Assessing Recurrent Acute Rhinosinusitis Development in Posttransplant Patients: A Study on Sinus Surgery Necessity.

Recurrent acute rhinosinusitis (RARS) is a rhinological condition defined by four or more episodes of acute rhinosinusitis (ARS) within a year, with each episode lasting at least 10 days and absence of symptoms between episodes. 1 , 2 The true incidence of RARS may be underestimated due to difficulty in differentiating it from chronic rhinosinusitis (CRS) or recurrent exacerbation of CRS. However, some studies estimate the incidence to be approximately 1 in 3000 among adults in Western populations. 3 Patients with RARS experience a significant disease burden, which is associated with an estimated direct healthcare cost of more than $100 per year per patient. 3 Additionally, a study has shown that RARS significantly reduces patients' quality of life, even during periods without active infection. 4 Despite its prevalence and the considerable disease burden it imposes, RARS remains poorly studied.

Several risk factors have been associated with the development of RARS, although the supporting evidence is limited. 1 , 2 The most frequently cited factors include allergic rhinitis (AR), both active and passive smoking, and anatomical abnormalities. 5 A recent case‐control study identified AR and primary antibody deficiency as the most significant contributors to RARS. 5 Additionally, the study reported a higher incidence of autoimmune disorders in patients with RARS, particularly rheumatoid arthritis, lupus, and inflammatory bowel disease. The study also found a strong association between asthma and RARS. 5 These findings suggest that evaluating these comorbidities should be considered when treating patients with RARS. However, little is known about the association of RARS in specific populations, such as immunocompromised individuals and transplant recipients.

Previous studies have documented a higher burden of CRS and recalcitrant disease in this population, identifying RARS as a risk factor for the development of CRS and recalcitrant disease in the posttransplant period. However, little is known about the burden of RARS in transplant recipients. Therefore, this study aims to determine the prevalence and risk factors for RARS among transplant recipients and assess the need for sinus surgery in patients who develop de novo RARS during the posttransplant period.

Materials and Methods

Data Source

This study conducts a retrospective cohort analysis of all transplant recipients who presented to Mayo Clinic and were seen in the rhinology clinic with a diagnosis of RARS. The diagnostic criteria for RARS used in this study were based on ICAR guidelines, defined as four or more episodes of ARS per year, each separated by distinct symptom‐free periods. ARS was characterized by sinonasal inflammation lasting less than 4 weeks, associated with a sudden onset of symptoms including purulent nasal drainage (anterior/posterior), nasal blockage, obstruction, congestion, facial pain, pressure, or both. 2 Patients with symptoms lasting longer than 12 weeks were classified in the non‐RARS group. Documentation of a sinus infection following a diagnosis of CRS was considered an acute exacerbation of CRS for the purposes of this study. Patients were enrolled between 2017 and 2022 across multiple care locations, including Florida, Arizona and Minnesota. Data were collected using the EPIC electronic medical records (EMR) system and securely stored in the web‐based Research Electronic Data Capture (RedCap) platform. The study was approved for multiple sites by the Mayo Clinic Institutional Review Board (IRB: 22‐000831).

Study Population

All patients who underwent either solid or nonsolid organ transplantation within the Mayo Clinic enterprise were screened in this study, irrespective of their previous or current rhinologic status. However, patients with a history of rhinologic issues before transplantation were excluded from the analysis. Exclusion criteria were based on screening ICD codes (Supplemental Table S1 , available online) and reviewing each individual medical chart, which included clinical notes, discharge summary, and appointment records. This review was conducted to identify indications of rhinologic conditions such as CRS with polyps, CRS without polyps, allergic fungal sinusitis, odontogenic sinusitis, acute invasive fungal sinusitis, and ARS. All patients with RARS were evaluated by a rhinologist, while those without RARS were screened and their data collected through medical chart review. Exclusion criteria included those who did not fulfill the de novo RARS criteria, 2 were younger than 18 years, or lacked proper documentation of their transplant history. Failure of medical therapy was defined as persistent symptoms despite adequate medical therapy (AMT) leading to a recommendation of sinus surgery. AMT included saline irrigation, nasal steroid spray, nasal steroid irrigation, and culture‐directed antibiotics. A chart review was conducted to gather data on patient demographics, Karnofsky performance status, and comorbidities. Endoscopy findings, as well as details on transplant history and posttransplant rhinologic outcomes, were evaluated in all patients. For the purpose of this study, patients were grouped based on the RARS diagnosis.

Statistical Analysis

Baseline characteristics were compared between patients diagnosed with RARS and those without this diagnosis of RARS during the posttransplant period. The association between categorical variables were assessed using ( χ 2 ) test to understand the differences between RARS and non‐RARS subgroups. Additional categorical variables were summarized using frequency and percentage. A univariate analysis was then performed to explore variables associated with posttransplant conditions, including hematological disorders and transplant‐related management. This analysis aimed to identify potential risk factors, which were subsequently stratified based on the presence or absence of RARS. The hematological variables examined included graft‐versus‐host disease (GVHD), duration of immunosuppression, primary immunodeficiency, malnutrition, number of immunosuppressants, and presence of organ rejection. Variables deemed clinically relevant or statistically significant ( P < .200) in the univariate logistic regression models were further analyzed in a multivariate framework using linear predictive spectral analysis, incorporating the FORTAN method. Upon completion, a sensitivity analysis was conducted to evaluate the accuracy of the predictive model in assessing the risk of developing RARS among transplant recipients.

Subsequently, a multivariate logistic regression analysis was performed adjusting for confounder factors, which demonstrated statistically significant differences in the univariate analysis between RARS groups, were identified as potential confounders and adjusted for the multivariate analysis. This multivariate analysis incorporated all risk factors found to be clinically relevant and statistically significant ( P < .05) in the preceding univariate analysis. The results of the multivariate regression identified the potential predictive factors, which were subsequently assessed through a sensitivity analysis. The frequencies and percentage of cases with RARS and medically recalcitrant disease were calculated. Data were analyzed using STATA software version 13 (StataCorp), with statistical significance set at the P < .05 level.

Likelihood Ratio Analysis

To address the imbalance observed in the RARS variable, where only 9.95% of the cases presented the event, the decision threshold was adjusted below the standard 0.5 to 0.3, and the SMOTE (Synthetic Minority Over‐sampling Technique) oversampling method was applied, which generates synthetic samples of the minority class to balance the class distribution. Additionally, a multivariable logistic regression analysis was performed using the variables with a P ‐value < .20 in the univariate analysis.

Results

Patients Characteristics

We identified 1116 patients with a history of organ transplant, of whom 111 (9.95%) developed RARS, and 5 (5.5%) progressed to recalcitrant disease necessitating endoscopic sinus surgery (ESS). The majority of the patients were male (61.3%), with a median age of 63 (with an interquartile range [IQR] of 52‐70 years). Among patients with RARS, the most common comorbidities were hypertension (81/111, 72.9%), asthma (16/111, 14.4%), viral infection such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV) (46/111, 41.4%), obstructive sleep apnea (OSA; 30/111, 27%), rheumatoid arthritis (5/111, 4.5%), and AR (45/111, 40.5%). In the RARS population, the average number of sinus infections per year was 6 (range: 4‐6). The most common symptoms during an ARS episode include nasal congestion (68/111, 61%), cough (48/111, 43%), nasal drainage (38/111, 34%), facial pain/pressure (40/111, 36%), and postnasal drainage (28/111, 25%), along with other symptoms of lower frequency. The most common endoscopic findings during the rhinologic visit in the RARS population included septal deviation (20/111, 18%), sinus mucosa edema (18/111, 16%), and purulent rhinorrhea (15/111, 13.5%). Cultures were performed in 17 out of 111 cases (15%), and only one patient required additional surgery following the initial ESS. The average time to development of RARS after transplant was 62 months (IQR 13.3‐73.1). The average follow‐up duration for the present cohort, comprising patients transplanted between 1991 and 2021, is 118 months (IQR 56.6‐157.8). During the posttransplant period, 102 of 111 patients (91.8%) experienced sinus infections, with an average of two episodes per year (range: 1‐6) after initiating medical management. Among those with RARS, 5 of 111 patients (4.5%) progressed to CRS, and 5 of 111 (4.5%) required ESS. Symptomatic resolution posttransplant was reported in 7 of 111 patients (6.3%), and 2 of 5 patients (40%) reported symptomatic improvement following ESS. Additional comparative characteristics between patients with RARS and those without RARS are detailed in Table 1 .

Transplant Characteristics

In the cohort of patients who developed RARS posttransplant, kidney transplantation was the most prevalent procedure (41 cases, 36.9%), followed by stem cell transplantation (31 cases, 27.9%). RARS was most frequently observed in cadaveric transplant recipients, occurring in 50 cases (45%). The distribution of hematological disorders significantly differed between patients with and without RARS. In the RARS group, the predominant hematological disorder was aplastic anemia (3.6%), with other notable conditions including Hodgkin's lymphoma (3.6%), myelodysplastic syndrome (MS; 9.9%), mantle cell lymphoma (3.6%), and neutropenia (40.5%). The RARS groups were noted to have a prolonged period of immunosuppression, with a mean of 70.5 months (range 44‐151 months), compared to a mean of 54 months (range 19‐99.6 months) in the non‐RARS group. Primary immunodeficiencies were also prevalent among the RARS group (11.7%), compared to the non‐RARS group (5.7%), more details show in Table 2 .

Univariate Analysis

We evaluated risk for RARS based on demographics, transplant‐related, and hematological characteristics ( 1 , 2 , 3 ). Asthma and viral infection were associated with an increased risk of developing RARS during the posttransplant period, with odds ratio of 1.97 (95% CI: 1.03‐3.96, P = .019) and 1.84 (95% CI: 1.20‐2.80), respectively. OSA also significantly raised the risk of RARS, with an odds ratio of 1.64 (95% CI: 1.01‐2.60, P = .029). Patients with rheumatoid arthritis and OSA demonstrated a significantly higher likelihood of developing RARS posttransplant, with odds ratio of 3.14 (95% CI: 0.88‐9.32, P = .022) and 1.64 (95% CI: 1.01‐2.60, P = .029), respectively. The presence of AR was linked to an increased risk of de novo RARS posttransplantation (OR: 1.12, 95% CI: 0.33‐2.92, P = .06). MS and mantle cell lymphoma were also significantly associated with an elevated risk of RARS, with odds ratio of 2.31 (95% CI: 1.04‐4.72, P = .014) and 3.12 (95% CI: 0.72‐10.53, P = .04), respectively. Primary immunodeficiency markedly increased the risk of developing RARS posttransplant, with an odds ratio of 2.19 (95% CI: 1.9‐4.22, P = .013). Additionally, prolonged immunosuppression duration was associated with an increased risk of RARS, with an odds ratio of 1.34 (95% CI: 0.41‐6.95, P = .0004).

Predictors of Developing RARS

Following multivariate analysis with adjustment for confounding factors, the FORTAN analysis excluded certain factors previously identified in the univariate analysis. The significant predictors associated with an increased risk of developing RARS during the posttransplant period included asthma (OR: 1.42, 95% CI: 0.83‐2.99, P = .156), RA (OR: 2.71, 95% CI: 0.90‐8.14, P = .075), OSA (OR: 2.30, 95% CI: 1.089‐2.90, P = .021), and viral infection (OR: 2.17, 95% CI: 1.046‐2.45, P = .030). Specific hematological conditions associated with RARS development included mantle cell lymphoma (OR: 2.20 [95% CI: 1.16‐13.89], P = .028), neutropenia (OR: 2.72 [95% CI: 1.19‐3.05], P = .007), and MS (OR: 2.07 [95% CI: 1.04‐5.09], P = .038). Living donor transplantation was identified as a potential protective factor (OR: 0.79, 95% CI: 0.27‐1.06, P = .074). Other protective factors identified included pancytopenia (OR: 0.14, 95% CI: 0.33‐0.95, P = .033), prednisone (OR: 0.68, 95% CI: 0.40‐1.07, P = .092), and cyclosporine (OR: 0.37, 95% CI: 0.20‐0.85, P = .018).

The adjusted logistic regression model indicated that asthma, OSA, RA, viral infections, and hematological conditions such as neutropenia, mantle cell lymphoma, and MS were significant predictors for posttransplant RARS development. Sensitivity analysis showed a specificity of 99.9%, with a positive predictive value of 75% and a negative predictive value of 90.1% when these factors were applied ( Table 3 ; Figures 1 and 2 ). The predictive model accounted for 89.78% (97/111) of the observed RARS cases in the cohort.

Likelihood Ratios

The likelihood ratio analysis presented in the table demonstrates that several past medical conditions, transplant types, and immunosuppressive therapies exert modest effects on the probability of developing RARS. Notably, conditions such as asthma, viral infections, and neutropenia show a slight increase in the likelihood of RARS when present, with positive likelihood ratios (LR+) ranging from 1.17 to 1.22. Conversely, the absence of these conditions significantly decreases the probability of RARS, as reflected by negative likelihood ratios (LR−) ranging from 0.15 to 0.18. Other factors, such as rheumatoid arthritis, living transplant recipients, and GVHD, also demonstrate similar trends, although the effects are more modest. Immunosuppressive therapy with cyclosporine has a relatively lower impact on RARS probability, indicated by an LR+ of 1.08 and an LR− of 0.24. Overall, while none of these factors drastically change the risk of RARS, their presence or absence offers valuable predictive insight. Further detailed information on these findings is available in the corresponding Table 4 .

Discussion

Our cohort assessed transplant recipients for RARS using ICAR guidelines. We observed an incidence of RARS at 9.94% among posttransplantation patients. This rate is notably higher than the national average. 3 This incidence may be underestimated due to the challenges in distinguishing RARS from CRS or acute exacerbation of CRS, and the limited availability of related studies. 2 , 6 The study identified independent predictive factors for posttransplant RARS, including past medical history of asthma, viral infection, RA, and OSA. Hematologic factors such as neutropenia, pancytopenia, mantle cell lymphoma, MS, GVHD, and specific immunotherapies like cyclosporine and prednisone were also significant. Additionally, our predictive model accurately identified 89.78% of RARS cases posttransplant.

We identified RA, asthma, viral infection, and OSA as predictive factors for the development of RARS posttransplant. An association between these comorbidities and the development of RARS in the general population 5 has also been described. Behnke et al conducted a case‐control study using multivariate regression, adjusting for age, and found that AR, primary antibody deficiency, and autoimmune disorders remained significant risk factors for the development of RARS. 5 While some of these factors were identified in our study, after adjusting our multivariate model, asthma, viral infection, and OSA remained significant risk factors, despite not being reported in the previously mentioned case‐control study. Asthma has been extensively studied in relation to CRS and acute exacerbation of CRS. 1 , 2 Previous studies have identified asthma as a risk factor for developing acute exacerbation of CRS, with a relative risk of 2.61. 7 Additionally, viral upper respiratory infections have also been associated with RARS. 8 Additionally, OSA has been linked to the exacerbation of CRS. In a prospective cohort study following patients over 5 years, 2.76% of those with OSA subsequently developed CRS, with an adjusted hazard ratio (HR) of 3.18 (95% CI: 2.27‐4.45) compared to those without OSA. The study concluded that patients with OSA have a higher risk of developing subsequent CRS, regardless of sex. 9 However, the impact of these factors on RARS and its treatment outcomes remains unclear. Given our identification of OSA as a risk factor for RARS, future studies need to be conducted to determine whether OSA in transplant patients is also associated with CRS.

We have identified specific factors associated with the development of RARS during the posttransplant period, including neutropenia, MS, and mantle cell lymphoma. Previous studies have also highlighted similar risk factors for CRS, and recalcitrant CRS, where neutropenia has been linked to the development of recalcitrant CRS in organ transplant recipients, with an odds ratio of 2.87. 10 Another study evaluating risk factors for recalcitrant CRS identified that neutropenia in nonsolid organ transplant recipients was associated with subsequent sinus surgery. 11 Similarly, the largest cohort examining rhinology conditions in transplant recipient reported neutropenia as a predictive factor for CRS. 12 RARS shares a similar pathophysiological mechanism with CRS, including anatomic obstructive abnormalities such as turbinate hypertrophy, conchae bullosa, stenosis of sinus ostia, Haller cells, and septal deviations. These anatomical variations may predispose the nasal cavity and paranasal sinuses to infection. 13 , 14 However, the evidence remains a subject of ongoing debate. While some studies have identified a modest association between septal deviation and rhinosinusitis, the clinical impact appears limited, suggesting that septal deviation is merely one of several contributing factors to CRS. 15 In addition to immunologic dysfunction and anatomic conditions, mantle cell lymphoma and MS have been independently identified as predictive factors for the development of de novo RARS during the posttransplant period.

In this study, several factors were identified as protective against the development of RARS, including being a living transplant recipient and the use of prednisone and cyclosporine, which have been associated with preventing the development of CRS. This adds to the literature, as previous studies have identified living transplantation as a protective factor for the development of both CRS and recalcitrant CRS. 16 Furthermore, prednisone and cyclosporine may reduce inflammation in these patients, potentially decreasing recurrence rates of sinus infections and extending symptom‐free periods. Previous studies have identified obesity as a risk factor for rhinologic conditions such as CRS. 17 However, our study's ability to establish a correlation between RARS and obesity is constrained by the absence of BMI data. Additionally, limitations stem from scarce literature on transplant‐associated rhinological diseases, the retrospective nature of our design, and the lack of comprehensive, external charting of clinical management for ARS episodes, which impeded further characterization of these episodes. These limitations may constrain the available data and introduce potential biases inherent in observational research. Additionally, the likelihood ratio analysis highlights that while individual past medical conditions and treatments examined show only modest changes in the likelihood of developing RARS, the cumulative effect of these factors may still hold clinical significance, particularly in high‐risk populations such as transplant recipients or patients undergoing immunosuppressive therapy. The small variations in likelihood ratios suggest that these factors alone are insufficient to serve as strong predictive markers for RARS but may provide valuable context when combined with other clinical variables. This underscores the need for a comprehensive, multifactorial approach to assessing the risk of RARS in clinical practice. Future studies should investigate whether integrating additional biomarkers or advanced risk stratification tools could enhance predictive accuracy and inform personalized treatment strategies. Furthermore, it is essential for future research to evaluate the impact of RARS on the quality of life of transplant recipients and assess these protective factors prospectively to better understand their real‐world implications.

Conclusion

This study provides the largest evaluation of RARS among transplant recipients, revealing a prevalence of 9.95%, which is significantly higher than the general population. This finding underscores the considerable burden of RARS in the transplant populations, highlighting the importance of recognizing this condition as a distinct clinical entity in posttransplant care. Our findings identify key risk factors such as asthma, viral infections, OSA, rheumatoid arthritis, and specific hematological conditions such as neutropenia, mantle cell lymphoma, and MS as associated comorbidities in the development of RARS in this unique patient population. Additionally, protective factors such as living donor transplantation and the use of cyclosporine and prednisone may help mitigate the risk of RARS, suggesting potential strategies for targeted interventions.

Author Contributions

Estephania Candelo , contributed to the study design, data collection, data cleaning, and statistical analysis; provided intellectual input in designing the study, wrote the manuscript, and reviewed and revised the final manuscript; Anyull Dayanna Bohorquez‐Caballero , contributed to data collection, data cleaning, and study design, reviewed and revised the final manuscript; Angela M. Donaldson , provided substantial intellectual contributions to the design and writing of the manuscript, reviewed and revised the final manuscript.

Disclosures

Competing interests

The authors declare no conflicts of interest.

Funding source

None.

Supporting information

Supporting Information.

Acknowledgments

We acknowledge Karol Castano‐Avila for her contributions to data collection for this project.

References

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