Table 1.

Summary of biomarkers for idiopathic sudden sensorineural hearing loss.

Author (Year)	Study Design	n	Age (Years)	Biomarker	Outcome	Conclusion
Öçal et al. (2020) [42]	Retrospective	40 patients, 45 controls	44.1 ± 14.2, 42.2 ± 13.8	CRP/Alb ratio, NLR	Mean CRP/Alb ratio was 0.95 ± 0.47 in the patient group and 0.74 ± 0.13 in the control group (p = 0.009). Mean CRP/Alb ratio and mean NLR were not significantly related.	CRP/Alb ratio was significantly higher in patients with SHL than in the control group.
Kang et al. (2020) [31]	Retrospective, case-control study	137 patients	≥ 45	Hb, WBC, neutrophils, lymphocytes, monocytes, NLR, platelets, PLR, glucose, HbA1c, BUN, Cr, AST, ALT, TC, TGs	NLR showed a linear correlation with hearing recovery in patients with SSNHL, with hearing gain (dB) = 56.698 − 3.718 × NLR (r2 = 0.451, p = 0.001). Hearing recovery at all frequencies was numerically higher in patients with low (< 6.661) than higher (≥ 6.661) NLR at all frequencies and was significantly higher at 500, 1000, 2000, 3000, and 4000 Hz. Hearing thresholds at 250, 500, 1000, 2000, 3000, and 4000 Hz in the low NLR group were significantly lower after treatment.	High NLR is associated with poor outcome of patients with SSNHL.
Zhang Weng et al. (2019) [14]	Retrospective	33 successive bilateral, 215 unilateral	48.67 ± 15.36, 42.71 ± 13.58	NLR, PLR, MLR, HDL, LDL, TC, TGs, Fibrinogen, PT, aPTT	NLR, MLR, and PLR in the successive bilateral SSNHL group were significantly higher (NLR: 5.72 ± 2.23 vs. 4.45 ± 2.82, p = 0.01; MLR: 0.25 ± 0.15 vs. 0.17 ± 0.11, p < 0.01; PLR: 190.70 ± 69.79 vs. 148.18 ± 65.67; p < 0.01); LDL level was significantly higher; HDL level was significantly lower (LDL: 3.79 ± 0.53 vs. 3.49 ± 0.74; HDL: 1.33 ± 0.32 vs. 1.44 ± 0.26; p < 0.05 for both); fibrinogen was significantly higher (4.03 ± 0.47 vs. 3.70 ± 0.65; p < 0.01).	NLR, PLR, MLR, LDL, fibrinogen and diabetes showed positive correlations with successive bilateral SSNHL. However, HDL was negatively correlated with successive bilateral SSNHL.
Sun and Xuan et al. (2019) [61]	Clinical study	14 patients, 24 controls	57.9 (15.4), 54.0 (9.9)	Prestin	Mean prestin concentration was 840.24 ± 496.22 pg/mL in the control group and 955.98 ± 2501.48 pg/mL in the patient group (p < 0.001).	Prestin may be a diagnostic rather than a prognostic biomarker in SSNHL.
Kaneva et al. (2019) [16]	Case-control study	27 patients, 24 controls	39.7 (27–51), 32.3 (25–47)	TC, TG, HDL, LDL, apoA-1, apoB, apoE, AIP, ATH index	No significant differences in TC, TGs and HDL-C between ISSNHL patients and the control group. Higher values of the apoB/apoA-I ratio, AIP and ATH index in patients with SSNHL indicated increased atherogenicity of the lipid profile.	High ATH index value is associated with the occurrence of SSNHL.
Tovi et al (2019) [60]	Retrospective	63 patients	47 ± 16 (18–77)	Prestin antibodies, C3, C4, ANA, ENA	No statistically significant association was found between prestin autoantibodies and audiologic parameters.	Anti-prestin antibodies are not a diagnostic biomarker for ISSNHL.
Qiao et al. (2019) [33]	Retrospective	60 patients 60 controls	45.62 ± 13.16, 49.62 ± 10.66	WBC, neutrophils, platelets, lymphocytes, NLR, PLR	Mean NLR and PLR were significantly higher in patients than controls and were significantly higher in those who did not than those who did respond to treatment.	Low NLR and PLR are associated with good outcome of SSNHL.
Yoon and Kim et al. (2019) [46]	Prospective	24 patients, 24 controls	43.12, 46.91	TNF-α, IL-10, 12, IFN-γ, mononuclear cells, clusters of differentiation 11c and 86	Mean percent monocytes (26.36% ± 4.3% vs. 14.32% ± 2.3%) and mean TNF-α level (15.8 ± 9.3 pg/mL vs. 12.4 ± 8.7 pg/mL) were significantly higher in the SSNHL than in the control group. Mean IFN-γ and IL-12 levels were significantly lower in the SSNHL group than the control group.	Increases in TNF-α level and monocyte population, and decreases in IFN-γ and IL-12 levels, might have critical roles in SSNHL.
Chen et al. (2018) [27]	Systematic review, meta-analysis	1029 patients, 1020 controls		NLR	NLR levels were higher than in the patient than in the control group (SMD = 1.65, 95% CI = 1.20–2.09, p < 0.001). NLR value was much higher in non-recovered patients than in recovered patients (SMD = 1.27, 95% CI: 0.62–1.92, p < 0.001).	Low NLR is associated with good outcome of SSNHL.
Oya et al. (2018) [22]	Meta-analysis	1577 patients		Fibrinogen	Fibronectin concentration did not differ significantly between SSNHL patients and controls. Serum fibrinogen level of the recovery group was significantly lower than that of the nonrecovery group (p = 0.027).	High fibrinogen level is associated with poor outcome of SSNHL.
Göde et al. (2018) [40]	Retrospective	23 patients 19 controls	47.91 ± 15.73, 35.16 ± 15.67	Procalcitonin, hs-CRP	Procalcitonin levels were significantly higher in patients than in the control group (p = 0.018).	High procalcitonin level is associated with SSNHL.
Sun et al. (2017) [38]	Retrospective	129 patients, 31 controls	44.68 ± 9.11, 43.00 ± 16.44, 43.44 ± 12.81, 43.69 ± 19.06, 51.06 ± 10.01	Platelets, lymphocytes, MPV, PLR	There was significant difference between each study group and the control group in terms of lymphocyte count (all p < 0.01). Compared to the control group, MPVs of AF-SSNHL and TD-SSNHL patients were significantly higher (p < 0.01) and PLRs were significantly higher (p = 0.03, p < 0.01, p < 0.01, and p < 0.01 for LF-, HF-, AF-, and TD-SSNHL, respectively). Lymphocytes, MPV, and PLR of the HF-SSNHL subgroup (all p < 0.01) and MPV of the AF-SSNHL subgroup (p = 0.04) differed significantly from those of the other subgroups.	Low MPV is associated with good outcome of AF-SSNHL. High lymphocytes and PLR, and low PMV, are associated with good outcome of HF-SSNHL.
Bulgurcu et al. (2017) [34]	Retrospective	21 patients, 24 controls	13.7 ± 3.2, 14.8 ± 2.9	Neutrophils, lymphocytes, platelets, NLR, PLR	Neutrophils, lymphocytes and NLR differed significantly between the patient and control groups (p = 0.017, p = 0.039 and p = 0.016, retrospectively).	Low NLR is an important marker of good prognosis of ISSNHL in pediatric patients.
Fasano et al. (2017) [15]	Retrospective, case-control study	131 patients, 77 controls	54, 52.5	Glucose, HbA1c, Uric acid, ALT, AST, Cr, CPK, TSH, CRP, Factor VIII, PT, TC, aPTT, homocysteine, fibrinogen, mutation prothrombin, LDL, mutation factor V, LP(a), HDL, TGs,	Blood glucose, HbA1C, Lp(a), and factor VIII concentrations were significantly higher in patients than controls (p < 0.05). Furthermore, blood glucose, HbA1C, uric acid, factor VIII, and homocysteine concentrations were significantly associated with severity of SSNHL.	The severity of SSNHL is associated with high blood glucose, HbA1c, uric acid, factor VIII, and homocysteine.
Gul et al. (2017) [56]	Retrospective	50 patients, 50 controls	43.98 ± 11.69, 43.5 ± 9.19	TOS, TAS, PON, OSI calculation, thiol/disulfide ratio	TOS, OSI, disulfide, disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol levels differed significantly between the study and control groups (p = 0.008, p = 0.018, p = 0.001, p = 0.006, p = 0.002, p = 0.002, respectively).	Increases in TOS, OSI and native thiol/total thiol, and decreases in disulfide, disulfide/native thiol and disulfide/total thiol, are associated with SSNHL.
Koçak et al. (2016) [13]	Retrospective, case-control clinical trial.	45 patients, 47 controls	31.1 (+7.4), 32.4 (+8.1)	Monocytes, HDL, MHR	MHRs did not differ significantly between patients and controls. (p = 0.574). However, the MHR was significantly higher in non-responders compared with responders (p = 0.005)	Low monocyte and MHR are associated with good outcome of SSNHL.
Oya et al. (2016) [21]	Prospective	61 defibrinogenation, 64 steroid	59.2 ± 14.9, 57.3 ± 16.5	PT-INR, aPTT, fibrinogen, PIC, SFMC, AT-III, PMG, α2PI, TAT	In patients who recovered completely, serum fibrinogen level before treatment was significantly higher in the defibrinogenation group than in the corticosteroid group.	Defibrinogenation therapy is more appropriate than corticosteroid therapy for profound hearing loss with high initial serum fibrinogen concentration.
Nonoyama et al. (2016) [66]	Retrospective	89 patients	54.2 ± 17.5	RBC, Hb, RDW, WBC, platelets, glucose, BUN, Cr, AST, ALT, NLR, MPV	Mean RDW was significantly higher in the non-recovered group (13.2% ± 1.0% compared with 12.7% ± 0.7% in the recovered group, p = 0.031) in a binary logistic regression model, RDW was associated with recovery from ISSNHL (odds ratio = 2.33, 95% confidence interval = 1.20–4.51, p = 0.012).	Higher RDW is associated with poor outcome of SSNHL.
Kum et al. (2015) [28]	Retrospective cross-sectional historical cohort	59 patients 59 controls	46.10 ± 11.91, 42.84 ± 11.85	NLR, MPV, platelets, WBC, neutrophils, lymphocytes	NLR levels were much higher in patients diagnosed with sudden hearing loss compared to the control group. Similarly, mean NLR was higher in non-recovered versus recovered patients (p = 0.001).	Low LNR is associated with good outcome of SSNHL.
Yang et al. (2015) [51]	Retrospective	36 patients, 71 controls	50.94 ± 18.62 50.25 ± 13.27	TLR2,3,4,7,8,9, MyD88, IRAK1, TRAF3,6, TBK1, IRF3,7, RELA	Expression levels of TLR2, 3, 4, 7, 8, and 9 genes were significantly higher in SSNHL patients than in normal controls (p < 0.05). Higher expression of the TLR2 gene was found in patients with profound hearing loss compared with those with less severe hearing loss (p < 0.05).	Higher expression of the TLR2 gene is associated with severity of SSNHL.
Seo et al. (2014) [25]	Retrospective	348 patients, 53 controls	48.19 ± 15.22, 48.22 ± 11.60	WBC, neutrophils, lymphocytes, monocytes, NLR, platelets, PLR, glucose, BUN, Cr, AST, ALT	Mean NLR and PLR were significantly higher in the patient than in the control group (p < 0.001). NLR was significantly higher in the non-recovered than in the recovered group (5.98 ± 4.22 vs. 3.50 ± 3.3, p < 0.001)	Low LNR is associated with good outcome of ISSNHL.
Weiss et al. (2014) [19]	Retrospective	127 patients, 81 controls	53.3 ± 17.1, 49.9 ± 12.6	Platelet glycoprotein (GpIa, GpIb, and GpIIIa) receptor densities, fibrinogen	Lower fibrinogen levels (p = 0.029) and lower GpIIIa receptor density (p = 0.037) were associated with hearing recovery.	Low fibrinogen and GpIIIa receptor density are associated with good outcome of SSNHL
Düzer et al. (2014) [57]	Retrospective	25 patients, 25 controls	39.48 (16–65), 34.16 (21–59)	Anti-HSP 70, PON	Pre- and post-treatment serum PON levels were significantly higher in the patient group than in the control group (p < 0.05). In patients with complete or partial recovery, pre- and post-treatment serum anti-HSP70 levels were significantly higher than in controls (p < 0.05).	High PON was associated with SSNHL. High anti-HSP 70 was associated with good outcome of SSNHL.
Demirhan et al. (2013) [45]	Prospective clinical trial	23 patients, 20 controls	52 (35–67) (age- and sex-matched)	TNF-α, IL-10,12	There were no significant differences between pre- and post-treatment values of TNF-α in treatment responders (p > 0.05). In treatment non-responders, post-treatment TNF-α was elevated compared to the pre-treatment value (p < 0.05).	High TNF-α is associated with poor outcome of SSNHL.
Masuda et al. (2012) [24]	Individual cohort study	43 patients, 10 controls	57 ± 15, 52 ± 15	Neutrophils, lymphocytes, monocytes, NKCA, IL-6, TNF, hs-CRP	Neutrophil counts above the reference range of a facility will be a useful indicator for poor prognosis of ISSHL.	High neutrophil count is associated with poor outcome of ISSHL.
Cadoni et al. (2010) [63]	Case-control study	43 patients, 43 controls	50 ± 14, 43 ± 11	TC, LDL, coenzyme Q10, platelet, prothrombin time, fibrinogen, ESR, CRP, serum gamma globulin level	On univariate logistic regression analysis, significant associations were found between SSNHL and high serum total cholesterol level (p < 0.001), high LDL level (p = 0.024), and low coenzyme Q10 level (p < 0.001). On multivariate logistic regression analysis, statistically significant associations were found between low nervonic acid (p = 0.005) (unsaturated), low coenzyme Q10 (p = 0.002), and high total cholesterol (p = 0.015) serum level and high risk of SSNHL.	Low nervonic acid, low coenzyme Q10, and high TC are associated with SSNHL.
Kassner et al. (2011) [48]	Retrospective	12 patients, 12 controls	45.0 ± 3.2, 45.4 ± 4.1	TC, HDL, LDL, TGs, lymphocytes, monocytes, neutrophils, eosinophils, basophils, leukocytes, CRP, sCD40, sCD40L, TNF-α	Acute SHL patients had high levels of sCD40 and sCD40L and a significantly decreased percentage (36%) of lymphocytess, especially T lymphocytes (28%). Proinflammatory CD40, TNF-α, cyclooxygenase-2, or CD38-positive T or B lymphocytes were significantly increased.	Low T lymphocytes, high sCD40, and high sCD40L are associated with SSNHL.
Yildiz et al. (2008) [23]	Retrospective	53 patients 80 controls	4–63, 18–60	FV 1691 G-A, PT 20210 G-A, MTHFR 677 C-T, FV 4070 A-G, EPCR gene 23-bp insertion, PAI-1 4G/5G mutation	The frequency of MTHFR 677 C-T mutation was significantly higher in the patient group than in the control group (p = 0.03).	MTHFR gene 677 C-T mutation is associated with SSNHL.

Abbreviations: CRP/Alb ratio: C-reactive protein/albumin ratio; NLR: neutrophil to lymphocyte ratio; SHL: sudden hearing loss; Hb: hemoglobin; WBC: white blood cell; PLR: platelet to lymphocyte ratio; TC: total cholesterol; TGs: triglycerides; HbA1c: hemoglobin A1c; BUN: blood urea nitrogen; Cr: Creatinine; AST: aspartate transaminase; ALT: alanine transaminase; ISSNHL: idiopathic sudden sensorineural hearing loss; MLR: monocyte lymphocyte ratio; HDL: high density lipoproteins; LDL: low density lipoproteins; PT: prothrombin time; aPTT: activated partial thromboplastin time; SSNHL: sudden sensorineural hearing loss; apoA-1, B, E: apolipoproteinA-1, B, E; AIP: atherogenic index of plasma; ATH index: atherogenic index; ANA: anti-nuclear antibodies; ENA: anti-extractable nuclear antigen; TNF-α: tumor necrosis factor- α; IL-10, 12: interleukin-10, 12; IFN-γ: interferon- γ; hs-CRP: high-sensitivity-c-reactive protein; TOS: total oxidant status; TAS: total antioxidant status; PON: paraoxonase; OSI: oxidative stress index; MPV: mean platelet volume; AF-SSNHL: all-frequency SSNHL; TD-SSNHL: total-deafness SSNHL; HF-SSNHL: high-frequency SSNH; LF-SSNHL: low-frequency SSNHL; CPK: creatine phosphokinase; Lp(a): lipoprotein a; TSH: thyroid-stimulating hormone; MHR: monocyte to HDL ratio; PIC: plasmin-α2 plasmin inhibitor complex; SFMC: soluble fibrin-monomer complex; AT-III: antithrombin-III; PMG: plasminogen; α2PI: α2-plasmin inhibitor; TAT: thrombin-antithrombin III complex; RBC: red blood cell; RDW: red cell distribution width; TLR: Toll-like receptor; MyD88: myeloid differentiation primary response 88; IRAK1: interleukin-1 receptor-associated kinase; TRAF3, 6: tumor necrosis factor receptor-associated factor; TBK1: TANK-binding kinase 1; IRF3, 7: interferon regulatory factor; RELA: v-rel avian reticuloendotheliosis viral oncogene homolog A; Anti-HSP 70: anti-heat shock protein 70; PON: paraoxonase; NKCA: natural killer cell activity; ESR: erythrocyte sedimentation rate; sCD40: soluble CD40; sCD40L: sCD40 ligand; FV 1691 G-A: factor V 1691 G-A; PT 20210 G-A: prothrombin 20210 G-A; MTHFR 677 C-T: methylene tetrahydrofolate reductase 677 C-T; FV 4070 A-G: factor V 4070 A-G; EPCR: endothelial cell protein C receptor; PAI-1: plasminogen activator inhibitor-1.