Association of early interleukin-6 level with injury severity and mortality in trauma patients: Systematic review and meta-analysis

Table 1 Summary and characteristics of the studies included in the systematic review and meta-analysis, mean ± SD/median (25^th-75^th percentiles)

Ref.	Study design	Country	Duration	Sample size total/gender (% male)	Age (years)	IL-6 within 24 hours (pg/mL) measuring time	ISS	Significant findings
Gołąbek-Dropiewska et al[7], 2018	Prospective cohort	Poland	NR	50/64%	39.5 (18-92)	10.65 (8.6-189.4) (24 hours)	26 (18-41)	Significantly higher levels of IL-6 on the first day after trauma in patients with ISS > 34
Binkowska et al[8], 2018	Prospective cohort	Poland	NR	32/71.9%	42.74 ± 18.41	ISS < 20: 42; ISS ≥ 20: 602 (at admission)	ISS > 20: n = 20; ISS < 20: n = 12	Statistically significant positive correlation between baseline levels of IL-6 and ISS (r = 0.64, P < 0.001)
Gupta et al[9], 2015	Prospective cohort	India	January 2010-January 2013	114/86%	34.3 ± 14.5	Survivors: 50 (10-90)2. Nonsurvivors: 250 (60-700)2, (24 hours)	18.71 ± 8.48	Serum levels of IL-6 on admission were significantly elevated in non-survivors (P < 0.05). IL-6 positively correlated with ISS (r = 0.6224, P < 0.0001)
El-Menyar et al[10], 2021	Prospective cohort	Qatar	October 2016-July 2019	250/98%	35.1 ± 10.1	137 (121-153)3 (at admission)	14.7 (13.4-15.9)3	Initial serum levels of IL-6 correlate with ISS (r = 0.40, P = 0.001)
Almahmoud et al[11], 2015	Retrospective case-control	United States of America	NR	472/69.9%	48.4 ± 0.9	ISS 1-15: 700; ISS 16-24: 1554; ISS > 24: 2176 (24 hours)	19.6 ± 0.5	Levels of IL-6 are elevated significantly in severe traumatic injury when compared to moderate and mild traumatic injury (P < 0.001)
Alper et al[12], 2016	Prospective cohort	Turkey	March 2014-July 2015	84/NR	ISS > 15: 42 ± 15.04; ISS ≤ 15: 38.75 ± 15.91	ISS > 15: 88.43 ± 8.10; ISS ≤ 15: 12.38 ± 7.52 (at admission)	NR	IL-6 levels are significantly elevated in patients with severe injuries (ISS > 15) compared to mild injuries (ISS ≤ 15) (P = 0.004)
Ebrahimpour et al[13], 2018	Prospective cohort	Iran	January 2013-December 2013	161/59.6%	39.28 ± 9.23	Died: 250.24 ± 21.96; survived: 251.27 ± 33.07 (24 hours)	29.24 ± 7.44	High levels of IL-6 on post-trauma day 1 are associated with high levels of ISS (P = 0.001). High levels of IL-6 on post-trauma day 2 are associated with mortality (P < 0.0001)
Akkose et al[14], 2007	Prospective cohort	Turkey	August 2003-May 2005	20/NR	36 ± 15	0.16 ± 0.06 (at admission)	24.8 ± 9.02	High IL-6 levels are associated with higher ISS (r = 0.448, P = 0.047). IL-6 is statistically insignificant in predicting mortality
Bogner et al[15], 2009	Retrospective	Germany	NR	58/69%	42 (18-89)	Patients receiving mass transfusion: 3752. Patients not receiving mass transfusion: 1502 (at admission)	35.4 ± 13.0	IL-6 was not significantly associated with higher ISS; however, patients who died within 90d after the trauma tended to have elevated IL-6 levels on admission and within the first 6 hours after trauma (P < 0.005)
Johansson et al[16], 2011	Prospective cohort	Denmark	2003-2005	75/7.7%	High syndecan-1: 45 (30-55)1. Low syndecan-1: 37 (29-48)1	High syndecan-1: 44.9 (13.5-95.5)1. Low syndecan-1: 7.8 (4.6-25.2)1 (at admission)	High syndecan-1: 23 (14-37)1. Low syndecan-1: 18 (14-28)1	IL-6 was correlated with ISS only in patients with high syndecan-1 (ρ = 0.41, P = 0.010)
Yagmur et al[17], 2005	Prospective cohort	Turkey	December 2003-April 2004	99/71.7%	Survivors: 25 ± 21. Non-survivors: 32 ± 22	ISS < 16: 134 ± 71. ISS ≥ 16: 202 ± 64 (24 hours)	Survivors: 9.8 ± 5.1. Non-survivors: 19.8 ± 12.7	Patients with ISS > 16 had higher IL-6 levels than patients with ISS ≤ 16 (P < 0.001). Patients who died from trauma also had elevated IL-6 (P = 0.05) compared to those who survived
Sousa et al[18], 2015	Prospective cohort	Portugal	January 2010 to December 2010	99/82.8%	31 (18-60)1	Admitted to ICU: 569 (177-1440). Not admitted to ICU: 190 (131-439)1 (24 hours)	29 (17-52)1	On-admission serum IL-6 levels correlated with ISS (r = 0.346, p not reported)
Taniguchi et al[19], 2016	Prospective cohort	Japan	March 2014 to December 2014	208/74%	ICU > 7 days: 58 (43-71)1. ICU ≤ 7 days: 40 (20-59)1	ISS 1-3: 302. ISS 4-8: 352. ISS 9-15: 552. ISS 16-24: 752. ISS ≥ 25: 1702 (at admission)	ICU > 7 days: 26 (17-35)1. ICU ≤ 7 days: 7 (1-14)1	On-admission IL-6 levels correlated with ISS (r = 0.459, P < 0.0001). Patients who died within 28 days had significantly higher IL-6 levels than survivors (P = 0.021)
Stensballe et al[20], 2009	Prospective cohort	Denmark	2004-2005	265/72.1%	38.1 (26-55)1	30 (10-79.3)1 (12 hours)	Survivors: 9 (4-16)1. Non-survivors: 38 (25-75)1	IL-6 correlated significantly with ISS (on-admission: r = 0.52, P < 0.0001; 6h: r = 0.69, P < 0.0001). Serum IL-6 was higher in patients who died within the first 30 days (P < 0.0001)
Laishram et al[21], 2024	Prospective cohort	India	November 2022-June 2024	119/85.7%	NR	Inapparent hypoxia: 61.84 (39.41-158.25)1. Sepsis: 125.72 (43.05-421.77)1. MODS: 270.87 (48.28-496.95)1. FES: 50.74 (IQR NR) (12 hours)	ISS < 9: n = 38. 9-15: n = 64. ISS 16-25: n = 9. ISS ≥ 25: n = 8	12 hours serum IL-6 levels correlated with ISS (r = 0.595, P < 0.001)

¹Reported as median (25^th-75^th percentiles).

²Data was reported in graph, precise values not available.

³Reported as median (95%CI).

MODS: Multiple organ dysfunction syndrome; FES: Fat embolism syndrome; IL: Interleukin; ISS: Injury severity score; IQR: Interquartile range; ELISA: Enzyme-linked immunosorbent assay; ICU: Intensive care unit; NR: Not reported.

Table 2 Interleukin-6 values of survivors and non-survivors, mean ± SD

Ref.	Survivors		Non-survivors		Significant difference	Time of IL-6 measure
	No. patients	IL-6 (pg/mL)	No. patients	IL-6 (pg/mL)
Akkose et al[14], 2007	14	0.15 ± 0.05	6	0.18 ± 0.08	> 0.05	On arrival
Stensballe et al[20], 20091	236	28 ± 5	29	200 ± 65	< 0.05	On arrival
						12 hours
Taniguchi et al[19], 20161	201	60 ± 10	7	420 ± 165	< 0.05	On arrival
Yagmur et al[17], 2005	21	86 ± 77	17	146 ± 134	0.05	On arrival
Bogner et al[15], 2009	47	NR	11	NR	< 0.05	On arrival, 6 hours
Ebrahimpour et al[13], 2018	136	251.27 ± 33.07	25	250.24 ± 21.96	> 0.05	24 hours
	136	223.53 ± 25.33	25	276.84 ± 12.51	< 0.05	48 hours
Gupta et al[9], 20151	77	70 ± 82	37	346 ± 445	< 0.05	On arrival
	77	96 ± 75	26	653 ± 576	< 0.05	72 hours

¹Approximated values from the figure.

NR: Not reported; IL: Interleukin.

Table 3 The quality of studies included in the systematic review and meta-analysis was assessed according to the Newcastle-Ottawa Scale for cohort studies

Ref.	Selection	Comparability	Outcome	Score
Gołąbek-Dropiewska et al[7], 2018	4	0	3	7/8
Binkowska et al[8], 2018	4	2	3	9/9
Gupta et al[9], 2015	3	0	3	6/8
Stensballe et al[20], 2009	3	2	2	7/8
El-Menyar et al[10], 2021	3	2	3	8/8
Almahmoud et al[11], 2015	3	2	2	7/8
Alper et al[12], 2016	4	0	2	6/9
Ebrahimpour et al[13], 2018	3	0	3	6/8
Akkose et al[14], 2007	4	0	2	6/8
Bogner et al[15], 2009	3	0	3	6/8
Johansson et al[16], 2011	3	2	2	7/9
Yagmur et al[17], 2005	4	1	2	7/9
Sousa et al[18], 2015	3	0	3	6/8
Taniguchi et al[19], 2016	3	0	2	5/8
Laishram et al[21], 2024	2	0	3	5/8