The CXCL9/10/11-CXCR3 axis as a predictor of COVID-19 progression: a prospective, case-control study

Çelik, Neslihan; Çelik, Onur; Laloğlu, Esra; Özkaya, Alev

doi:10.1590/0037-8682-0128-2023

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Revista da Sociedade Brasileira de Medicina Tropical

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Major Article • Rev. Soc. Bras. Med. Trop. 56 • 2023 • https://doi.org/10.1590/0037-8682-0128-2023 copy

The CXCL9/10/11-CXCR3 axis as a predictor of COVID-19 progression: a prospective, case-control study

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

This study examined the relationship between levels of the chemokines CXCL9, CXCL10, CXCL11, and CXCR3 and mortality in patients with COVID-19..

Methods:

A total of 71 patients hospitalized with COVID-19 and 35 health workers with no symptoms and negative SARS-CoV-2 PCR results were included in the study. CXCL9, CXCL10, CXCL11, and CXCR3 levels were measured in blood samples using enzyme-linked immunosorbent assays. Participants were divided into three groups: healthy individuals, patients with mild to moderate pneumonia, and patients with severe pneumonia. Patients were also divided into sub-groups according to the outcome: dead and survived.

Results:

Serum CXCL9, CXCL10, CXCL11, and CXCR3 levels were significantly higher in patients with severe COVID-19 than in those with non-severe COVID-19; were higher in both patient groups than in the control group; and were higher in patients who died than in those who survived. Lymphocyte counts, and fibrinogen and PaO₂/FiO₂ levels were significantly lower in patients with severe COVID-19 than in those with moderate disease. Patients with COVID-19 also had elevated neutrophil/lymphocyte ratios, neutrophil counts, and lactate dehydrogenase, C-reactive protein, D-dimer, and ferritin levels.

Conclusions:

This study confirmed that CXCL9, CXCL10, CXCL11, and CXCR3 levels are associated with disease severity in patients with COVID-19. These laboratory parameters can help to estimate disease severity and predict outcomes, and are useful in clinical decision-making.

Keywords:
COVID-19; CXCL9/10/11-CXCR3 axis; Prognosis

Parameter	Reference value	Moderate Mean [SD]	Severe Mean [SD]	p
		n=30	n=41
Age (years)		65.5 [15.9]	66.1 [13.1]	0.882
WBC (cells/µL)	4390-11590	9446 [4120]	14750 [5438]	0.001
Lymphocytes (cells/µL)	1210-3770	958 [454]	560 [316]	0.001
Neutrophils (cells/µL)	2100-8800	7542 [4187]	9345 [4016]	0.03
NLR		9.4 [7.1]	23.2 [15.6]	0.001
AST (U/L)	13-40	73.2 [42.3]	66.0 [36.5]	0.857
ALT (U/L)	7-40	106.7 [65.4]	96.9 [73.2]	0.854
LDH (U/L)	120-246	422.3 [125.2]	620.7 [176.1]	0.001
GGT (U/L)	0-73	76.1 [64.9]	72.3 [68.2]	0.124
ALP (U/L)	46-116	144.1 [53.8]	136.7 [48.5]	0.825
Creatinine (mg/dL)	0.7-1.3	1.2 [0.7]	1.0 [0.6]	0.75
Prothrombin time (s)	12-16	13.2 [1.7]	14.5 [4.2]	0.06
CRP (mg/dL)	0-5	56.7 [45.2]	146.5 [82.4]	0.001
Troponın (ng/dL),	0-45	24.7 [62.5]	36.4 [45.3]	0.125
PaO₂/FiO₂		265.7 [84.3]	164.2 [28.5]	0.001
D-dimer (ng/mL)	0-500	1250,4 [1672.3]	2944.8 [4550.1]	0.006
Ferritin (ng/mL)	22-322	614.8 [362.4]	1450.2 [316.5]	0.001
Fibrinogen (ng/mL)	200-400	530.5 [154.6]	412.5 [130.8]	0.001

Parameter	Moderate disease Mean [SD]	Severe disease Mean [SD]	Healthy controls average [SD]	p
	n=30	n=41	n=35
CXCL9 (pg/mL)	704.55 [471.14]	940.09 [498.83]	194.64 [88.13]	<0.043 ^a <0.001 ^b,c
CXCL10 (pg/mL)	159.62 [43.63]	288.66 [102.71]	71.01 [39.77]	<0.001 ^a,b,c
CXCL11 (pg/mL)	139.64 [67.58]	290.52 [60.23]	93.49 [54.29]	<0.001 ^a,b <0.008 ^c
CXCR3 (pg/mL)	559.38 [234.64]	896.85 [326.77]	163.48 [52.30]	<0.001 ^a,b,c

Symptom	CXCL9 Mean [SD]	CXCL10 Mean[SD]	CXCL11 Mean [SD]	CXCR3 Mean [SD]	P*
	(pg/mL)	(pg/mL)	(pg/mL)	(pg/mL)
Fever					p^a=0.016 p^b,c,d<0.001
Yes	957 [494]	278 [110]	278 [76]	876 [340]
No	672 [461]	171 [51]	153 [78]	578 [237]
Tachypnea					p^a=0.025 p^b,c,d<0.001
Yes	950 [510]	280 [109]	281 [74]	887 [339]
No	683 [442]	168 [46]	149 [72]	561 [216]
Muscle or joint pain					p^a=0.028 p^b,c,d<0.001
Yes	948 [501]	281 [108]	280 [75]	878 [346]
No	685 [459]	166 [45]	150 [74]	575 [221]
Sore throat					p^a=0.045 p^b,c,d<0.001
Yes	703 [469]	169 [50]	155 [76]	590 [232]
No	941 [500]	282 [109]	279 [76]	875 [349]
Headache					p^a=0.012 p^b,c,d<0.001
Yes	970 [543]	287 [106]	286 [69]	902 [341]
No	673 [380]	166 [47]	151 [75]	564 [209]
Somnolence					p^a=0.026 p^b,c,d<0.001
Yes	949 [503]	281 [108]	283 [71]	283 [71]
No	683 [454]	167 [47]	146 [72]	146 [72]
Shortness of breath					p^a=0.036 p^b,c,<0.001 p^d=0.001
Yes	940 [509]	275 [109]	275 [73]	857 [300]
No	687 [447]	171 [57]	153 [85]	597 [329]
Nausea/vomiting					p^a=0.005 p^b,c,d<0.001
Yes	648 [419]	166 [49]	149 [70]	559 [218]
No	981 [508]	284 [107]	283 [74]	897 [335]

Parameter	Mild to moderate involvement	Severe involvement	p
	Mean [SD]	Mean [SD]
CXCL9 (pg/mL)	596 [223]	1351 [529]	<0.001
CXCL10 (pg/mL)	196 [53]	314 [138]	<0.001
CXCL11 (pg/mL)	190 [79]	304 [90]	<0.001
CXCR3 (pg/mL)	604 [184]	1068 [363]	<0.001

Parameter	Survivors Mean [SD]	Non-survivors Mean [SD]	p
	n=42	n=29
CXCL9 (pg/mL)	613 [200]	1170 [610]	< 0.001
CXCL10 (pg/mL)	206 [50]	275 [144]	< 0.005
CXCL11 (pg/mL)	210 [77]	251 [120]	< 0.08
CXCR3 (pg/mL)	630 [171]	934 [425]	< 0.001

Sociedade Brasileira de Medicina Tropical - SBMT Sociedade Brasileira de Medicina Tropical - SBMT, Núcleo de Medicina Tropical UnB, Sala 43C 70904-970, E-mails: rsbmt@uftm.edu.br | artes.rsbmt@gmail.com | sbmt@sbmt.org.br , WhatsApp: SBMT (61) 9.9192-6496, WhatsApp: RSBMT (34) 9.9996-5807 - Brasília - DF - Brazil
E-mail: rsbmt@uftm.edu.br

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[1] Corresponding author: Neslihan Çelik. e-mail:drneslihancelik@yahoo.com.tr