the family history of HLA-B27, an established risk factor contributing to the notably high heritability of AS was not included in the adjustments. Secondly, the comorbid conditions obtained from medical records remain to be further comprehensively collected. A piece of evidence has shown that many viral infections, including SARS-CoV-2, EBV and HPV are likely to be related with a substantial risk for autoimmune and autoinflammatory connective tissue disorders[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Further research is needed to exclude the impact of viral infection on the risk of AS in chronic tonsillitis and adenoiditis. What\u0026rsquo;s more, data on the primary pathogens of chronic tonsillitis, indicators associated with the precise severity of chronic tonsillitis, such as C-reactive protein and erythrocyte sedimentation rate and prior antibiotic and antiviral medication use for its treatment was insufficiency. Additionally, we lack of data on the time interval between the diagnosis dates of chronic tonsillitis and AS, thereby preventing us from investigating investigate the impact of cumulative tonsillitis duration on AS risk.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis large-scale cohort study revealed that chronic tonsillitis and adenoiditis was associated with increased risk of AS after adjusting for confounders and demographics. Further investigation is needed to clarify the basic mechanism of the association. Prospective studies are warranted to identify the necessity of regular follow-ups and patient education of AS for those patients who had diagnosed with chronic tonsillitis and adenoiditis with potential long-term immune-related complications.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Ankylosing spondylitis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePSM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Propensity score matching\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Body mass index\u003c/p\u003e\n\u003cp\u003eSMD \u0026nbsp; \u0026nbsp; \u0026nbsp; Standardized mean differences\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Hazard ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTh17 \u0026nbsp; \u0026nbsp; \u0026nbsp; T helper cell 17\u003c/p\u003e\n\u003cp\u003eTNF-\u0026alpha; \u0026nbsp; \u0026nbsp; \u0026nbsp;Tumor necrosis factor-alpha\u003c/p\u003e\n\u003cp\u003eIL-6 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Interleukin-6\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the researchers who contributed in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.W.W., J.C.C.W. and Z.H.Y. were involved in the design of the study, writing of the manuscript, and discussion of mechanism. Y.H.W conducted the data analysis and interpretation. X.W.W. and Y.Z. drafted the manuscript. Y.W. and S.J.D. provided critical feedback and helped shape the interpretation of the results. Z.H.Y. and J.C.C.W. were involved in the supervision and revision of the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by The Key Laboratory of Traditional Chinese Medicine Arthritis Diagnosis and Treatment Research in Zhejiang Zhejiang Province (grant number A-2023-W2008).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe de-identified data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants gave informed consent to participate. This study was approved by the Institutional Review Board for Ethics of Chung Shan Medical University Hospital (IRB number: CS2-21176) and performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSharip, A. and J. Kunz, \u003cem\u003eUnderstanding the Pathogenesis of Spondyloarthritis.\u003c/em\u003e Biomolecules, 2020. \u003cstrong\u003e10\u003c/strong\u003e(10).\u003c/li\u003e\n\u003cli\u003eDean, L.E., et al., \u003cem\u003eGlobal prevalence of ankylosing spondylitis.\u003c/em\u003e Rheumatology (Oxford), 2014. \u003cstrong\u003e53\u003c/strong\u003e(4): p. 650-7.\u003c/li\u003e\n\u003cli\u003eBraun, J. and J. Sieper, \u003cem\u003eAnkylosing spondylitis.\u003c/em\u003e Lancet, 2007. \u003cstrong\u003e369\u003c/strong\u003e(9570): p. 1379-1390.\u003c/li\u003e\n\u003cli\u003eSieper, J., et al., \u003cem\u003eAxial spondyloarthritis.\u003c/em\u003e Nat Rev Dis Primers, 2015. \u003cstrong\u003e1\u003c/strong\u003e: p. 15013.\u003c/li\u003e\n\u003cli\u003eSmith, J.A. and R.A. Colbert, \u003cem\u003eReview: The interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond.\u003c/em\u003e Arthritis Rheumatol, 2014. \u003cstrong\u003e66\u003c/strong\u003e(2): p. 231-41.\u003c/li\u003e\n\u003cli\u003eMauro, D., et al., \u003cem\u003eAnkylosing spondylitis: an autoimmune or autoinflammatory disease?\u003c/em\u003e Nat Rev Rheumatol, 2021. \u003cstrong\u003e17\u003c/strong\u003e(7): p. 387-404.\u003c/li\u003e\n\u003cli\u003eBilski, R., et al., \u003cem\u003eEnvironmental and Genetic Determinants of Ankylosing Spondylitis.\u003c/em\u003e Int J Mol Sci, 2024. \u003cstrong\u003e25\u003c/strong\u003e(14).\u003c/li\u003e\n\u003cli\u003eLesmeister, M.J., M.R. Bothwell, and M.L. Misfeldt, \u003cem\u003eToll-like receptor expression in the human nasopharyngeal tonsil (adenoid) and palantine tonsils: a preliminary report.\u003c/em\u003e Int J Pediatr Otorhinolaryngol, 2006. \u003cstrong\u003e70\u003c/strong\u003e(6): p. 987-92.\u003c/li\u003e\n\u003cli\u003eSurj\u0026aacute;n, L., Jr., \u003cem\u003eTonsils and lympho-epithelial structures in the pharynx as immuno-barriers.\u003c/em\u003e Acta Otolaryngol, 1987. \u003cstrong\u003e103\u003c/strong\u003e(5-6): p. 369-72.\u003c/li\u003e\n\u003cli\u003eHodson, A.H., \u003cem\u003eImmunology of the tonsils.\u003c/em\u003e J R Soc Med, 1991. \u003cstrong\u003e84\u003c/strong\u003e(1): p. 58.\u003c/li\u003e\n\u003cli\u003eAllen, H.B., et al., \u003cem\u003ePsoriasis, chronic tonsillitis, and biofilms: Tonsillar pathologic findings supporting a microbial hypothesis.\u003c/em\u003e Ear Nose Throat J, 2018. \u003cstrong\u003e97\u003c/strong\u003e(3): p. 79-82.\u003c/li\u003e\n\u003cli\u003eCunningham, M.W., \u003cem\u003ePathogenesis of group A streptococcal infections and their sequelae.\u003c/em\u003e Adv Exp Med Biol, 2008. \u003cstrong\u003e609\u003c/strong\u003e: p. 29-42.\u003c/li\u003e\n\u003cli\u003eGroot, J., et al., \u003cem\u003ePresence of streptococci and frequent tonsillitis among adolescents with psoriasis.\u003c/em\u003e Br J Dermatol, 2021. \u003cstrong\u003e184\u003c/strong\u003e(4): p. 758-759.\u003c/li\u003e\n\u003cli\u003eHarabuchi, Y. and M. Takahara, \u003cem\u003ePathogenic role of palatine tonsils in palmoplantar pustulosis: A review.\u003c/em\u003e J Dermatol, 2019. \u003cstrong\u003e46\u003c/strong\u003e(11): p. 931-939.\u003c/li\u003e\n\u003cli\u003eTakahara, M., et al., \u003cem\u003eTreatment outcome and prognostic factors of tonsillectomy for palmoplantar pustulosis and pustulotic arthro-osteitis: A retrospective subjective and objective quantitative analysis of 138 patients.\u003c/em\u003e J Dermatol, 2018. \u003cstrong\u003e45\u003c/strong\u003e(7): p. 812-823.\u003c/li\u003e\n\u003cli\u003eDemesh, D., J.M. Virbalas, and J.P. Bent, \u003cem\u003eThe role of tonsillectomy in the treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).\u003c/em\u003e JAMA Otolaryngol Head Neck Surg, 2015. \u003cstrong\u003e141\u003c/strong\u003e(3): p. 272-5.\u003c/li\u003e\n\u003cli\u003eLindstr\u0026ouml;m, U., et al., \u003cem\u003eChildhood hospitalisation with infections and later development of ankylosing spondylitis: a national case-control study.\u003c/em\u003e Arthritis Res Ther, 2016. \u003cstrong\u003e18\u003c/strong\u003e(1): p. 240.\u003c/li\u003e\n\u003cli\u003eChao, W.C., et al., \u003cem\u003eAssociation between tonsillitis and newly diagnosed ankylosing spondylitis: A nationwide, population-based, case-control study.\u003c/em\u003e PLoS One, 2019. \u003cstrong\u003e14\u003c/strong\u003e(8): p. e0220721.\u003c/li\u003e\n\u003cli\u003eWei, J.C., et al., \u003cem\u003eThe association between Candida infection and ankylosing spondylitis: a population-based matched cohort study.\u003c/em\u003e Curr Med Res Opin, 2020. \u003cstrong\u003e36\u003c/strong\u003e(12): p. 2063-2069.\u003c/li\u003e\n\u003cli\u003eWei, C.Y., et al., \u003cem\u003eRisk of ankylosing spondylitis following human papillomavirus infection: A nationwide, population-based, cohort study.\u003c/em\u003e J Autoimmun, 2020. \u003cstrong\u003e113\u003c/strong\u003e: p. 102482.\u003c/li\u003e\n\u003cli\u003eAttaway, A.H., et al., \u003cem\u003eSubacute Invasive Pulmonary Aspergillosis Associated with Ankylosing Spondylitis.\u003c/em\u003e Am J Respir Crit Care Med, 2016. \u003cstrong\u003e193\u003c/strong\u003e(5): p. 572-3.\u003c/li\u003e\n\u003cli\u003eSmatti, M.K., et al., \u003cem\u003eViruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms.\u003c/em\u003e Viruses, 2019. \u003cstrong\u003e11\u003c/strong\u003e(8).\u003c/li\u003e\n\u003cli\u003eZhang, X., et al., \u003cem\u003eAssociation Between Infections and Risk of Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.\u003c/em\u003e Front Immunol, 2021. \u003cstrong\u003e12\u003c/strong\u003e: p. 768741.\u003c/li\u003e\n\u003cli\u003eTrier, N.H. and G. Houen, \u003cem\u003eAntibody Cross-Reactivity in Auto-Immune Diseases.\u003c/em\u003e Int J Mol Sci, 2023. \u003cstrong\u003e24\u003c/strong\u003e(17).\u003c/li\u003e\n\u003cli\u003eMcGonagle, D.G., et al., \u003cem\u003eThe role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies.\u003c/em\u003e Ann Rheum Dis, 2019. \u003cstrong\u003e78\u003c/strong\u003e(9): p. 1167-1178.\u003c/li\u003e\n\u003cli\u003eKhan, M.A., S.B. Yong, and J.C. Wei, \u003cem\u003eAnkylosing spondylitis: History, epidemiology, and HLA-B27.\u003c/em\u003e Int J Rheum Dis, 2023. \u003cstrong\u003e26\u003c/strong\u003e(3): p. 413-414.\u003c/li\u003e\n\u003cli\u003eWang, B., et al., \u003cem\u003eInduction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection.\u003c/em\u003e Proc Natl Acad Sci U S A, 2010. \u003cstrong\u003e107\u003c/strong\u003e(13): p. 5937-42.\u003c/li\u003e\n\u003cli\u003eTodorović, M.M. and E.Z. Zvrko, \u003cem\u003eImmunoregulatory cytokines and chronic tonsillitis.\u003c/em\u003e Bosn J Basic Med Sci, 2013. \u003cstrong\u003e13\u003c/strong\u003e(4): p. 230-6.\u003c/li\u003e\n\u003cli\u003eLi, J., et al., \u003cem\u003eThe aberrant tonsillar microbiota modulates autoimmune responses in rheumatoid arthritis.\u003c/em\u003e JCI Insight, 2024. \u003cstrong\u003e9\u003c/strong\u003e(18).\u003c/li\u003e\n\u003cli\u003eAsquith, M., et al., \u003cem\u003eHLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influence the Gut Microbiome.\u003c/em\u003e Arthritis Rheumatol, 2019. \u003cstrong\u003e71\u003c/strong\u003e(10): p. 1642-1650.\u003c/li\u003e\n\u003cli\u003eGiefing-Kr\u0026ouml;ll, C., et al., \u003cem\u003eHow sex and age affect immune responses, susceptibility to infections, and response to vaccination.\u003c/em\u003e Aging Cell, 2015. \u003cstrong\u003e14\u003c/strong\u003e(3): p. 309-21.\u003c/li\u003e\n\u003cli\u003eGoetzl, E.J., et al., \u003cem\u003eGender specificity of altered human immune cytokine profiles in aging.\u003c/em\u003e Faseb j, 2010. \u003cstrong\u003e24\u003c/strong\u003e(9): p. 3580-9.\u003c/li\u003e\n\u003cli\u003eLim, S.H., et al., \u003cem\u003eAutoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19.\u003c/em\u003e JAMA Netw Open, 2023. \u003cstrong\u003e6\u003c/strong\u003e(10): p. e2336120.\u003c/li\u003e\n\u003cli\u003eRobinson, W.H., et al., \u003cem\u003eEpstein-Barr virus as a potentiator of autoimmune diseases.\u003c/em\u003e Nat Rev Rheumatol, 2024. \u003cstrong\u003e20\u003c/strong\u003e(11): p. 729-740.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Chronic tonsillitis and adenoiditis, Ankylosing spondylitis, Cohort","lastPublishedDoi":"10.21203/rs.3.rs-8106028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8106028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003eTo assess the incidence rate and risk of ankylosing spondylitis (AS) in patients with chronic tonsillitis and adenoiditis compared with those without chronic tonsillitis and adenoiditis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eAll patients with chronic tonsillitis and adenoiditis (n = 104,956) in the TriNetX (2016–2023) were individually matched up with control subjects without chronic tonsillitis and adenoiditis by age and sex (n = 104,956). All of the patients were tracked until an AS event was noted. Cox proportional hazards regression was used to calculate the HRs for the development of AS, adjusting for age, sex, urbanization, lifestyle, medications, and comorbidities. The Kaplan-Meier method was used to plot the cumulative incidence curves. Subgroup analyses examined the association between chronic tonsillitis and adenoiditis and AS in subgroups stratified by age, sex, and, race. To ensure the robustness of the findings, in this sensitivity analysis, this study incorporated five different negative outcome controls.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe chronic cohort had a 1.41(95%C.I. = 1.11–1.80) times higher risk of AS than that of the non-chronic tonsillitis and adenoiditis cohort after adjusting for age, sex, race, BMI, socioeconomic status, lifestyle, medical utilization, comorbidities, and medications. Moreover, the cumulative incidence curves plotted by the Kaplan-Meier method revealed that after 7 follow-up years, the chronic tonsillitis and adenoiditis cohort displayed a higher cumulative incidence of AS than that of the non-chronic tonsillitis and adenoiditis cohort (Log-rank test p = 0.005). Additionally, subgroup analyses indicated stronger associations in females (HR = 1.36, 95% CI: 1.02–1.80) and individuals aged 18–64 years (HR = 1.39, 95% CI: 1.08–1.78). Sensitivity analyses using negative outcome controls (e.g., burns, cancer) confirmed specificity of the association.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003eOur study revealed that patients with chronic tonsillitis and adenoiditis had a higher risk of developing AS compared with non-chronic tonsillitis and adenoiditis patients, especially in females and those below 65 years old. These findings highlight the potential role of chronic upper airway inflammation in AS pathogenesis and warrant further investigations.\u003c/p\u003e","manuscriptTitle":"Risk of ankylosing spondylitis following chronic tonsillitis and adenoiditis: a retrospective cohort study utilizing TriNetX global collaborative network","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 16:50:47","doi":"10.21203/rs.3.rs-8106028/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-16T10:08:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-14T13:44:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T14:45:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144062090410676614044983361698166289398","date":"2026-04-08T14:22:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T06:55:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106646055488288268510390537453446025296","date":"2026-04-02T02:09:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"13821187653154550477100737509834175051","date":"2026-04-01T17:29:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302969918721653545145691296455568213312","date":"2026-04-01T16:08:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-19T19:24:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116309014796224029408835982602830161200","date":"2026-02-18T02:29:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T02:21:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-04T14:52:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-26T13:14:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-26T11:57:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-11-26T11:50:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8eb78235-120b-4155-a4c3-e2558a1dd735","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T21:24:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 16:50:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8106028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8106028","identity":"rs-8106028","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}