Abstract
Objective
Cell division cycle 42 (CDC42) participates in the pathogenesis of some T‐cell‐mediated inflammatory diseases via regulating CD4+ T‐cell differentiation and inflammation response. This study aimed to evaluate the correlation of CDC42 and T helper (Th)1/Th2 cytokines with disease risk, effusion viscosity, and hearing loss degree of otitis media with effusion (OME).
Methods
CDC42, interleukin (IL)‐4, and interferon‐gamma (IFN‐γ) in effusion and serum of 78 OME patients were determined by enzyme‐linked immunosorbent assay. Besides, the effusion (irrigating fluid) and serum samples of 30 controls (adenoid hypertrophy patients without OME) were also obtained for CDC42, IL‐4, and IFN‐γ determination.
Results
Effusion CDC42 and IL‐4 were elevated in OME patients compared with controls (both p < 0.001). Effusion CDC42 was positively correlated with effusion IL‐4 in OME patients (p = 0.004) and controls (p = 0.012) but was not related to effusion IFN‐γ (both p > 0.050). Additionally, effusion CDC42 (p = 0.025) and IL‐4 (p = 0.023) were increased in OME patients with mucoid effusion compared to patients with serous effusion, while effusion IFN‐γ was of no difference between those patients (p = 0.215). Meanwhile, elevated effusion CDC42 (p = 0.012) and IL‐4 (p = 0.033) were linked with increased hearing loss degrees, whereas effusion IFN‐γ was not related to hearing loss degrees (p = 0.057). Moreover, the findings of serum CDC42, IL‐4, and IFN‐γ showed similar trends as effusion ones; nonetheless, their correlation with disease features was generally weaker.
Conclusion
OME patients present with elevated CDC42 and IL‐4 levels; the latter factors are intercorrelated and positively associate with effusion viscosity and hearing loss degree.
Keywords: cell division cycle 42, effusion viscosity, hearing loss degree, interleukin‐4 and interferon‐gamma, otitis media with effusion
Effusion and serum samples of 78 otitis media with effusion (OME) patients and 30 controls were obtained for cell division cycle 42 (CDC42), interleukin (IL)‐4, and interferon‐gamma (IFN‐γ) determination. Subsequently, it was observed that effusion CDC42 and IL‐4 were elevated in OME patients than those in controls (both p < 0.001). Effusion CDC42 was positively correlated with effusion IL‐4 in OME patients (p = 0.004) and controls (p = 0.012). Additionally, effusion CDC42 and IL‐4 were positively related to effusion viscosity and hearing loss degrees in OME patients (all p < 0.050). Moreover, the findings of serum CDC42, IL‐4, and IFN‐γ showed similar trends as effusion ones, whereas their correlation with disease features was generally weaker. Collectively, OME patients present with elevated CDC42 and IL‐4 levels; the latter factors are intercorrelated and positively associate with effusion viscosity and hearing loss degree.
1. INTRODUCTION
Otitis media with effusion (OME) is a common (bacterial or viral) infectious disease involving the mucosal lining of the middle ear, whose clinical symptoms mainly contain otalgia, hearing loss, etc. 1 , 2 Although some OME patients might automatically recover within three months, many patients still suffer from OME recurrence or progression (even after appropriate treatment), which increases the risk of long‐term tympanic membrane abnormalities and hearing loss. 3 , 4 , 5 Meanwhile, hearing loss tends to bring great burdens to patients, such as communication obstacles, cognitive function impairments, and quality of life reduction. 6 Consequently, finding some potential risk factors correlating with hearing loss is helpful for the recognition of OME.
Cell division cycle 42 (CDC42) is a small hydrolase of guanosine triphosphate (GTPase) of the Rho family, which is a fundamental regulator of various biological procedures, including CD4+ T‐cell differentiation, and inflammation response. 7 , 8 , 9 For instance, one previous study discloses that CDC42 promotes the differentiation of CD4+ T cells into T helper (Th) 2 cells. 8 Besides, another study suggests that CDC42 would aggravate the imbalance of Th1/Th2 cells and mediate eosinophilic inflammation. 9 Combining that the Th1/Th2 cytokine imbalance and immunologic/allergic inflammation are also involved in the OME pathogenesis and development, CDC42 is hypothesized as an etiological factor in OME. 10 , 11 , 12 , 13 Until now, only one study discloses that CDC42 facilitates middle ear mucosal proliferation in animal models, which would contribute to the disease progression of OME 14 ; however, the detailed clinical role of CDC42 in OME patients has not been reported yet.
Thus, this study determined CDC42 and Th1/Th2 cytokines in both effusion and serum samples, aiming to evaluate their correlation with disease risk, effusion viscosity, and hearing loss degree of OME.
2. METHODS
2.1. Participants
Seventy‐eight OME patients who came to our hospitals (Maternal and Child Health Hospital of Hubei Province, Women and Children's Hospital of Hubei Province, and Xiangyang Hospital of Traditional Chinese Medicine, Hubei University of Chinese Medicine) between May 2021 and February 2022 were consecutively included in this prospective two‐center study. The OME patients' inclusion criteria were (1) diagnosed as OME; (2) age ≥18 years old; (3) scheduled for myringotomy or ventilation tube insertion; (4) conductive hearing loss. The OME patients' exclusion criteria were (1) history of Down's syndrome, cleft palate, or other craniofacial anomalies; (2) hyperemic tympanic membrane at the time of collection; (3) acute middle ear infection; (4) sensorineural hearing loss. Besides, thirty patients were recruited as controls. The controls' inclusion criteria were (1) diagnosed as adenoid hypertrophy; (2) was not OME; (3) age ≥18 years old. The controls were excluded for the same exclusion criteria as OME patients. The Institutional Review Board approved this study. All participants' written informed consents were obtained.
2.2. Clinical data and sample collection
The effusion viscosity and hearing loss degree of OME patients were recorded. The hearing loss degree was classified referring previous study. 15 The OME patients' effusions from the tympanic cavity were obtained. After the tympanic cavity irrigated with 0.5 ml of sterile saline, the controls' irrigating fluid was obtained through suction set. 16 Besides, serum samples of OME patients and controls were gathered after enrollment. The serum samples were stored at −80°C for further detection.
2.3. Enzyme‐linked immunosorbent assay
The concentrations of CDC42, interferon‐gamma (IFN‐γ), and interleukin (IL)‐4 in effusion (irrigating fluid) and serum were determined by commercial Enzyme‐linked immunosorbent assay (ELISA) kits (Cat. EH0844, Cat. AQ‐H0164‐B, Cat. EH0199, Wuhan Fine Biotech Co., Ltd.). The procedures were processed via the manufacturer's protocols strictly. Briefly, the standards and test samples with the dilution buffer were added to the wells, then incubated them for 90 minutes at 37°C. The plate was washed for 2 times with washing buffer. Subsequently, 100 μl Biotin‐labeled antibody working solution was added to each well and incubated for 60 minutes at 37°C. Then, secondary antibody conjugated with horseradish peroxidase (HRP) was added for 30 min incubation at room temperature (25°C). Hundred microliters of 3,3′, 5,5′‐tetramethylbenzidine development solution was added to each well, followed by 100 μl stop solution. Finally, the plate was read at both 450 nm in an absorbance microplate reader. Standard curve was made with the standard samples, and all experimental values fell on the standard curve.
2.4. Statistical analysis
The statistical analyses were calculated via SPSS v27.0 (IBM Corp.). The graphs were mapped through GraphPad Prism v8.01 (GraphPad Software Inc.). The comparison was evaluated via the Mann–Whitney U test (for skewed distributed continuous variables) or the Student t‐test (for normally distributed continuous variables). The diagnostic ability of variables was evaluated by the receiver operating characteristic (ROC) curve. The correlation was calculated through Spearman's rank correlation test. A p value <0.05 was regarded as statistically significant.
3. RESULTS
3.1. Characteristics
The mean age of OME patients and controls was 35.9 ± 9.2 years and 37.9 ± 10.2 years, accordingly (p = 0.328, Table 1). OME patients consisted of 27 (34.6%) females and 51 (65.4%) males, while there were 12 (40.0%) females and 18 (60.0%) males in controls (p = 0.602). In OME patients, 38 (48.7%) patients presented with serous fluid, while the other 40 (51.3%) patients presented with mucoid fluid. With respect to hearing loss degree, 28 (35.9%), 41 (52.6%), and 9 (11.5%) patients were assessed as slight, mild, and moderate hearing loss, respectively. The detailed characteristics are displayed in Table 1.
TABLE 1.
Characteristics of OME patients and controls
| Items | OME patients (N = 78) | Controls (N = 30) | Statistic (t/χ 2 ) | p value |
|---|---|---|---|---|
| Age (years), mean ± SD | 35.9 ± 9.2 | 37.9 ± 10.2 | −0.983 | 0.328 |
| Gender, n (%) | ||||
| Female | 27 (34.6) | 12 (40.0) | 0.272 | 0.602 |
| Male | 51 (65.4) | 18 (60.0) | ||
| Effusion viscosity, n (%) | ||||
| Serous | 38 (48.7) | – | – | – |
| Mucoid | 40 (51.3) | – | ||
| Hearing loss degree, n (%) | ||||
| Slight | 28 (35.9) | – | – | – |
| Mild | 41 (52.6) | – | ||
| Moderate | 9 (11.5) | – | ||
Abbreviations: OME, otitis media with effusion; SD, standard deviation.
3.2. Effusion CDC42, IFN‐γ, and IL‐4 levels
Effusion CDC42 level was elevated in OME patients than that in controls (median (interquartile range [IQR]): 0.70 (0.34–1.08) pg/ml vs. 0.11 (0.00–0.27) pg/ml, p < 0.001, Figure 1A) with a pleasing value for differentiating OME patients from controls (area under the curve (AUC): 0.871, 95% confidence interval (CI): 0.805–0.936, Figure 1B).
FIGURE 1.
Effusion CDC42 and IL‐4 levels were up‐regulated in OME patients compared to controls. The comparison of effusion CDC42 level between OME patients and controls (A) and its differentiating value of OME from controls (B). The comparison of effusion IL‐4 level between OME patients and controls (C) and its differentiating value of OME from controls (D). The comparison of effusion IFN‐γ level between OME patients and controls (E) and its differentiating value of OME from controls (F). CDC42, cell division cycle 42; IL‐4, interleukin‐4; OME, otitis media with effusion; IFN‐γ, interferon‐gamma
Similarly, effusion IL‐4 was also up‐regulated in OME patients compared with controls (p < 0.001, Figure 1C) with a good value to distinguish OME patients from controls (AUC: 0.809, Figure 1D). Whereas effusion IFN‐γ level only showed an increasing trend (without statistical significance) in OME patients compared with controls (p = 0.088, Figure 1E), whereas it could not distinguish OME patients from controls (AUC: 0.606, Figure 1F).
3.3. Correlation of effusion CDC42 level with IFN‐γ and IL‐4 levels
Effusion CDC42 level was positively associated with effusion IL‐4 level (r s = 0.327, p = 0.004, Figure 2A), and it displayed a negative correlating trend (lacked statistical significance) with effusion IFN‐γ level (r s = −0.194, p = 0.089, Figure 2B) in OME patients. With respect to the controls, effusion CDC42 level was positively correlated with effusion IL‐4 level (r s = 0.455, p = 0.012, Figure 2C), but not IFN‐γ level (r s = −0.073, p = 0.702, Figure 2D).
FIGURE 2.
Effusion CDC42 level was positively related to IL‐4 level in OME patients and controls. The association of effusion CDC42 level with effusion IL‐4 level (A) and effusion IFN‐γ level (B) in OME patients. The association of effusion CDC42 level with effusion IL‐4 level (C) and effusion IFN‐γ level (D) in controls. CDC42, cell division cycle 42; IL‐4, interleukin‐4; OME, otitis media with effusion; IFN‐γ, interferon‐gamma
3.4. Correlation of effusion CDC42, IFN‐γ, and IL‐4 levels with OME features
Effusion CDC42 level (p = 0.025, Figure 3A) and effusion IL‐4 level (p = 0.023, Figure 3B) were increased in OME patients with mucoid effusion compared to patients with serous effusion; while IFN‐γ level was of no difference between those patients (p = 0.215, Figure 3C). Moreover, up‐regulated effusion CDC42 level (p = 0.012, Figure 3D) and effusion IL‐4 level (p = 0.033, Figure 3E) were associated with increased hearing loss degrees in OME patients. Whereas elevated effusion IFN‐γ level only displayed a correlating trend (without statistical significance) with declined hearing loss degrees (p = 0.057, Figure 3F).
FIGURE 3.
Effusion CDC42 and IL‐4 levels were positively associated with effusion viscosity and hearing loss degree in OME patients. Comparison of effusion CDC42 (A), IL‐4 (B), and IFN‐γ (C) levels between patients with serous effusion and patients with mucoid effusion. Comparison of effusion CDC42 (D), IL‐4 (E), and IFN‐γ (F) levels among patients with slight, mild, and moderate hearing loss degrees. CDC42, cell division cycle 42; IL‐4, interleukin‐4; OME, otitis media with effusion; IFN‐γ, interferon‐gamma
3.5. Serum CDC42, IFN‐γ, and IL‐4 levels
Serum CDC42 level was elevated in OME patients compared with controls (median (IQR): 11.30 (7.16–13.81) pg/ml vs. 6.99 (5.31–9.05) pg/ml, p < 0.001, Figure 4A) with a good value to differentiate OME patients from controls (AUC: 0.765, 95% CI: 0.677–0.853, Figure 4B).
FIGURE 4.
Serum CDC42 and IL‐4 levels were up‐regulated in OME patients than those in controls. The comparison of serum CDC42 level between OME patients and controls (A) and its differentiating value of OME from controls (B). The comparison of serum IL‐4 level between OME patients and controls (C) and its differentiating value of OME from controls (D). The comparison of serum IFN‐γ level between OME patients and controls (E) and its differentiating value of OME from controls (F). CDC42, cell division cycle 42; IL‐4, interleukin‐4; OME, otitis media with effusion; IFN‐γ, interferon‐gamma
Also, serum IL‐4 level was increased in OME patients than that in controls (p < 0.001, Figure 4C) with a relatively good value to differentiate OME patients from controls (AUC: 0.742, Figure 4D). Differently, serum IFN‐γ level only exhibited a decreasing trend (without statistical significance) in OME patients compared with controls (p = 0.073, Figure 4E), and it could not distinguish OME patients from controls (AUC: 0.612, Figure 4F).
3.6. Correlation of serum CDC42 with IFN‐γ, IL‐4 levels, and OME features
The intercorrelation of CDC42 with IL‐4 and IFN‐γ was also detected in serum, which showed that serum CDC42 level was positively related to IL‐4 in OME patients (r s = 0.290, p = 0.010) and controls (r s = 0.457, p = 0.011), but it was not associated with IFN‐γ level in OME patients (r s = −0.161, p = 0.158) or controls (r s = −0.214, p = 0.256) (Table 2).
TABLE 2.
Correlation of CDC42 with IFN‐γ and IL‐4 in serum
| Items | CDC42 | |
|---|---|---|
| r s | p value | |
| OME patients | ||
| IL‐4 | 0.290 | 0.010 |
| IFN‐γ | −0.161 | 0.158 |
| Controls | ||
| IL‐4 | 0.457 | 0.011 |
| IFN‐γ | −0.214 | 0.256 |
Abbreviations: CDC42, cell division cycle 42; IFN‐γ, interferon‐gamma; IL‐4, interleukin‐4; OME, otitis media with effusion.
Serum CDC42 level (p = 0.040) and IL‐4 level (p = 0.024) were both up‐regulated in patients with mucoid effusion compared with patients with serous effusion, whereas serum IFN‐γ level was not different between those patients (p = 0.897). Regarding the hearing loss degree, elevated serum IL‐4 level was linked with increased hearing loss degrees (p = 0.018). Furthermore, up‐regulated serum CDC42 level only exhibited a correlating trend (lacked statistical significance) (p = 0.082) with elevated hearing loss degree; increased serum IFN‐γ level showed a correlating trend (p = 0.074) (lacked statistical significance) with reduced hearing loss degree (Table 3).
TABLE 3.
Correlation of serum CDC42, IFN‐γ, and IL‐4 with disease features in OME patients
| Items | Effusion viscosity | Hearing loss degree | |||
|---|---|---|---|---|---|
| Serous | Mucoid | Slight | Mild | Moderate | |
| CDC42 (pg/ml) | |||||
| Median (IQR) | 9.75 (6.78–12.63) | 11.94 (8.80–15.89) | 9.49 (6.53–12.40) | 11.69 (7.74–14.58) | 11.49 (10.44–13.96) |
| Statistic (Z, r s ) | −2.049 | 0.198 | |||
| p value | 0.040 | 0.082 | |||
| IL‐4 (pg/ml) | |||||
| Median (IQR) | 18.35 (14.41–24.63) | 23.54 (17.98–34.51) | 18.66 (14.52–21.34) | 21.92 (17.16–34.37) | 29.77 (17.22–46.57) |
| Statistic (Z, r s ) | −2.259 | 0.267 | |||
| p value | 0.024 | 0.018 | |||
| IFN‐γ (pg/ml) | |||||
| Median (IQR) | 4.60 (1.77–8.60) | 3.38 (2.14–7.54) | 5.06 (2.24–8.54) | 2.89 (1.54–7.64) | 2.64 (1.07–6.47) |
| Statistic (Z, r s ) | −0.130 | −0.204 | |||
| p value | 0.897 | 0.074 | |||
Abbreviations: CDC42, cell division cycle 42; IFN‐γ, interferon‐gamma; IL‐4, interleukin‐4; OME, otitis media with effusion; IQR, interquartile range.
4. DISCUSSION
The abnormal level of CDC42 has been noticed in some T‐cell‐mediated inflammatory/allergic diseases. 7 , 17 , 18 For instance, one study shows that CDC42 is up‐regulated in obese asthma children compared with controls. 18 Another study discloses that the CDC42 level was decreased in rheumatoid arthritis patients than that in healthy controls. 17 The current study found the elevated effusion CDC42 level in OME patients than that in controls; meanwhile, effusion CDC42 level exhibited a good value to reflect OME risk. The probable reason was listed as follows: CDC42 was recognized as a key regulator of immune cell homeostasis, whose increased level would greatly elevate Th2 cell proportion and further cause Th1/Th2 imbalance. 8 Moreover, immune‐cell dysregulation, Th2 cell increment, and Th1/Th2 imbalance participated in the OME etiopathogenesis. 19 As a result, effusion CDC42 level displayed a pleasing value to reflect OME risk. Furthermore, this study also exhibited that effusion IL‐4 level possessed a favorable value for predicting OME risk, which could be explained by that elevated IL‐4 (Th2 secreted cytokine) was reported to promote cellular and molecular processes of inflammation in the middle ear and further involved in the OME pathogenesis. 20 Consequently, effusion IL‐4 level showed a good value to reflect OME risk.
Apart from the dysregulated levels, the intercorrelation of CDC42, IL‐4, and IFN‐γ was also investigated in some immune/inflammation‐related diseases, including acute ischemic stroke, inflammatory bowel disease, and ankylosing spondylitis. 21 , 22 , 23 For example, one study suggests that CDC42 is positively related to IL‐4, but not associated with IFN‐γ in acute ischemic stroke patients. 23 Another study indicates that blood CDC42 is negatively correlated with tumor necrosis factor‐alpha, but not related to IFN‐γ in ankylosing spondylitis patients. 22 In the present study, effusion CDC42 level was positively associated with effusion IL‐4 level in OME patients and controls, but not with effusion IFN‐γ level. Possible reasons might be as follows: (1) CDC42 promoted T‐cell differentiation into Th2 cells via induction of glycolysis, and IL‐4 was mainly secreted by Th2 cells. 9 Therefore, up‐regulated effusion CDC42 level was linked with increased effusion IL‐4 level in OME patients and controls. (2) CDC42 mainly facilitated T‐cell differentiation into Th2 cells, and Th1 cell proportion was indirectly influenced. 23 Hence, the correlation between effusion CDC42 and IFN‐γ (Th1 secreted cytokine) was relatively weak in OME patients.
Notably, the current study disclosed that effusion CDC42 and IL‐4 levels were up‐regulated in OME patients with mucoid effusion compared with patients with serous effusion; meanwhile, elevated effusion CDC42 and IL‐4 levels were linked with increased hearing loss degrees in OME patients. The probable explanations might be as follows: (1) Elevated CDC42 level could facilitate immune impairment. 24 In addition, OME patients with mucoid effusion were more likely to be identified as immune‐cell dysfunction compared with patients with serous effusion. 25 Subsequently, effusion CDC42 level was increased in OME patients with mucoid effusion than that in patients with serous effusion. (2) CDC42 enhanced Th1/Th2 imbalance, which would further accelerate eustachian tube dysfunction; besides, aggravated eustachian tube dysfunction tended to cause deteriorated hearing loss. 26 Therefore, elevated effusion CDC42 level was related to increased hearing loss degrees in OME patients. (3) As aforementioned, IL‐4 facilitated the inflammation in the middle ear, and the latter factor was associated with elevated effusion viscosity as well as hearing loss degrees. 20 Therefore, up‐regulated effusion IL‐4 level was linked with elevated effusion viscosity and hearing loss degrees in OME patients.
This study also detected CDC42, IL‐4, and IFN‐γ levels in serum; interestingly, some mild differences were observed between the effusion data and serum data. Firstly, serum IFN‐γ level disclosed a decreasing trend in OME patients compared with controls, which was contrary to the result in effusion. The possible reason might be as follows: The effusion samples obtained from controls needed sterile saline to irrigate, which could not be obtained directly. Thus, the concentration of effusion CDC42, IL‐4, and IFN‐γ in controls would be reduced. On the contrary, the results in serum would not be affected by the diluent. Thus, the IFN‐γ level exhibited diverse results between serum and effusion (irrigating fluid). Secondly, it was found that the correlation of CDC42, IL‐4, and IFN‐γ with hearing loss degree was generally more obvious in effusion compared with serum, which might be explained by that: the effusion samples reflected the hearing loss degree more directly than those in serum.
Some limitations were observed in this study. Firstly, this was a small‐scale study with an entire of 78 OME patients and 30 controls, which might cause weakened statistical power. Secondly, OME also frequently occurred in children, while the ages of patients in the present study were all ≥18 years old; consequently, the CDC42, IFN‐γ, and IL‐4 levels in pediatric OME patients deserved further studies. Thirdly, the longitudinal variation of CDC42 at different timepoints might be helpful for monitoring the clinical outcomes of OME patients, while this issue remained unanswered in the current study. Fourthly, the mismatch of patients' number between the patients and controls would interfere with the statistical power. Fifthly, CDC42 is nonnegligible in several bacterial or viral infection processes according to the previous studies. 27 , 28 , 29 Whereas the correlation of CDC42 with infection in OME patients remained unknown, which deserved further exploration.
In summary, CDC42 and IL‐4 levels are positively intercorrelated, and their up‐regulated levels reflect elevated effusion viscosity as well as hearing loss degree in OME patients, which serve as potential biomarkers for disease surveillance of OME.
CONFLICT OF INTEREST
None.
CONSENT TO PARTICIPATE
All participants' written informed consents were obtained.
CONSENT FOR PUBLICATION
Not applicable.
Wu D, Yang Y, Duan C. Cell division cycle 42 positively correlates with T helper 2 cytokine, effusion viscosity, and hearing loss degree in otitis media with effusion patients. J Clin Lab Anal. 2022;36:e24681. doi: 10.1002/jcla.24681
DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.