Association of systemic inflammatory biomarkers with hearing loss: Results from NHANES 1999–2020 analyses

doi:10.21203/rs.3.rs-4700565/v1

Background:Hearing loss (HL) is a prevalent global health issue with a complex etiology in whichinflammation plays a significant role. The systemic immune inflammatory index (SII), a novel biomarker reflecting systemic inflammation, is hypothesized to correlate with HL.

Methods: Utilizing National Health and Nutritional Health Survey (NHANES) data from 1999–2020, this study analyzed the relationship between the SII and HL, categorized ashigh-frequency hearing loss (HFHL) orspeech-frequency hearing loss (SFHL). Blood samples were collected to calculate the SII. Weighted multivariate linear and logistic regression analyses were used to examine the linear relationship between the SII and hearing loss. After the SII was categorized into quartiles, a trend test was applied to assess the linear association between the SII and HL. Subgroup analysis was conducted to explore the correlation between the SII and HL across different sexes.

Results: Univariate logistic regression analysis revealed no significant correlation between the SII and the occurrence of hearing loss or SFHL (p>0.05), but there was a correlation between the SII and HFHL. Multivariate logistic regression revealed a significant positive correlation between the third quartile of the SII and hearing loss. In the second quartile, there was a significant positive correlation between the SII and SFHL. For HFHL, a significant positive correlation between the SII and HFHL was present only in the crude model and in the second and third quartiles. Stratified analysis of clinical variables revealed a positive correlation between SII and the onset of hearing loss in those with never alcohol intake and moderate alcohol intake, a positive correlation between the SII and HFHL in those with moderate alcohol intake,and a negative correlation between the SII and SFHL in those with a normal BMI, aged older than 60 years, and who were former smokers. In the RCSplot, a reverse U-shaped association was observed between the SII and the prevalence of hearing loss and SFHL (nonlinear p<0.05). There was a positive correlation between the SII and the incidence of HFHL. After stratification by sex, the SII showed a reverse U-shaped association with hearing loss in males and a positive correlation in females.

Conclusion: The SII is positively correlated with HFHL and shows a potential U-shaped relationship with HL and SFHL. In males, there was a reverse U-shaped association between the SII and hearing loss, while in females, there was a positive correlation.

Biological sciences/Immunology

Health sciences/Medical research

Hearing loss

SFHL

HFHL

Systemic immune inflammation index (SII)

Macrophages.

Hearing loss (HL) is a widespread health problem with a variety of causes that affects people throughout their lives and is the third leading cause of disability worldwide¹. In 2021, the WHO released the first World Hearing Report, which pointed out that chronic diseases such as hypertension, diabetes and central obesity are high risk factors for hearing loss. The reason for the greater risk of hearing loss in smokers may be the antioxidant and vascular effects of cigarette smoke or the direct ototoxic effects affecting the neurotransmission of auditory stimuli. Men are more likely to experience hearing loss, mainly due to their greater exposure to activities related to noise-induced hearing loss and the positive effects of estrogen on hearing function in women. There is significantly more melanin in the cochlea in African Americans than in Caucasians, which accounts for the reduced risk of age-related hearing loss in African Americans. The report predicts that by 2050, one in four people worldwide will suffer from hearing loss². Therefore, we need to pay more attention to hearing in high-risk groups and look for potential mechanisms underlying this disease.

The SII is the systemic immune inflammation index (SII), which was first defined in 2014 as the platelet count × neutrophil count/lymphocyte count³. The SII is a good and stable new inflammatory marker that can reflect the local immune response and systemic inflammatory response of the human body. The greater the SII is, the stronger the inflammation and the weaker the immune response of the patient, which has been verified in many diseases, such as colorectal cancer⁴, cervical cancer⁵ and cerebrovascular disease⁶.

The pathogenesis of hearing loss is relatively complex, and studies have shown that inflammation is one of the possible mechanisms of age-related hearing loss⁷ and noise-induced hearing loss⁸. Therefore, we speculate that the SII, which reflects the level of inflammation throughout the body, may be potentially linked to hearing loss. Therefore, this cross-sectional study was conducted using 1999–2020 NHANES data to explore the relationship between the SII and hearing loss.

2.1 The data source

The National Health and Nutritional Health Survey (NHANES) is an extensive cross-sectional survey conducted nationwide. It is an extensive multiagency program designed to monitor adults' and children's health and nutritional status across the United States⁹. The survey is unique in its combination of interviews and detailed physical examinations. A multistage stratified probability design was adopted in the population sampling of the survey to make the sample representative of the entire American population.

The data set consisted of demographic, body measurement, laboratory, and questionnaire data. In this study, a data set of 11 cycles (1999–2020) from the NHANES database of the National Center for Health of the United States was selected¹⁰. More information from the NHANES can be found on the website (https://www.cdc.gov/nchs/nhanes/index.htm).

2.2. Audiometric measures and hearing loss

All hearing loss data were obtained from the examination database. All age-matched participants were required to undergo a hearing test in the NHANES. Participants who were unable to remove hearing aids for testing or who had earaches who could not tolerate headphones were excluded from the audiometric component. Participants with self-reported ear disease, excessive cerumen, or abnormal otoscopy results were not included in this study. Before the testing began, an ambient noise survey was conducted using a Quest 1800 sound level meter. All audiometric examinations will be administered to participants by examiners at the MEC.

Hearing threshold tests at frequencies of 500, 1000, 2000, 3000, 4000, 6000 and 8000 Hz were performed on the participants’ left and right ears. The modified Hughson–Westlake procedure was used for testing, and the automatic test mode of the audiometer was used. The instruments used for the audiometric components included an Interacoustics Model AD226 audiometer with standard earphones (TDH-49 P) and inserted earphones (https://wwwn.cdc.gov/Nchs/Nhanes/2015-2016/AUX_I.htm). The examiners were trained by certified audiologists from the National Institute for Occupational Safety and Health.

Hearing loss is defined as a pure tone average > 25 dB in both ears of adults. Participants were considered to have hearing loss if their hearing thresholds were greater than 25 dB in either ear at any frequency (500, 1000, 2000, 3000, 4000, 6000, or 8000 Hz)¹¹. This study further investigated two different hearing loss types, namely, speech-frequency hearing loss (SFHL) and high-frequency hearing loss (HFHL), and these two types are not mutually exclusive. The hearing thresholds for SFHL are 500, 1000, 2000 and 4000 Hz, and those for HFHL are 3000, 4000 and 6000 Hz¹².

2.2. Systemic immune-inflammation index

The SII is derived from blood samples, which undergo rigorous laboratory testing in accordance with standardized sampling protocols to ensure the validity and comparability of the data. Blood samples are typically collected on survey vehicles or at specified sampling sites, followed by processing and testing within the laboratory. The calculation of the SII is based on a precise formula, the SII Z platelet count/lymphocyte count, which is utilized by the NHANES to gauge the inflammatory status of surveyed individuals^13–15.

2.3. Covariables

The covariates included body mass index (BMI), age, the ratio of family income to poverty, triglycerides, total cholesterol, HDLcholesterol, LDL cholesterol, alcohol consumption, cancer status, sex, ethnicity, marital status, education, diabetes status, hypertension status, and smoking status.

2.4. Statistical analysis

The participants’ demographics were evaluated by the SII quartile using the chi-square test and t test. The linear relationships between the SII and HL were examined using weighted multivariate linear and logistic regression analyses. After transforming the SII score from a continuous variable to a categorical variable (quartile), a trend test was used to examine the trend of the linear association between the SII and HL. Subgroup analysis was used to investigate the association between the SII and AAC in people of different sexes.

In the 1999–2020 NHANES, a total of 5501 participants were included in the final analysis after excluding missing covariates. Tables 1, 2, and 3 list the characteristics of the survey participants. The overall age was 46.75 ± 0.36 years. Among them, 5205 (94.62%) participants were identified as hearing loss patients, with an average age of 47.21 ± 0.36; 4519 (82.15%) participants were identified as SFHL patients, with an average age of 47.77 ± 0.40 years. A total of 4205 (76.44%) participants were identified as HFHL patients with a mean age of 48.90 ± 0.39 years. The incidence of hypertriglyceridemia, cancer and hypertension was greater in the three hearing loss groups than in the nonhearing loss group (P < 0.05).

Table 1

Demographic characteristics and laboratory examination of individuals with hearing loss
Characteristics	Total(n = 5501)	No	Hearing Loss(n = 5205)	Pvalue
BMI, (kg/㎡)	28.74(0.14)	28.90(0.62)	28.73(0.15)	0.8
Age, (years)	46.75(0.36)	38.96(0.95)	47.21(0.36)	< 0.0001
Ratio of family income to poverty	3.04(0.05)	2.92(0.13)	3.04(0.05)	0.34
Triglyceride, (mg/dl)	104.00( 72.00,151.00)	95.00(67.00,133.00)	104.00(72.00,152.00)	0.01
Total-Cholesterol, (mg/dl)	192.00(167.00,219.00)	190.00(164.00,215.00)	192.00(167.00,220.00)	0.2
HDL-Cholesterol, (mg/dl)	51.00(43.00,63.00)	51.00(43.00,61.00)	51.00(43.00,63.00)	0.7
LDL-Cholesterol, (mg/dl)	114.00( 91.00,138.00)	113.00(90.00,135.00)	114.00(91.00,138.00)	0.66
SII	465.26(341.13,645.00)	435.88(295.83,640.44)	467.79(343.78,645.00)	0.12
Drinking alcohol, (%)				0.03
never	10.68	10.01	10.71
former	13.52	13.19	13.54
mild	37.63	28.53	38.18
moderate	17.41	24.01	17.01
heavy	20.76	24.26	20.55
Cancer, (%)				0.002
No	91.00	96.78	90.65
Yes	9.00	3.22	9.35
Gender, (%)				0.24
Male	48.80	44.46	49.06
Female	51.20	55.54	50.94
Ethnicity, (%)				0.02
white	70.71	64.66	71.08
mexican	6.86	8.34	6.77
black	10.31	14.97	10.03
other	12.12	12.03	12.12
Marital status, (%)				< 0.0001
Married	57.89	46.72	58.55
Widowed	5.04	2.03	5.22
Divorced	9.35	9.59	9.33
Separated	2.00	2.46	1.97
Never married	17.46	27.57	16.85
Living with partner	8.27	11.62	8.06
Education, (%)				0.94
Under high school	14.93	14.13	14.98
High school or equivalent	22.88	23.52	22.84
Above high school	62.19	62.35	62.18
Diabetes, (%)				0.76
no	90.96	90.26	91.00
yes	9.04	9.74	9.00
Hypertension, (%)				< 0.0001
no	63.28	76.85	62.47
yes	36.72	23.15	37.53
Smoking, (%)				0.06
never	53.17	57.17	52.94
former	25.35	18.44	25.76
now	21.48	24.39	21.30
SIIQ(%)				0.05
Q1	21.98	30.25	21.48
Q2	26.03	25.37	26.07
Q3	26.13	19.05	26.55
Q4	25.87	25.33	25.90

Table 2

Demographic characteristics and laboratory examinations of individuals with SFHL
Characteristics	Total(n = 5501)	No	SFHL(n = 4519)	Pvalue
BMI, (kg/㎡)	28.74(0.14)	28.88(0.34)	28.71(0.16)	0.67
Age, (years)	46.75(0.36)	42.07(0.56)	47.77(0.40)	< 0.0001
Ratio of family income to poverty	3.04(0.05)	2.95(0.08)	3.05(0.05)	0.17
Triglyceride, (mg/dl)	104.00( 72.00,151.00)	99.00(69.00,140.00)	105.00(73.00,152.00)	0.01
Total-Cholesterol, (mg/dl)	192.00(167.00,219.00)	192.00(169.00,218.00)	192.00(167.00,220.00)	0.99
HDL-Cholesterol, (mg/dl)	51.00(43.00,63.00)	51.00(43.00,62.00)	51.00(43.00,63.00)	0.88
LDL-Cholesterol, (mg/dl)	114.00( 91.00,138.00)	116.00(92.00,137.00)	113.00(91.00,138.00)	0.43
SII	465.26(341.13,645.00)	472.27(329.33,674.29)	462.86(343.20,639.27)	0.48
Drinking alcohol, (%)				0.02
never	10.68	11.91	10.40
former	13.52	12.20	13.81
mild	37.63	32.74	38.71
moderate	17.41	19.20	17.01
heavy	20.76	23.95	20.06
Cancer, (%)				< 0.0001
No	91.00	95.48	90.01
Yes	9.00	4.52	9.99
Gender, (%)				< 0.0001
Male	48.80	41.26	50.45
Female	51.20	58.74	49.55
Ethnicity, (%)				0.002
white	70.71	66.78	71.58
mexican	6.86	7.18	6.79
black	10.31	13.50	9.61
other	12.12	12.54	12.02
Marital status, (%)				0.002
Married	57.89	54.32	58.67
Widowed	5.04	2.74	5.55
Divorced	9.35	10.27	9.15
Separated	2.00	2.72	1.84
Never married	17.46	21.12	16.66
Living with partner	8.27	8.83	8.14
Education, (%)				0.84
Under high school	14.93	14.48	15.03
High school or equivalent	22.88	23.60	22.72
Above high school	62.19	61.91	62.25
Diabetes, (%)				0.18
no	90.96	92.25	90.68
yes	9.04	7.75	9.32
Hypertension, (%)				0.003
no	63.28	68.05	62.23
yes	36.72	31.95	37.77
Smoking, (%)				0.01
never	53.17	54.29	52.93
former	25.35	20.82	26.34
now	21.48	24.89	20.73
SIIQ(%)				0.02
Q1	21.98	24.25	21.48
Q2	26.03	21.59	27.01
Q3	26.13	25.55	26.25
Q4	25.87	28.60	25.27

Table 3

Demographic characteristics and laboratory examinations of individuals with HFHL
Characteristics	Total(n = 5501)	No	HFHL(n = 4205)	Pvalue
BMI, (kg/㎡)	28.74(0.14)	28.84(0.27)	28.71(0.16)	0.67
Age, (years)	46.75(0.36)	40.13(0.48)	48.90(0.39)	< 0.0001
Ratio of family income to poverty	3.04(0.05)	2.95(0.08)	3.06(0.05)	0.16
Triglyceride, (mg/dl)	104.00( 72.00,151.00)	99.00(68.00,146.00)	105.00(74.00,153.00)	0.001
Total-Cholesterol, (mg/dl)	192.00(167.00,219.00)	191.00(166.00,216.00)	192.00(167.00,221.00)	0.28
HDL-Cholesterol, (mg/dl)	51.00(43.00,63.00)	51.00(43.00,62.00)	51.00(43.00,63.00)	0.65
LDL-Cholesterol, (mg/dl)	114.00( 91.00,138.00)	114.00(93.00,138.00)	113.00(91.00,138.00)	0.79
SII	465.26(341.13,645.00)	454.50(321.76,641.41)	468.92(346.25,645.33)	0.14
Drinking alcohol, (%)				< 0.001
never	10.68	9.93	10.92
former	13.52	11.94	14.04
mild	37.63	33.16	39.09
moderate	17.41	21.62	16.04
heavy	20.76	23.35	19.92
Cancer, (%)				< 0.0001
No	91.00	95.01	89.69
Yes	9.00	4.99	10.31
Gender, (%)				< 0.0001
Male	48.80	41.56	51.16
Female	51.20	58.44	48.84
Ethnicity, (%)				< 0.0001
white	70.71	64.29	72.81
mexican	6.86	8.10	6.45
black	10.31	13.02	9.43
other	12.12	14.59	11.31
Marital status, (%)				< 0.0001
Married	57.89	51.56	59.95
Widowed	5.04	2.08	6.01
Divorced	9.35	9.16	9.41
Separated	2.00	2.07	1.98
Never married	17.46	24.27	15.24
Living with partner	8.27	10.86	7.42
Education, (%)				0.21
Under high school	14.93	14.18	15.17
High school or equivalent	22.88	21.11	23.46
Above high school	62.19	64.72	61.37
Diabetes, (%)				0.01
no	90.96	93.60	90.10
yes	9.04	6.40	9.90
Hypertension, (%)				< 0.0001
no	63.28	71.48	60.61
yes	36.72	28.52	39.39
Smoking, (%)				0.03
never	53.17	56.25	52.17
former	25.35	21.81	26.50
now	21.48	21.94	21.32
SIIQ(%)				0.1
Q1	21.98	25.06	20.97
Q2	26.03	24.78	26.44
Q3	26.13	24.82	26.55
Q4	25.87	25.33	26.04

The associations between the systemic inflammatory response indices and hearing loss are shown in Table 4. Univariate logistic regression analysis of the risk of hearing loss, speech frequency hearing loss (SFHL) and high-frequency hearing loss (HFHL) revealed that there was no significant correlation between the SII and hearing loss or SFHL (p > 0.05), but the SII was correlated with HFHL (p < 0.05).

Table 4

logistic regression was used to explore the relationship between SII and its quartile and hearing loss
	Hearing loss						SFHL							HFHL
	SII						SII							SII
	crude model		Model 1		Model 2		crude model		Model 1		Model 2			crude model			Model 1			Model 2
character	95%CI	P	95%CI	P	95%CI	P	95%CI	P	95%CI	P	95%CI	P	95%CI		P	95%CI		P	95%CI		P
SII	1.00 (1.00,1.00)	0.19	1.00 (1.00,1.00)	0.33	1.00 (1.00,1.00)	0.34	1.00 (1.00,1.00)	0.30	1.00 (1.00,1.00)	0.15	1.00 (1.00,1.00)	0.20	1.00 (1.00,1.00)		0.05	1.00 (1.00,1.00)		0.18	1.00 (1.00,1.00)		0.17
pvalue		0.19		0.33		0.34		0.3		0.15		0.2			0.05			0.18			0.17
	SIIQ						SIIQ							SIIQ
	crude model		Model 1		Model 2		crude model		Model 1		Model 2			crude model			Model 1			Model 2
Q1	ref		ref		ref		ref		ref		ref		ref			ref			ref
Q2	1.45 (0.95,2.21)	0.09	1.37 (0.88,2.15)	0.16	1.36 (0.87,2.13)	0.18	1.41 (1.11,1.80)	0.01	1.36 (1.05,1.76)	0.02	1.38 (1.07,1.79)	0.01	1.27 (1.01,1.61)		0.04	1.23 (0.97,1.55)		0.09	1.23 (0.96,1.57)		0.10
Q3	1.96 (1.18,3.26)	0.01	1.86 (1.09,3.18)	0.02	1.93 (1.13,3.29)	0.02	1.16 (0.91,1.48)	0.22	1.12 (0.87,1.45)	0.38	1.16 (0.90,1.50)	0.25	1.28 (1.02,1.60)		0.03	1.24 (0.98,1.57)		0.08	1.25 (0.98,1.60)		0.08
Q4	1.44 (0.85,2.44)	0.17	1.35 (0.78,2.35)	0.29	1.35 (0.76,2.39)	0.30	1.00 (0.77,1.29)	0.99	0.97 (0.73,1.27)	0.80	1.00 (0.77,1.31)	0.99	1.23 (0.95,1.60)		0.12	1.19 (0.90,1.56)		0.22	1.19 (0.90,1.57)		0.21
pvalue		0.13		0.21		0.21		0.54		0.42		0.59			0.15			0.26			0.23
SII crudel model: SII model 1: SII, age, sex, eth model 2: SII, alcohol.user, bmi, cancer, age, sex, eth, mar, poverty, edu, DM, Hypertension, smoke, fast_triglyceride_mg.dl, fast_total_cholesterol_mg.dl, hdl_cholesterol_mg.dl, ldl_cholesterol_mg.dl SIIQ crudel model: SIIQ model 1: SIIQ, age, sex, eth model 2: SIIQ, alcohol.user, bmi, cancer, age, sex, eth, mar, poverty, edu, DM, Hypertension, smoke, fast_triglyceride_mg.dl, fast_total_cholesterol_mg.dl,hdl_cholesterol_mg.dl, ldl_cholesterol_mg.dl

We used multivariate logistic regression and linear regression to evaluate the independent effects of the SII on hearing loss, SFHL, and HFHL. According to multivariate logistic regression, after adjusting for several confounding variables [1.86 (1.09, 3.18)] and all confounding variables [1.93 (1.13, 3.29)] in the coarse model [1.96 (1.18, 3.26)], in the third quartile, there was a significant positive correlation between the SII and hearing loss (p < 0.05). In the coarse model [1.41 (1.11, 1.80)], after adjusting for several confounding variables [1.36 (1.05, 1.76)] and all confounding variables [1.38 (1.07, 1.79)], there was a significant positive correlation between the SII and SFHL in the second quartile (p < 0.05). For HFHL, only in the crude model was there a significant association between the SII and HFHL in the 2nd and 3rd quartiles (p < 0.05), and the risk of HFHL increased with increasing SII. See Table 4 for details.

After the SII was classified into quartiles, a stratified analysis of clinical variables was performed. The results showed that for hearing loss, never alcohol intake and moderate alcohol intake (never alcohol intake and moderate alcohol intake), the SII was positively correlated with the incidence of hearing loss, and as the SII increased layer by layer, the risk of hearing loss increased. For SFHL, the SII was significantly correlated with the incidence of SFHL in individuals with a normal BMI, age > 60 years, and smoking status (former smokers), and the risk of SFHL gradually decreased with increasing SII. In HFHL, the SII was positively associated with the onset of HFHL in individuals with moderate alcohol intake, with participants in the highest quartile of the SII having a 115% increased risk of developing HFHL compared to participants in the lowest quartile of the SII [2.15 (1.18, 3.93)].See Table 5 for details.

Table 5

Association between SII quartile and different risk of hearing loss after multivariate logistic regression Association between SII quartile and HL after multivariate logistic regression
character	Q1	Q2	p	Q3	p	Q4	P	p for trend	p for interaction
sex									0.17
Male	ref	2.33( 1.21,4.49)	0.01	2.49( 1.20, 5.14)	0.01	1.43( 0.65, 3.16)	0.37	0.3
Female	ref	0.88(0.45,1.70)	0.7	1.52(0.74,3.13)	0.25	1.14(0.54,2.41)	0.73	0.43
bmi_cut									0.06
normal	ref	2.69(1.15,6.29)	0.02	2.57(1.16,5.70)	0.02	1.15(0.54,2.44)	0.71	0.69
low	ref	0.91(0.47,1.78)	0.79	1.78(0.81, 3.94)	0.15	1.00(0.43, 2.33)	1	0.64
high	ref	1.16(0.57,2.34)	0.68	1.53(0.73,3.22)	0.26	1.98(0.79,4.96)	0.14	0.13
age_cut									0.85
=<60	ref	1.35(0.84,2.16)	0.21	2.00(1.14,3.50)	0.02	1.37(0.74,2.54)	0.32	0.2
> 60	ref	1.40(0.29,6.77)	0.68	1.16( 0.26, 5.11)	0.84	0.90( 0.23, 3.61)	0.88	0.82
alcohol.user									0.47
never	ref	1.19(0.44,3.22)	0.72	2.05(0.63, 6.69)	0.23	2.78(0.92, 8.35)	0.07	0.05
former	ref	1.33( 0.35,5.02)	0.67	2.68( 0.69,10.38)	0.15	1.49( 0.37, 6.10)	0.57	0.47
mild	ref	0.95(0.39, 2.27)	0.9	1.16(0.43, 3.09)	0.77	0.55(0.31, 0.99)	0.05	0.14
moderate	ref	2.14(0.93, 4.93)	0.07	2.51(1.07, 5.91)	0.04	3.66(1.43, 9.39)	0.01	0.01
heavy	ref	1.47(0.60, 3.60)	0.39	1.89(0.68, 5.29)	0.22	0.97(0.35, 2.65)	0.95	0.96
smoke									0.57
never	ref	1.25(0.73,2.13)	0.41	1.74(0.94,3.21)	0.08	1.46(0.73,2.92)	0.28	0.19
former	ref	1.53(0.62, 3.77)	0.35	1.16(0.47, 2.88)	0.75	1.10(0.42, 2.85)	0.85	0.97
now	ref	1.75(0.77, 3.95)	0.18	4.61(1.42,14.91)	0.01	1.51(0.54, 4.20)	0.42	0.43
Hypertension									0.98
no	ref	1.34(0.81, 2.23)	0.25	1.87(1.02, 3.40)	0.04	1.27(0.64, 2.49)	0.49	0.33
yes	ref	1.56(0.67, 3.66)	0.3	1.98(0.86, 4.54)	0.11	1.54(0.64, 3.71)	0.33	0.34
DM									0.42
no	ref	1.32(0.81,2.14)	0.26	1.97(1.12,3.49)	0.02	1.23(0.67,2.23)	0.5	0.33
DM	ref	1.54(0.44, 5.38)	0.49	1.02(0.24, 4.40)	0.98	3.43(1.02,11.58)	0.05	0.12
Association between SII quartile and SFHL after multivariate logistic regression

According to the RCS plot, there was an inverted U-shaped association between the SII and the incidence of hearing loss and SFHL (nonlinear P < 0.05, Fig A and Fig B). As the SII increases, the risk of hearing loss and SFHL increases significantly. When the SII reaches the inflection point, the curve then shows a downward trend. The SII was positively correlated with the incidence of HFHL (Fig C). After stratification by sex, the SII showed an inverted U-shaped correlation with hearing loss in males and a positive correlation with hearing loss in females (Fig D). See Fig. 1 for details.

Hearing loss (HL) is the number of decibels greater than the normal hearing threshold of the human ear at a certain frequency. After fully considering the high-frequency hearing loss associated with hearing impairment, the World Health Organization (WHO) promulgated a new classification standard in 1997, adding a hearing threshold of 4000 Hz compared with the previous standard. hearing impairment below 4000 Hz is referred to as speech-frequency hearing loss (SFHL), and hearing impairment above 4000 Hz is referred to as high-frequency hearing loss (HFHL). As of 2023, 466 million people worldwide are living with hearing loss, 34 million of whom are children¹⁶. This disease has great psychological influence and burden on individuals and society. The SII is a new predictor of inflammatory diseases and malignant tumors, as well as a new inflammatory indicator¹⁷, which can reflect the local immune response and systemic inflammation of the whole body. This hematological marker has the advantages of being convenient and inexpensive, and the results can be obtained almost immediately¹⁸. In recent years, the use of peripheral blood indicators to study inflammation and the immune response in patients with HL has been reported. The SII may indicate vascular endothelial injury and local arteriolar inflammation. The development of HL is also believed to be related to local inflammatory cell infiltration and injury, but the specific relationship between HL and the SII is still unclear and needs further exploration.

In our study, we found that there was a significant correlation between the SII and HL. However, after logistic regression analysis with different variables, the correlation between the two variables changed. Univariate logistic regression analysis revealed that there was no significant correlation between the SII and the occurrence of HL or SFHL (p > 0.05), but there was a correlation between the SII and HFHL (p < 0.05). According to multivariate logistic regression, after adjusting for several confounding variables [1.86 (1.09, 3.18)] and all confounding variables [1.93 (1.13, 3.29)] in the coarse model [1.96 (1.18, 3.26)], in the third quartile, there was a significant positive correlation between the SII and hearing loss (p < 0.05). In the coarse model [1.41 (1.11, 1.80)], after adjusting for several confounding variables [1.36 (1.05, 1.76)] and all confounding variables [1.38 (1.07, 1.79)], there was a significant positive correlation between the SII and SFHL in the second quartile (p < 0.05). For HFHL, only in the crude model was there a significant association between the SII and HFHL in the 2nd and 3rd quartiles (p < 0.05), and the risk of HFHL increased with increasing SII. This indicates that there are still other confounding factors in this regression model, and more relevant influencing factors can be explored.

After further stratifying the clinical variables, we found that the trend between the SII and HL, SFHL, and HFHL varied in populations with different characteristics. The SII was positively associated with the incidence of hearing loss in people with no or moderate alcohol intake. In people with moderate alcohol intake, the SII is positively associated with HFHL. However, in the groups with a normal BMI, age > 60 years and smoking status, the SII was inversely associated with SFHL. This finding is consistent with the RCS analysis. According to the limited cubic spline curve of the prevalence relationship between the three types of hearing loss patients, the SII was positively correlated with the incidence of HFHL; however, the SII was positively correlated with the incidence of hearing loss and SFHL, while the SII was positively correlated with the incidence of HFHL. In addition, after the RCS analysis of sex, it was found that the SII was positively correlated with the incidence of HL in females, and the SII was inversely U-shaped with the incidence of HL in males.

To our knowledge, this is the first study to examine the relationship between the SII and HL. Yuting Yao et al. previously reported that the blood immune marker SII in patients with both low-frequency and high-frequency hearing loss was significantly greater than that in normal controls¹⁹. In addition, Xu Zhang et al. reported that patients with sudden sensorineural hearing loss (SSNHL) exhibit inflammatory and immune responses in vivo, and the SII plays an important role in predicting the prognosis and guiding treatment of these patients. The greater the SII is, the worse the therapeutic effect is for such patients²⁰. Yuting Yao et al. also showed that the immune and inflammatory response of the cochlea may be the common pathophysiology of all patients with SSNHL ¹⁹. In this immune response, the presence of macrophages in the cochlea plays a very important role. Previous studies have shown that macrophages in the cochlea can maintain cochlear homeostasis and are essential for defending against pathogens and limiting inappropriate inflammation^21–23. The presence of macrophages facilitates immune surveillance under physiological conditions, detection of infection barriers, and contact of synapses to maintain homeostasis ²⁴. Resident macrophages are also associated with angiogenesis ^25,26. In the blood labyrinth barrier, tight connections between cochlear microvascular endothelial cells are crucial for maintaining inner ear homeostasis, cochlear internal potential and normal hearing ²⁷. Moreover, the accumulation of cochlear macrophages can also increase ototoxicity ^28,29. There is increasing evidence that hearing impairment is closely related to cochlear macrophages ^30[30]. The different effects of macrophages on the cochlea may be related to certain functional differences among subtypes of resident macrophages in the cochlea ²⁴. The different effects of macrophages on the cochlea may be related to certain functional differences among subtypes of resident macrophages in the cochlea ^31–34. Moreover, macrophages distributed in different parts of the cochlea express different molecules ³⁰, and macrophages on the basement membrane are morphologically different in the apical and basal parts of the mature cochlea ³⁵. The bottom ring of the cochlea and the top ring feel that the sound frequency is also different; the bottom ring feels a high-frequency sound, and the top ring feels a lowfrequency sound. The activity of macrophages in different parts of the cochlea may affect the perception of different frequencies, but the specific relationship between the two needs to be further explored.

Our study can help clinicians assess risk stratification in patients with HL, clarify prognostic value, encourage early intervention and reduce disability rates, and use patient assessment for individualized treatment. We used a nationally representative sample, and our study is representative of the multiracial and gender-diverse population of the United States. In addition, the large sample size included in our study allowed us to perform subgroup analyses. Of course, more research is required in the future.

Our study has several limitations. First, this was a cross-sectional analysis; thus, temporality cannot be ascertained. Furthermore, despite adjusting for several relevant confounders, we were unable to rule out the impact of additional confounding factors; therefore, our findings should be interpreted with caution. Moreover, the study included a number of limitations. For instance, we studied the peripheral blood inflammatory markers of 80 SSNHL patients on the basis of existing clinical data. These SSNHL patients had only available data at the time of admission, and the follow-up time was short. Second, the studies were limited to cells, and no in-depth studies have been performed. Future prospective studies with larger sample sizes and exploration at the gene level are needed. It is still worth noting the results of our study despite these limitations.

Conflicts of interest Qiuyang Wang, Yaojie Wang, Jing Tian, Lisha He, Guoxin Huang, Chenge Qin, Xiaodan Li, Sheng Cheng, Huazhang Tan declare that they have no conflict of interest.

Data availability statement:

The data utilized in this study are publicly available from the National Health and Nutrition Examination Survey (NHANES) and can be accessed at [NHANES Data and Documentation](https://wwwn.cdc.gov/nchs/nhanes/Default.aspx). Data also can be obtained by contacting Qiuyang Wang.

Ethics Statement:

For GBD study, a waiver of informed consent was reviewed and approved by the Institutional Review Board of the University of Washington.

Funding:

We are very grateful for the support of Hubei Science and Technology Foundation Project（YFXM2023000340), Science Research Foundation of Yunnan Education Bureau(2023Y0631) and Natural Science Foundation project of Hubei Province (2024AFB262).

Contribution statement

Q.W, G.H and J.T designed the study. Y.W, L.H, G.H and C.Q contribute equally. Y.W, L.H, G.H, C.Q, S.C and H.T analysed and interpreted the data. Q.W and J.T is the guarantor of this work. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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No competing interests reported.

Association of systemic inflammatory biomarkers with hearing loss: Results from NHANES 1999–2020 analyses

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1 The data source

2.2. Audiometric measures and hearing loss

2.2. Systemic immune-inflammation index

2.3. Covariables

2.4. Statistical analysis

3. Results

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 1