The prognostic and predictive value of platelet parameters in diabetic and nondiabetic patients with sudden sensorineural hearing loss

Abstract Background We aimed to evaluate the association between mean platelet volume, platelet distribution width (PDW), platelet count (PC) and plateletcrit (PCT), and the presence of sudden sensorineural hearing loss (SSNHL) and treatment response. In the literature, there is no study that investigates the platelet functions in diabetic patients with SSNHL. Methods The patients were retrospectively assigned into Group 1 (68 diabetic patients with SSNHL), Group 2 (63 nondiabetic patients with SSNHL) and Group 3 (64 healthy controls). Results PC was not significantly different between the groups (p > 0.05). MPV, PDW and PCT values were significantly higher in Group 1 as compared to Groups 2 and 3 (p < 0.05). Platelet parameters were not significantly different between the patients who were responsive and nonresponsive to the treatment. Therefore, the platelet parameters did not affect prognosis significantly in this study samples (p > 0.05). Conclusions This study showed that platelet parameters did not have a significant effect as a prognostic and predictive value in diabetic and nondiabetic patients with SSNHL. Further studies with more homogenous and larger study groups investigating the platelet parameters are needed to demonstrate microvascular damage and vascular alterations induced by diabetes mellitus.


Introduction
Sudden sensorineural hearing loss (SSNHL) is defined as a 30 dB or more sensorineural hearing loss that occurs within 72 h at least in three consecutive frequencies. The prevalence of the disease is reported to be 5-20/100,000. The etiological factors can be determined in 10-15% of the cases, approximately [1][2][3]. Although it may occur at any age, SSNHL is rarely seen in the childhood with a worse prognosis and prevalent between ages of 50 and 60 with no gender difference. A number of factors regarding the disease such as etiology, treatment protocols and prognosis have not been fully elucidated to date. Infectious, vascular, cardiologic, immunologic, hematologic, genetic and ototoxic factors, stress, perinatal complications, rheumatologic diseases, diabetes mellitus (DM), tumors and cardiovascular surgeries are claimed as etiological factors [3][4][5][6][7]. Also, studies reporting the increased frequencies of SSNHL in pathological conditions including sickle cell anemia, macroglobulinemia, Burger, cardiovascular and connective tissue diseases exist in the literature [5,6]. Neutrophil, lymphocyte and platelet values derived from routine hemogram analyses and their proportions were determined as prognostic and predictive indicators in several studies without any widely accepted precise parameters [8][9][10][11][12][13][14][15]. In SSNHL, tinnitus, dizziness, nausea and vomiting, aural fullness and findings of the upper airway infection can also be seen along with the hearing loss [4,16].
Mean platelet volume (MPV) is an indicator that addresses the size, function and production rate of platelets. The platelets with bigger sizes are more active and prone to aggregate [12,17]. A number of studies reported a correlation between MPV values and cardiovascular diseases, stroke, thrombosis and inflammation [10,13,17]. Platelet distribution width (PDW), platelet count (PC) and plateletcrit (PCT) also constitute other important parameters. PDW characteristically reflects the discrepancies in platelet volumes.
In the present study, we aimed to evaluate the association between SSNHL in diabetic and nondiabetic patients, and MPV, PDW, PC and PCT values with the determination of predictive and prognostic values of these parameters. Platelet values were reported in different studies with contradictory results in the literature [9][10][11][12][13][14][15]. However, studies concerning their prognostic value are still limited with the absence of a study focused on platelet values and DM.

Patients
The present study involved a total of 131 patients, including 68 diabetic and 63 nondiabetic patients who had been diagnosed with SSNHL at Kayseri Training and Research Hospital between March 2016 and July 2018. Age-and sexmatched 64 participants served as the control group. SSNHL was defined as a hearing loss of 30 dB or greater at least in three consecutive frequencies, over a period of 72 h or less [1]. All patients received 1 mg/kg systemic methylprednisolone (Mustafa Nevzat İlaç Sanayi A.Ş., Istanbul, Turkey) with a tapering dose of 20 mg every 3 days. Follow-up and regulation of blood glucose levels were performed in all patients. Oral lansoprazol (Nobel İlaç Sanayi A.Ş., Istanbul, Turkey) 30 mg/day was prescribed for gastric mucosal protection. Intratympanic dexamethasone (ITS; Deva Holding A.Ş., Istanbul, Turkey) and/or hyperbaric oxygen therapy (HBOT) were combined with systemic steroid treatment as salvage therapy. Five doses of ITS were applied every other day. Patients received ten sessions of HBOT composed of 2.5 ATA for 120 min per day. Patients who were benefited from HBOT according to audiometric findings received additional ten sessions of HBOT.
The inclusion criteria for the study were as follows: 18-65 age, initiation of therapy in the first 7 days and no treatment before the application in our clinic.
Patients with retrocochlear pathology, ototoxicity, perilymphatic fistula and acoustic trauma, history of previous SSNHL and ear surgery, presence of ear disease (tympanic membrane perforation, chronic otitis media, etc.), autoimmune disease, hyperlipidemia, chronic renal failure, cardiovascular disease and newly diagnosed DM were excluded from the study. DM was diagnosed when HbA1c was ≥6.5%.
In this study, diabetic patients and nondiabetic patients with SSNHL were assigned into Group 1 and Group 2, respectively, whereas healthy controls were included in Group 3.
Informed consent: Informed consent has been obtained from all individuals included in this study.
Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance with the tenets of the Helsinki Declaration and has been approved by the authors' institutional review board or equivalent committee.

Audiometric evaluation
The diagnosis of SSNHL was performed according to a complete otorhinolaryngological examination and pure tone audiometry (PTA). Pure-tone thresholds of 250-8,000 Hz frequencies and speech discrimination scores were evaluated in PTA. Patients were classified according to the Siegel criteria in agreement with the initial and 3rd-month hearing thresholds. The patients were categorized into four types according to Siegel's criteria based on their hearing thresholds at the beginning and at the end of the 3rd month ( Table 1).

Biochemical and hematological evaluation
Before the commencement of treatment, all patients were examined in terms of full blood count and hemostasis panel. Blood samples were collected in EDTA tubes in order to analyze MPV, PDW, PCT and PC values.

Statistical evaluation
Data were analyzed using the SPSS software v22 (SPSS Inc, Chicago, IL, USA). Normality of data distribution was analyzed using the Kolmogorov-Smirnov test.
Mann-Whitney U and Kruskal-Wallis tests were used for quantitative comparisons, whereas Wilcoxon's signed-rank and Pearson's chi-square tests were performed for comparisons between the groups. Significance was considered for p < 0.05 for all comparisons.

Results
Groups 1, 2 and 3 consisted of 68, 63 and 64 patients, respectively. There was no significant difference between the groups in terms of age and sex distributions ( Table 2). The pretreatment average PTAs were 55.47 ± 24.32 and 53.59 ± 22.05 in Group 1 and Group 2, respectively, and there were no statistically significant differences between these values. But, in both groups, the values were significantly lower in responsive patients than in unresponsive patients (p = 0.036; Figure 1).
The comparisons of MPV, PDW, PCT and PC values between the groups are shown in Table 2. MPV, PDW and PCT values were significantly higher in Group 1 as compared to Groups 2 and 3, while there was no significant difference between Groups 2 and 3. Also, no significant difference was found between the groups in terms of PC. There was no significant difference in terms of platelet parameters between responsive and unresponsive patients to the treatment in Groups 1 and 2 ( Table 3).

Discussion
The etiology, pathogenesis and treatment modalities of SSNHL have not yet been fully understood. There are several studies concerning SSNHL in the literature. Due to the higher prevalence of SSNHL among the patients with cardiovascular disease and thromboembolic risk factors, vascular occlusion theory is widely accepted. The absence of collateral blood supply supports the   theory. SSNHL is also prevalent in patients with DM and hypercholesterolemia who have higher atherosclerotic risk factors [6,18]. Platelets play an important role in the presence of atherothrombosis and interact with leukocytes in the damaged endothelium resulting in thrombus formation. The process of inflammation triggers the presence of thrombus formation and vice versa. In particular, platelets with higher volumes are more prone to aggregate with platelet agonists such as ADP, collagen and adrenalin. These platelets secrete more prothrombotic and vasoactive factors including thromboxane A2, serotonin and ATP; therefore, they have a more inflammatory characteristic [19]. During the inflammatory process, the release of integrins located over the platelets such as p-selectin raises and causes increased adhesion and thrombotic environment. Accordingly, high MPV levels were detected in several vascular and inflammatory events such as DM, myocardial infarction, stroke and sepsis [20,21]. Due to the presence of insulin resistance in DM, platelet turnover accelerates, the platelet life span shortens and platelet parameters may interrupt including MPV and PDW levels. MPV values were found to be higher in patients with retinopathy and microalbuminuria [22]. Therefore, in the present study, we constituted an extra group composed of SSNHL and DM in order to reveal the alteration of platelet parameters in detail. Platelet parameters derived from the complete blood count were studied in several pathological conditions including cardiovascular, inflammatory and oncological diseases due to being a cheap and routine laboratory examination and revealed contradictory results in these studies [17][18][19][20][21][22][23][24][25].
The effect of platelet parameters on the prognosis of SSNHL has not been extensively investigated in the literature. Also, to our knowledge, there is no study in the literature that has investigated platelet parameters in diabetic patients with SSNHL. On the other hand, the studies focusing on the predictive value of parameters have revealed conflicting results. Seo et al. [14] reported that PC had a predictive value but had no prognostic significance. In another study, PC was also found to have no predictive value [15]. In the present study, PC was also found to have no significant predictive and prognostic values.
In the study by Ulu et al. [10] conducted in 2013, the authors concluded that the MPV and PDW values were significantly higher in the study group when compared to the control group, whereas PC was lower. However, results contradictory to Ulu et al. exist in the literature [9,12]. In the present study, MPV, PDW and PCT values were significantly higher in Group 1 as compared to Groups 2 and 3, whereas there was no significant difference between Groups 2 and 3 ( Table 1). Ji et al. [26] reported a meta-analysis and demonstrated that there was no significant difference among the MPV values and between controls. Sun et al. [27] reported an association between MPV values and poor prognosis.
The prevalence of DM was reported higher among the patients with SSNHL [28]. Aimoni et al. [6] found that the prevalence of DM was 15.6% among the patients with SSNHL, whereas it was 8.5% among the control group. This result supported that DM has induced microangiopathy. Weng et al. [29] reported that hearing loss in the contralateral ear and the profound-type hearing loss in the lesion ear were commonly noted in diabetic patients with SSNHL. Also, the authors determined that diabetic patients with SSNHL had a poor prognosis that might be attributed to the microvascular damage of the inner ear. On the contrary, Seo et al. [30] found that there is no difference between diabetic and nondiabetic SSNHL patients on recovery when matched with sex, age and initial hearing level, so DM itself is not a poor prognostic indicator for SSNHL. But, in the present study, recovery values were significantly lower in diabetics (Group 1) as compared to nondiabetics (Group 2). In the present study, we aimed to investigate the prognostic value of platelet parameters (MPV, PDW and PCT) in diabetic patients with SSNHL and also evaluate whether it is an indirect finding of microvascular damage in DM [23][24][25].
In the present study, we found that the values of platelet parameters (MPV, PDW and PCT) were significantly higher in Group 1 than those of Group 2. However, the difference was not significant between the patients who were responsive and nonresponsive to the treatment protocol in Groups 1 and 2. Therefore, we have concluded that these parameters did not have a prognostic value.
The present study has some limitations. In particular, the prognostic value of platelet parameters and microvascular damage may be reflected more objectively if the additional variables regarding the duration and treatment protocols of DM and the status of the blood regulation were included in the present study. Larger studies with more homogenous patient groups may be useful for elucidating the relationship between DM and platelet parameters.

Conclusion
In the present study, we have concluded that the platelet parameters (MPV, PDW, PCT and PC) alone had no prognostic and predictive values in the diabetic and nondiabetic patients with SSNHL. Further studies are required for evaluating the microvascular damage and vascular alterations induced by DM.

Conflict of interest:
The authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.