Otitis media with effusion in adults during the SARS-CoV-2 epidemic

Abstract

Objectives

The purpose of this study was to investigate the fluctuations in the prevalence of individuals diagnosed with otitis media with effusion (OME) during the SARS-CoV-2 pandemic, while also evaluating the persistence of SARS-CoV-2 in middle ear effusion (MEE) and assessing the effectiveness of tympanocentesis as a treatment modality for OME in this specific period.

Methods

The total number of outpatients and patients diagnosed with OME in our department was recorded for January 2022 and January 2023. Thirty patients (aged 15–86 years) were categorized into two groups: group A (n = 12), who developed OME during their SARS-CoV-2 infection and group B (n = 18), who experienced OME after the resolution of SARS-CoV-2 infection. All patients underwent otoendoscopic tympanocentesis (without a ventilation tube), where MEE and nasopharyngeal secretions were simultaneously collected for SARS-CoV-2 detection by polymerase chain reaction. The time interval from SARS-CoV-2 infection to tympanocentesis, results of SARS-CoV-2 detection, preoperative and postoperative average hearing threshold, and Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores were documented.

Results

The proportion of outpatients with OME in January 2023 was higher than that in January 2022. There were five patients who had positive test results for SARS-CoV-2 on MEE after tympanocentesis. These 5 patients underwent tympanocentesis at a mean of 28 ± 7.28 days following confirmation of SARS-CoV-2 infection. The ETDQ-7 scores of group A exhibited a reduction from 21.85 ± 4.8 to 10.00 ± 4.07 following tympanocentesis, while the ETDQ-7 scores of group B also demonstrated a decrease from 21.22 ± 4.65 to 10.11 ± 3.68 after undergoing tympanocentesis. The tympanocentesis was effective in both groups.

Conclusions

The study confirmed that the proportion of outpatients with OME in the Clinics of Otolaryngology during the SARS-CoV-2 epidemic increased significantly. SARS-CoV-2 RNA was detectable in MEE of COVID-19-related OME patients. Tympanocentesis was therapeutic for OME during SARS-CoV-2 infection, which facilitated viral clearance in MEE.

Introduction

After the official announcement issued by the World Health Organization (WHO) that COVID-19 is a pandemic globally, significant research has been undertaken to research the long-term implications of recovering from COVID-19. This research has resulted in WHO introducing the term “long COVID.” ¹ Despite limited research in this field, reports indicate a possible link between SARS-CoV-2 infection and otitis media with effusion (OME).

In OME, fluid accumulates in the middle ear without indication or manifestation of ongoing infection ² and is one of the most commonly encountered diseases in otolaryngology. A decreased incidence of OME during the SARS-CoV-2 pandemic has previously been reported.^3,4 These studies were based on the number of patients who were hospitalized, but an unknown number of patients were not hospitalized for fear of the pandemic, clearly affecting the statistical results. With the change in the epidemic situation, the change in the incidence of OME remains to be further investigated.

The most objective clinical feature of OME is middle ear effusion (MEE), and changes in MEE can reflect the progress of OME. The development of MEE may be associated with eustachian tube dysfunction, viral or bacterial infection, and the immune response. With the progress of detection technology, the role of viruses in this process has received extensive attention. Previously, Pitkaranta et al. reported that human rhinovirus (HRV) and other viral RNA were detected from 30% of MEE samples of OME children, ⁵ which confirmed the viral contribution to the development of OME. According to the 2022 guidelines in Japan, OME among children is thought to be significantly influenced by pathogens. ⁶ Raad et al. ⁷ reported a patient with negative COVID-19 results from an oropharyngeal swab, but the MEE tested positive. Kadriyan proposes middle ear fluid as an alternative diagnosis for COVID-19. ⁸ Furthermore, Frazier et al. ⁹ identified SARS-CoV-2 in the middle ear and mastoid of deceased individuals with COVID-19, although the duration of virus presence in MEE was not reported. Nevertheless, both studies suggest the potential existence of SARS-CoV-2 within the middle ear, potentially playing a role in the emergence of middle ear disorders subsequent to COVID-19.

Tympanocentesis is an important minor surgical procedure that facilitates the diagnosis and treatment of OME and other middle ear diseases. Not only can tympanocentesis immediately relieve the clinical symptoms of OME, it can also extract MEE for culture and sensitivity testing. ¹⁰ Tympanocentesis is commonly practiced in clinical settings across multiple nations; however, efficacy data regarding its use in treating COVID-19-associated OME are lacking.

In the late stage of SARA-CoV-2 infection, the sequelae of COVID-19 gradually become more prominent. Studies on the retention and clearance of SARS-CoV-2 in various human tissue types will likely be helpful in the identification and management of these sequelae. Stein et al. ¹¹ detected SARS-CoV-2 on multiple biological tissues and bodily fluids from the corpses of individuals who died of COVID-19, indicating that systemic infection could also persist in the body for months due to SARS-CoV-2. However, similar studies investigating the presence of SARS-CoV-2 in the MEE of patients with COVID-19-associated OME have not been undertaken. Therefore, the study aimed to assess the proportion of outpatients with OME during the SARS-CoV-2 epidemic period, collect MEE of patients with OME following infection caused by SARS-CoV-2, and evaluate the persistence of SARS-CoV-2 in that MEE, thereby evaluating the therapeutic effect of tympanocentesis at this stage of OME.

Materials and methods

Study population

We reviewed and collected both the total number of patients and the number of individuals diagnosed with OME who presented to the outpatient clinic of our hospital in January 2023 and January 2022. There was no large-scale outbreak of COVID-19 in our region in January 2022, whereas that number increased significantly in January 2023.

Thirty patients with SARS-CoV-2 infection and subsequent OME were included and divided into groups A and B. Group A had OME symptoms that appeared during SARS-CoV-2 infection, whereas group B had OME symptoms that appeared after a negative nasopharyngeal swab test for SARS-CoV-2.

Inclusion criteria

1. Complaints of aural fullness and/or hearing loss, otoendoscopy that demonstrated the presence of MEE, including yellowing and retraction of the tympanic membrane and the middle ear showing an air–fluid level or bubbles;

2. Type B tympanogram;

3. Conductive hearing loss detected by pure tone audiometry (PTA);

4. A clear history of SARS-CoV-2 infection.

Exclusion criteria

1. Patients aged below 15 years or with no previous history of SARS-CoV-2 infection were excluded in the study;

2. Other types of otitis media;

3. History of ear surgery or use of ototoxic drugs;

4. Women in the prenatal or postnatal period;

5. Individuals with psychiatric disorders or genetic diseases;

6. Patients with incomplete medical records.

PTA was performed by a qualified technician in a soundproof room, and the patient's air and bone conduction thresholds were detected and recorded at 500, 1000, 2000, and 4000 Hz. Tympanograms were obtained using a standard 226 Hz probe tone, and the results were described as types A, B, and C. The external auditory canal, tympanic membrane, and middle ear were examined by otoendoscopy. The Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7) encompasses seven criteria, with a score between 1 and 7 for each item and a total score ranging from 7 to 49 points. With a total score of 14.5 or above regarded as abnormal, higher scores suggested greater severity of symptoms. Patients were required to fill out the ETDQ-7 before and at 7 days after tympanocentesis.

MEE acquisition and detection

All patients underwent endoscopic tympanocentesis by the same chief physician in otolaryngology. Briefly described, following strict disinfection, the tympanic membrane was punctured with a tympanocentesis needle under otoscopic control, and the liquid in the tympanic cavity was extracted and retained. Nasopharyngeal secretions were collected under nasal endoscopy. SARS-CoV-2 was detected by PCR.

MEE, transferred in a volume of 0.5–1 ml, was carefully placed into a collection tube containing 3 ml of virus preservation solution and the tube cap was securely fastened. After gently rotating the nasopharyngeal swab once it reached the posterior wall of the nasopharynx, it was slowly withdrawn. The swab head was then placed into the tube containing 3 ml virus preservation medium and the tube cap was tightly screwed on. The specimens were temporarily stored at −80°C in a refrigerator and sent for examination within 4 h.

Data collection

Detailed data were collected from 30 patients enrolled in the study, including the SARS-CoV-2 test results of MEE and nasopharyngeal secretions after each tympanocentesis, and the dates of SARS-CoV-2 infection, onset of OME symptoms, and tympanocentesis. PTA results and ETDQ-7 results were recorded before and at 7 days after tympanocentesis. The mean hearing threshold was calculated using the air derivative values of PTA at 500, 1000, 2000, and 4000 Hz.

Data statistics

The data analysis was conducted using SPSS version 25 (IBM, Chicago, USA). For statistical analysis, an unpaired T-test was employed when the data followed a normal distribution. However, in the case of non-normal distributions, the Mann-Whitney U test was used instead. The Kruskal-Wallis one-way analysis of variance was employed to analyze nonparametric data with multiple comparisons. Subsequently, adjusted P values were obtained using Holm's Stepdown Bonferroni procedure. Qualitative data expressed as the number of cases (%) were analyzed using Fisher's exact test or chi-square test to examine the test rate and constituent ratio. When the P value is <0.05, statistical significance is considered.

Results

In January 2022, the total number of outpatients in our department was 1270, of whom 36 patients were diagnosed with OME, accounting for 2.83% of the total number. In January 2023, a total of 1034 outpatients were presented to our department, including 82 (7.93%) OME patients, which was significantly higher than the proportion of OME patients in the same period of 2022 (P < 0.05; Table 1).

Table 1.

Proportion of outpatients with OME in January 2022 and January 2023.

Time	Total number of clinics, N	Number of diagnosed OME, N (%)	χ2	P value
Y1	1270	36(2.83)	30.457	0.000
Y2	1034	82(7.93)

Y1: January 2022; Y2: January 2023.

The data are expressed in numbers and percentages. P < 0.05 value was regarded as significant. OME: otitis media with effusion.

Thirty patients included in the study had a mean age of 53.8 years (range 15–86 years), including 20 males and 10 females. Group A comprised 12 patients with OME symptoms during SARS-CoV-2 infection, the average age of the group was 50.83 ± 13.86 years, with 10 males and 2 females aged 30–73 years. Group B included 18 patients who developed OME indications after SARS-CoV-2 infection turned negative, including 10 males and 8 females, aged from 15 to 86 years, with an average age of 55.78 ± 17.68 years (Table 2).

Table 2.

Age and gender of groups A and B.

Variable	Group A (N = 12)	Group B (N = 18)	P value
Age, year	50.83 ± 13.86	55.78 ± 17.68	0.422
Gender, N			0.114
Male	10	10
Female	2	8

The data are expressed in mean ± standard deviation or in numbers. P < 0.05 value was regarded as significant.

After the initial tympanocentesis, among the 30 patients, 2 patients from group A and 3 patients from group B exhibited positive SARS-CoV-2 results in their MEE tests (Table 3). The tympanocentesis procedure was performed on these 5 patients at an average of 28 ± 7.28 days after confirming SARS-CoV-2 infection and at an average of 10 ± 7.52 days from the onset of OME symptoms. The remaining 25 patients in both groups had a negative initial MEE SARS-CoV-2 test, with an average interval of 39.6 ± 11.45 days between confirming SARS-CoV-2 infection and subsequent tympanocentesis, as well as 23.56 ± 14.19 days from OME symptom onset to tympanocentesis. The time interval from infection to treatment and the duration of OME symptoms were significantly shorter in MEE-positive patients compared with MEE-negative patients (Table 4).

Table 3.

Number of OME patients MEE negative or positive in groups A and B.

Variable	Group A, N	Group B, N	P value
The first puncture			1
Total number	12	18
MEE negative	10	15
MEE positive	2	3
The second puncture			0.678
Total number	4	4
MEE negative	4	4
MEE positive	0	0

The data are expressed in numbers. MEE: middle ear effusion; OME: otitis media with effusion.

Table 4.

Differences in T1 and T2 between OME patients MEE negative or positive.

Variable	MEE negative (N = 25)	MEE positive (N = 5)	P value
T1	39.6 ± 11.45	28 ± 7.28	0.039
T2	23.56 ± 14.19	10 ± 7.52	0.049

T1: Time interval from SARS-CoV-2 infection to tympanocentesis.

T2: Time interval from the onset of OME symptoms to tympanocentesis.

The data are expressed in mean ± standard deviation. P < 0.05 value was regarded as significant. MEE: middle ear effusion; OME: otitis media with effusion.

In group A, the mean hearing thresholds were 44.27 ± 21.24 and 31.35 ± 17.13 dB before and at 7 days after the first tympanocentesis, respectively, and the average scores of ETDQ-7 were 21.85 ± 4.8 and 10.00 ± 4.07 points, respectively. Both the mean hearing thresholds and ETDQ-7s in group A were significantly different before and after the first tympanocentesis (P < 0.05). In group B, the mean hearing thresholds were 44.10 ± 20.95 and 32.64 ± 20.33 dB before and at 7 days after the first tympanocentesis. The average scores of ETDQ-7 were 21.22 ± 4.65 and 10.11 ± 3.68, respectively. In group B, the average hearing threshold before and after the first tympanic membrane puncture was significantly different (P < 0.05). However, the mean hearing threshold and ETDQ-7 were not statistically significant between groups A and B before and at 7 days after surgery (Table 5). All 30 patients had an ETDQ-7 >14.5 before surgery, while a total of 8 patients in groups A and B still had an ETDQ-7 >14.5 after surgery. They underwent a second tympanocentesis, and the second test for MEE virus was negative (Table 3).

Table 5.

Differences in PTA and ETDQ-7 between groups A and B.

Variable	Group A (N = 12)	Group B (N = 18)	P value
PTA, dB
Before surgery	44.27 ± 21.24	44.1 ± 20.95	0.972#
After surgery	31.35 ± 17.13	32.64 ± 20.33	1.000#
P value	0.001*	0.000*
ETDQ-7
Before surgery	21.58 ± 4.8	21.22 ± 4.65	0.838#
After surgery	10 ± 4.07	10.11 ± 3.68	1.000#
P value	0.000*	0.000*

The data are expressed in mean ± standard deviation or in numbers.

* Preoperative versus postoperative comparison.

#

The comparison between groups A and B.

P < 0.05 value was regarded as significant. ETDQ: Eustachian Tube Dysfunction Questionnaire; PTA: pure tone audiometry.

Discussion

To our knowledge, limited numbers of studies have been reported on COVID-19-related OME, and despite a small sample size, this study is still the largest case series to date.

A retrospective research performed by Iannella et al. ³ exhibited that the incidence of OME was reduced during the quarantine period of COVID-19. Coincident with the quarantine policies being lifted, the number of outpatient medical visits by patients with OME increased. At present, the principal epidemic strain of COVID-19 is omicron, which results in a higher prevalence of symptoms in the upper respiratory tract compared to the lower respiratory tract. ¹² The frequent incidence of viral infections in the upper respiratory tract has been recognized as a potential predisposing factor for OME. ¹³ Uranaka et al. ¹⁴ demonstrated that several key factors influencing the transmission of SARS-CoV-2 are widely expressed in the pharyngeal duct, middle ear space, and cochlea, indicating susceptibility to SARS-CoV-2 infection within these tissues. After cancelation of strict quarantine measures, the infection of the upper respiratory tract resulting from SARS-CoV-2 showed a significant upward trend, which logically led to an increase in the incidence of OME. Previous studies have identified two mechanistic reasons for the increase: first, upper respiratory tract infection leads to Eustachian tube dysfunction, resulting in negative pressure in the middle ear and MEE. Second, the drop in middle ear pressure may also trigger the aspiration of infectious nasopharyngeal secretions and the development of MEE. ¹⁵ One of the key findings derived from this research was the definitive increase in the count of patients with OME in the midst of the SARS-CoV-2 pandemic suggesting that the onset of OME was related to SARS-CoV-2 infection. The preoperative ETDQ-7 of all patients was >14.5, indicating that all patients had Eustachian tube dysfunction, which might be an important basis and way of OME during this viral epidemic.

Pitkaranta et al. ⁵ showed that although the HRV was rapidly inactivated in MEE, its RNA could be detected for 35 days or even 8 weeks. In our study, 5 patients who tested positive for SARS-CoV-2 on MEE had a history of SARS-CoV-2 infection dating back as far as 37 days. This phenomenon provides evidence of the persistence of SARS-CoV-2 RNA detectability in MEE from patients with COVID-19-associated OME. Patients with an initially negative MEE for SARS-CoV-2 could not entirely exclude the possibility that SARS-CoV-2 was previously present in their MEE but cleared immunologically. Previous research have shown the persistence of SARS-CoV-2 specific immune responses for approximately 1 year in most patients, ¹⁶ and Swartz et al. ¹⁷ found that most studies determined that natural antibodies formed in response to SARS-CoV-2 infection usually lasted 3–6 months. Takada proposed that the decreased levels of IgG in both serum and MEE could be attributed to the persistence and recurrence of OME. ¹⁸ These investigations provide strong evidence for the significant role of antibodies in eradicating virus from MEE. On the one hand, the time interval from SARS-CoV-2 infection to tympanocentesis in MEE-positive patients was short, and the virus was not completely cleared by antibodies. On the other hand, eustachian tube dysfunction caused MEE to fail to discharge from the middle ear, which led to virus persistence in MEE. Our findings would be consistent with that explanation, although SARS-CoV-2 antibody levels were not measured.

The effectiveness of tympanocentesis was demonstrated in patients with OME during SARS-CoV-2 infection. Additionally, it facilitated viral clearance. Earlier studies have shown that the existence of respiratory viruses can be detected in the MEE of OME patients, including rhinovirus ¹⁵ and respiratory syncytial virus. ¹⁹ Pichichero concluded that selective use of tympanocentesis in patients with refractory or recurrent middle ear disorder could assist in guiding appropriate treatment and avoiding unnecessary drug or surgical intervention. ²⁰ In the present study, the patient's tympanic membranes healed completely following tympanocentesis, and the symptoms were relieved significantly immediately following the procedure. Only eight patients underwent a second tympanocentesis due to re-development of fluid in the middle ear. These results confirmed that hearing was significantly improved, and the ETDQ-7 scores decreased in most patients at 7 days after a single tympanocentesis; therefore, tympanocentesis appears to be effective in the treatment of OME that has emerged during this SARS-CoV-2 epidemic. MEE testing for SARS-CoV-2 in all patients undergoing a second tympanocentesis was negative for the presence of SARS-CoV-2, even in those who tested positive previously. Importantly, tympanocentesis seemed to help clear the virus.

However, it is noteworthy that the limited number of patients and the short duration of the study may have influenced the results. Additionally, due to technological limitations, we were unable to conduct a more detailed biological analysis of MEE, which will be our focus for future research.

Conclusions

Our study confirmed that the proportion of patients with OME among the total number of outpatients in the Otolaryngology Clinic during the SARS-CoV-2 epidemic period was higher, as compared with that during the non-epidemic period, indicating an increased incidence of OME following the relaxation of strict quarantine measures. After a certain duration following SARS-CoV-2 infection and the onset of OME, the presence of SARS-CoV-2 RNA can still be detected. The persistence of SARS-CoV-2 RNA detection in MEE of patients with COVID-19-associated OME may be attributed to the narrow time gap between tympanocentesis treatment and SARS-CoV-2 infection, as well as eustachian tube dysfunction. The procedure of tympanocentesis exhibits a specific therapeutic efficacy in the management of OME during the COVID-19 pandemic, facilitating the elimination of viral RNA from MEE.