Evaluation of Routine Ear, Nose, and Throat Screening in Heart Transplant Candidates: A Retrospective Cohort Study

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P ATIENTS with end-stage heart failure refractory to medication can be treated with a heart transplant (HTx) or the implantation of a left ventricular assist device (LVAD) as a bridge to transplant (BTT) [1]. In our center, these procedures have been performed since 1984 and 2006, respectively. Before being placed on the waiting list, all patients are subjected to a thorough screening procedure in accordance with the guidelines of the International Society for Heart and Lung Transplantation [2−4]. In these guidelines, dental examination [2], screening of systemic chronic infectious diseases [2−4], and a general recommendation to treat localized infections [4] are mentioned. However, routine ear, nose, and throat (ENT) screening is not specifically recommended.
A consultation by an ENT specialist and conventional sinus radiography are both included in the screening protocol at our center. These are performed to detect asymptomatic infections and neoplasms, which may flare up under a treatment regimen of immunosuppressive drugs after transplant. However, we do not know the yield of ENT screening in patients with end-stage heart failure listed for HTx because specific studies are missing. The yield of ENT screening in liver and kidney transplant candidates has been explored before. The screening of chronic rhinosinusitis in liver transplant candidates resulted in better survival if sinusitis treatment preceded transplant but did not prevent infectious complications [5]. In contrast, ENT screening in kidney transplant candidates revealed no additional benefit [6]. The aim of our current study was to evaluate the results of ENT screening in a large cohort of candidates for HTx.

MATERIALS AND METHODS
All patients who were screened between 2012 and 2020 for either HTx or LVAD as a BTT >18 years were included in this study. The electronically stored medical records were retrospectively reviewed. The ENT screening consisted of a visit to the outpatient clinic, including history taking and physical examination (with nasal endoscopy when indicated), combined with conventional sinus radiography. When a patient had multiple ENT screenings, data from the last screening procedure were used. After completing the full screening procedure, all patients were discussed in a multidisciplinary team of cardiologists and thoracic surgeons to decide whether patients were eligible for listing for HTx or LVAD as a BTT. To compare pretransplant and post-transplant findings, all visits of patients to the ENT outpatient clinic after HTx were also reviewed.

Statistical Analysis
All continuous data were first checked for normal distribution (Shapiro-Wilk test). Normally distributed data are displayed as mean (SD), whereas non-normally distributed data are shown as a median (IQR; 25th and 75th percentiles). The categorical data are presented as numbers with percentages. The proportions were compared with x 2 test. The threshold for statistical significance was set at P <.05. Data were analyzed using SPSS statistics 25 (IBM SPSS, Inc, Armonk, NY, United States). This study was approved by the Medical Ethics Committee of the Erasmus Medical Center (MEC-2020-0717) and carried out conforming to the Declaration of Helsinki.

Pretransplant evaluation
When also including minor complaints, ENT symptoms were present during the screening consultation in 88 patients (35.1%). Every abnormal finding during physical examination was noted, which was observed in 116 patients (46.2%), the majority related to nasal crusting ( Table 2).
A conventional sinus radiograph was made in 221 patients (88.0%), of which 14 (5.6%) showed varying degrees of sinus opacification. Subsequently, in 10 (4.0%) of those 18 patients a computed tomography (CT) of the sinuses was performed, of which 4 (1.5%) showed signs of an infection (sinus) or neoplasm (detailed in paragraph below and Table 3). Eighteen patients (7.2%) had a follow-up consultation, in which no new findings arose that contraindicated HTx.
Sixty-four patients (25.5%) received treatment (advice) after ENT consultation, of which most was deemed irrelevant with respect to the decision to list a patient for HTx (Table 2). Specifically, most of these cases involved advice on nasal hygiene. One patient was diagnosed with polypoid tissue in the nose, for which local and systemic corticosteroids were prescribed. The  ENT, ear, nose, and throat; HTx, heart transplant. patient had a follow-up consultation at our institution, at which no nasal polyps were observed anymore.

ARTICLE IN PRESS
After completing the full screening procedures and review by the multidisciplinary team, 191 patients (76.1%) were accepted for HTx or LVAD implantation as a BTT, whereas 60 patients (23.9%) were rejected. In all cases, ENT consultation or sinus radiography did not influence the listing decision.

Outcome of ENT Screening Protocol
Based on 10 patients (4.0%) diagnosed with sinusitis or a neoplasm (Table 3), the number needed to screen was 25. Most of these patients did not have matching symptoms. In 8 of these cases (3.2% of total study group), opacification of the paranasal sinuses (indicative for sinusitis) was observed on radiologic examination. Nasal rinsing with saline or a nasal spray was advised in half of the patients. Two patients were referred to the maxillofacial surgeon on suspicion of an odontogenic origin, antibiotics were prescribed in 1 patient, 2 patients did not receive any treatment at all, and in 1 patient treatment is unknown. None of the patients with sinusitis received endoscopic sinus surgery.
Two patients (0.8% of total study group) were diagnosed with a neoplasm. One had a pleomorphic adenoma in the parotid gland, which is a benign tumor but has the potency of malignant transformation over time [7]. Surgical resection was not chosen at that time because of comorbidity, and afterward this patient successfully underwent transplant. In follow-up the adenoma showed no growth, and the patient did not give any complaints. The other patient had a unilateral nasal polyp on the left side. The biopsy specimen showed severe dysplasia of the squamous epithelium and additional resection was acquired through endoscopic sinus surgery. After resection, pathology showed moderate dysplasia in which no invasive growth was seen.

Post-transplant Evaluation
During the study period, a total of 126 patients (42.6%) received HTx; 40 of those had previously been implanted with an LVAD as a BTT. In this group, 34 patients were referred to the ENT surgeon because of specific complaints after HTx ( Table 4). None of these complaints correlated with the screening data prior to surgery or in any way influenced the postoperative course.
Only 1 patient developed chronic rhinosinusitis (in combination with otitis media with effusion) after HTx. Despite immunosuppressive medication, the course was mild, and the patient was treated with nasal steroids only. Another patient, who missed out on the ENT screening presented with a beginning cholesteatoma. The disease stabilized after cleaning and could be handled conservatively.
At the time of the data review, 193 of all screened patients (76.9%) were still alive. Mortality was significantly higher in the group of 10 patients diagnosed with sinusitis or a neoplasm (50% vs 22%; P = .04, x 2 test), but the causes of death were not related to any ENT pathology. The median follow-up time was 4.8 years (IQR, 2.7-6.6 years), counted from the date of the listing decision, after completing the total screening procedure.

DISCUSSION
We evaluated the outcome of standard ENT screening in patients with end-stage heart failure who were candidates for HTx. The screening consisted of a visit to the ENT outpatient clinic combined with conventional sinus radiography. In the majority of patients, the findings during ENT screening were deemed irrelevant and did not influence the decision to list patients for HTx. Only 10 of a total of 251 patients were diagnosed with sinusitis or a neoplasm, resulting in a number needed to screen of 25. ENT findings did not influence the decision to list patients for HTx or LVAD implantation in any of the cases. In addition, ENT infections after HTx or LVAD implantations were rare and no malignant neoplasms were detected.

Pretransplant Screening
In solid-organ transplant recipients, the incidence of rhinosinusitis is reported to range between 1.3% and 11.0% [8,9], which is in line with the general population [10]. Specifically in HTx recipients, the occurrence of sinusitis ranges from 0.5% to 37% [11−13]. In our study, 8 of the 10 cases showed signs of an infection, all of them involving the paranasal sinuses, which adds up to a prevalence of 3.2%.
In the general population, malignant neoplasms of the head and neck area constitute 3% of all cancers and strongly relate to tobacco use and alcohol intake [14]. We did not identify any malignant neoplasms in our study cohort because the 2 neoplasms we found were both benign. Even in screening of liver transplant candidates, who commonly have a risk profile that includes a history of smoking and daily alcohol use, few cases A total of 126 patients received HTx, 40 of whom had previously been implanted with an LVAD as a BTT. After HTx, 34 patients were referred to the ENT outpatient clinic because of specific complaints.
of head and neck cancer are detected, ranging from 0.17% to 1.3% [15,16]. This demonstrates that pretransplant screening for ENT malignant neoplasms, even in high-risk patients, has a low yield. In liver transplant candidates, it has been suggested to screen all patients with a significant history of smoking [15]. However, the current data set does not provide any evidence to warrant an extrapolation of this recommendation to our population of HTx candidates.

Post-transplant Evaluation
Of a total of 126 patients who underwent HTx, only 1 patient developed chronic rhinosinusitis afterward, resulting in a prevalence of 0.8%. None of the 10 patients diagnosed with sinusitis or neoplasm in the screening had a complicated course after HTx. Similar observations have been reported in literature: in a cohort of liver and kidney transplant recipients no complicated sinusitis was witnessed [17], and the presence of pretransplant chronic rhinosinusitis does not contribute to mortality after liver transplant [18].
Solid-organ transplant recipients have a 3-to 5-fold risk of developing a malignant neoplasms, probably owing to the effect of immunosuppressive therapy and the impact of pre-existing risk factors [19]. Specifically in HTx recipients, the risk of developing a malignant neoplasm 1 to 5 years after transplant has been estimated to be around 11%, of which (nonmelanoma) skin cancer is the most common subtype found [20]. The occurrence of ENT malignant neoplasms is generally limited to several cases in large cohort studies [21−23], which is a result of its low incidence. Of note, the relative risk of developing an ENT malignant neoplasms after transplant is markedly increased compared with the general population [24,25]. None of the patients in our cohort developed head and neck malignant neoplasms after transplant.

Adaptation of Screening Protocol
In aiming to minimize hospital visits for HTx candidates, we adjusted the screening protocol after reviewing the results of our data. The conventional sinus radiography has been replaced by a CT scan of the sinuses, and ENT screening is only needed in case of abnormal radiologic findings or specific complaints. Although radiation exposure is higher during a CT of the sinuses (0.12 mSv compared with 0.0044 mSv with conventional sinus radiography; averages calculated by a radiation expert in our hospital), we still consider this acceptable. In comparison, worldwide average annual exposure to radiation amounts to 2.4 mSv per individual [26].

Limitations
The retrospective nature of this study has several limitations that need to be addressed. First, not all patients with abnormal findings on sinus radiography were referred for a CT scan, which may have led to missing out on cases. Second, follow-up of treatment of pretransplant patients was not always performed, thereby incorrectly giving clearance for listing for HTx. Furthermore, the diagnostic methods were suboptimal: most patients received anterior rhinoscopy, which is inferior to nasal endoscopy, and conventional sinus radiography is inferior to a CT scan with respect to detecting pathology. This may have resulted in an underestimation of the number of patients with pathologic ENT findings. Lastly, the follow-up period after transplant can be considered rather short when studying the occurrence of malignant neoplasms in transplant recipients. Because patients were not routinely screened after transplant, a malignant neoplasm in its preclinical stage could be overlooked.

CONCLUSIONS
In conclusion, the outcome of ENT screening in a cohort of candidates eligible for HTx was investigated. Of 251 patients, only 10 were diagnosed with an infection or a neoplasm, most without matching complaints. All of these cases would also have been detected on a CT of the sinuses, which is why we believe that this modality can replace the current ENT screening. Visiting the ENT outpatient clinic should only be necessary in case of abnormal CT scan results or in case of specific complaints.

DATA AVAILABILITY
The data that has been used is confidential.

DISCLOSURE
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.