CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course
Abstract
:1. Introduction
2. Results
2.1. Characteristics of the Study Group
2.2. Expression of Select Chemokines at the mRNA Level
2.3. Expressions of Selected Complement System Elements at the mRNA Level
2.4. Concentration of Select Chemokines at the Protein Level
2.5. Concentration of Selected Complement System Elements at The Protein Level
2.6. CMV Status
3. Discussion
- -
- Lower mRNA expression and higher concentrations of CXCL8 and CCL2 in the plasma correlated with more severe courses of COVID-19.
- -
- CMV-positive status correlated with a more severe COVID-19 course.
- -
- CXCL8, CCL2, and CMV seropositivity should be considered as new prognostic factors for severe COVID-19 courses.
4. Materials and Methods
4.1. Study Group
4.2. General Health Questionnaire
4.3. Material
4.3.1. Plasma Collection
4.3.2. RNA Isolation
Viral RNA Isolation
Blood Mononuclear Cell RNA Isolation
4.3.3. qRT-PCR
qRT–PCR Assays for Detecting SARS-CoV-2 RNA
qRT–PCR Assays for Evaluating Complement and Chemokine mRNA Expressions
4.3.4. Luminex Assay
4.3.5. Enzyme-Linked Immunosorbent Assay (ELISA)—Serological Assays for Specific Anti-SARS-CoV-2 IgM, IgG, IgA, and Anti-CMV IgG Antibodies Detection
4.4. Statistical Analysis
5. Study Limitations
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BMG | Beta-2-microglobulin |
BMI | body mass index |
C4BPA | complement component 4 binding protein alpha |
C5AR1 | complement component 5a receptor 1 |
CCL3 | C-C motif chemokine ligand 3 (macrophage inflammatory protein-1α—MIP-1α) |
CCR1 | C-C motif chemokine receptor 1 |
CFD | Complement factor D |
CMV | cytomegalovirus |
CR1 | complement receptor type 1 |
CRS | cytokine release syndrome |
CT | computed tomography |
CXCL10 | C-X-C motif chemokine ligand 10 (interferon gamma-induced protein 10—IP-10) |
DPP9 | dipeptidyl peptidase 9 |
ELISA | enzyme-linked immunosorbent assay |
G-CSF | granulocyte colony stimulating factor |
GROα | growth-regulated oncogene-α (CXCL1) |
ICU | intensive care unit |
IL-1α | interleukin-1α |
IL-6 | interleukin 6 |
IL-8 | interleukin 8 (CXCL8) |
IL-10 | interleukin 10 |
IFN-α | interferon-α |
ISG | interferon-stimulated gene |
MASP-2 | mannose-binding protein-associated serine protease 2 |
Tr5‘6wq222MBL | Mannose-binding lectin |
MCP-1 | monocyte chemoattractant protein-1 (CCL2) |
MCP-3 | monocyte chemotactic protein-3 (CCL7) |
NF-κB | nuclear factor kappa-light-chain-enhancer of activated B cells |
non-ICU | non-intensive care unit patients |
RT-PCR | real-time polymerase chain reaction |
STEMI | ST-segment elevation myocardial infarction |
TNF-α | tumor necrosis factor-α |
TPO | thrombopoietin |
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Parameter | SARS-CoV-2 Negative Controls (n = 80) | SARS-CoV-2 Positive Patients (n = 210) | p | |
---|---|---|---|---|
Age (mean ± SD) | 56.27 ± 5.56 | 57.78 ± 14.16 | 0.052 | |
Sex (male/female) | 5/75 | 114/96 | <0.001 | |
Body mass index (mean ± SD) | 25.85 ± 4.74 | 29.17 ± 5.52 | <0.001 | |
Parameter | SARS-CoV-2 positive patients non-ICU (n = 160) | SARS-CoV-2 positive patients ICU (n = 50) | ||
Percent of patient population (%) | 76.19 | 23.81 | ||
Age (mean ± SD) | 56.26 ± 14.53 | 62.64 ± 11.79 | <0.01 | |
Sex (male/female) | 85/74 | 28/22 | 1 | |
Body mass index (mean ± SD) | 28.87 ± 5.55 | 30.44 ± 5.42 | 0.04 | |
% of patients with a given parameter | Medical history | |||
Hypertension | 44.38 | 54 | 0.25 | |
Diabetes | 20.63 | 20 | 1 | |
Ischemic heart disease | 7.5 | 12 | 0.38 | |
Hypercholesterolemia | 14.38 | 14 | 1 | |
Liver disease | 0.63 | 2 | 0.42 | |
Respiratory system disease | 8.13 | 14 | 0.27 | |
Rheumatic disease | 9.38 | 10 | 1 | |
Cancer | 10.63 | 10 | 1 | |
Other diseases | 33.13 | 50 | 0.04 | |
Tobacco use (previous/now) | 43.13/5.63 | 30/0 | <0.001 | |
Current medications | ||||
Drugs taken on a permanent basis | 63.75 | 46 | 0.03 | |
NSAIDs | 12.5 | 16 | 0.49 | |
Statins | 15 | 22 | 0.28 | |
Antihypertensive drugs | 47.5 | 46 | 0.87 | |
Anticoagulants | 7.5 | 6 | 1 | |
Cardiac drugs | 7.5 | 14 | 0.17 | |
Anti-asthmatic drugs | 8.13 | 10 | 0.77 | |
Other drugs | 41.25 | 38 | 0.74 |
Parameter | Negative Controls (n = 80) | |
---|---|---|
% of patients with a given parameter | Medical history | |
Hypertension | 14.08 | |
Diabetes | 2.82 | |
Ischemic heart disease | 0 | |
Hypercholesterolemia | 8.45 | |
Liver disease | 0 | |
Respiratory system disease | 0 | |
Rheumatic disease | 11.27 | |
Cancer | 4.41 | |
Other diseases | 0 | |
Tobacco use (previous/now) | 40.26/33.80 | |
Current medications | ||
Drugs taken on a permanent basis | 21.27 | |
NSAIDs | 8.45 | |
Statins | 5.63 | |
Antihypertensive drugs | 15.49 | |
Anticoagulants | 6.63 | |
Cardiac drugs | 0 | |
Anti-asthmatic drugs | 2.82 | |
Other drugs | 16.90 |
Time of Sample Collection | Day 1 | Day 7 | Day 14 | Day 28 | |
---|---|---|---|---|---|
Groups | CMV (+) (n = 185) | ||||
Number of individuals within the group | n = 181 | n = 122 | n = 69 | n = 58 | |
Chemokine expression | Gene relative expression level | ||||
mean ± SD (IQR) | CXCL8 | 0.32 ± 0.30 (0.21) | 0.87 ± 0.70 (0.65) *** | 0.93 ± 0.82 (0.67) *** | 0.74 ± 0.61 (0.59) ** |
CCL2 | 0.55 ± 0.77 (0.23) | 0.35 ± 0.38 (0.21) | 0.39 ± 0.34 (0.28) | 0.65 ± 0.78 (0.37) | |
CCR1 | 1.09 ± 0.66 (0.98) | 0.77 ± 0.45 (0.69) * | 0.92 ± 0,49 (0.84) | 0.93 ± 0.48 (0.81) | |
Chemokine concentration | Protein concentration (pg/mL) | ||||
Mean ± SD (IQR) | CXCL8 | 4.90 ± 3.66 (4.07) | 2.44 ± 1.61 (2.04) * | 3.46 ± 3.13 (1.96) | 3.41 ± 1.8 (3.11) |
CXCL10 | 259.36 ± 203.24 (234) | 64.11 ± 46.51 (51.76) *** | 46.06 ± 41.20 (29.12) *** | 50.59 ± 36.30 (41.82) *** | |
CCL2 | 268.67 ± 160.97 (232) | 210.87 ± 123.17 (182.5) ** | 257.36 ± 164.32 (222.5) | 244.45 ± 129.27 (221) | |
CCL3 | 331.06 ± 154.05 (346) | 103.89 ± 39.08 (92.80) *** | 101.05 ± 49.59 (92.79) *** | 104.11 ± 52.29 (80.01) *** | |
Complement expression | Gene relative expression level | ||||
Mean ± SD (IQR) | C4BPA | 0.60 ± 0.65 (0.37) | 1.13 ± 0.89 (0.99) *** | 1.04 ± 0,99 (0.62) * | 1.10 ± 0.80 (0.84) ** |
C5AR1 | 0.71 ± 0.32 (0.70) | 0.82 ± 0.36 (0.80) * | 1.94 ± 1.56 (1.42) *** | 0.95 ± 0.44 (0.93) * | |
CFD | 1.35 ± 1.17 (0.87) | 1.71 ± 1.42 (1.08) * | 3.38 ± 2.93 (2.48) *** | 2.00 ± 1.42 (1.42) * | |
CR1 | 0.83 ± 0.42 (0.78) | 0.53 ± 0.26 (0.47) ** | 1.30 ± 0.77 (1.33) | 1.53 ± 0.68 (1.53) *** | |
Complementconcentration | Protein concentration (ng/mL) | ||||
Mean ± SD (IQR) | C9 | 90,070.67 ± 22,913.75 (88,300) | 59,470.25 ± 22,633.56 (56,900) *** | 6130.59 ± 2099.12 (5730) *** | 4680.26 ± 1786.52 (4730) *** |
CFD | 4153.29 ± 1170.17 (3923.83) | 3599.13 ± 1064.72 (3476.6) * | 3869.71 ± 1024.44 (3817.65) | 5038.22 ± 1344.68 (4732.5) * | |
C2 | 26,629.12 ± 6388.90 (26,174.4) | 19,602.25 ± 5044.71 (19,233) *** | 19,343.79 ± 5003.17 (19,436.8) *** | 21,253.07 ± 4590.60 (21,145.8) *** |
Time of sample collection | Day 1 | Day 7 | Day 14 | Day 28 | |
---|---|---|---|---|---|
Groups | CMV (−) (n = 25) | ||||
Number of individuals within the group | n = 21 | n = 10 | n = 10 | n = 11 | |
Chemokine expression | Gene relative expression level | ||||
Mean ± SD (IQR) | CXCL8 | 0.49 ± 0.40 (0.35) | 1.77 ± 1.06 (2.22) *** | 1.67 ± 1.97 (0.76) *** | 0.85 ± 0.61 (0.83) ** |
CCL2 | 0.63 ± 0.83 (0.36) | 0.32 ± 0.12 (0.27) | 2.05 ± 2.43 (0.44) | 0.85 ± 0.71 (0.58) | |
CCR1 | 0.91 ± 0.49 (0.78) | 0.82 ± 0.28 (0.68) * | 1.24 ± 0.48 (1.14) | 1.01 ± 0.34 (0.92) | |
Chemokine concentration | Protein concentration (pg/mL) | ||||
Mean ± SD (IQR) | CXCL8 | 4.47 ± 2,90 (3.93) | 3.03 ± 2.32 (1.97) *** | 3.78 ± 3.09 (2.87) | 3.38 ± 2.21 (2.64) |
CXCL10 | 195.20 ± 132.24 (199.5) | 63.24 ± 31.96 (62.34) *** | 46.60 ± 38.58 (30.03) *** | 29.23 ± 7.47 (31.23) *** | |
CCL2 | 255.20 ± 126.41 (243) | 191.52 ± 91.80 (202.5) * | 234.31 ± 133.63 (200) | 260.14 ± 89.04 (236) | |
CCL3 | 287.33 ± 139.65 (284.5) *** | 144.60 ± 72.02 (119) *** | 134,54 ± 77,57 (125) *** | 83.18 ± 42.47 (80.01) *** | |
Complement expression | Gene relative expression level | ||||
Mean ± SD (IQR) | C4BPA | 0.28 ± 0.29 (0.18) | 0.98 ± 1.44 (0.49) | 0.41 ± 0.39 (0.43) | 0.75 ± 0.56 (0.65) |
C5AR1 | 0.59 ± 0.34 (0.59) | 0.69 ± 0.54 (0.74) | 0.94 ± 0.82 (0.92) | 1.10 ± 0.62 (1.18) | |
CFD | 0.89 ± 0.64 (0.82) | 0.89 ± 0.57 (0.84) | 1.63 ± 1.00 (1.26) | 1.84 ± 0.93 (1.55) | |
CR1 | 0.77 ± 0.42 (0.67) | 0.43 ± 0.16 (0.38) | 0.56 ± 0.22 (0.55) | 2.07 ± 0.79 (2.01) * | |
Complement concentration | Protein concentration (ng/mL) | ||||
Mean ± SD (IQR) | C9 | 89,665 ± 20,673.83 (86,700) | 56,705 ± 20,082.18 (54,875) * | 4158.75 ± 1272.43 (4577.5) *** | 3480 ± 837.71 (3235) *** |
CFD | 4074.60 ± 1041.90 (3750.7) | 3965.14 ± 1257.85 (3843.28) * | 4075.83 ± 851.52 (4157.25) | 4743.12 ± 1160.92 (4324) * | |
C2 | 27,041.32 ± 4977.20 (28,002.1) | 19,133.4 ± 3607.63 (19,404.8) *** | 19,675.76 ± 3839.96 (18381) *** | 21,176.18 ± 3482.16 (21,065.4) *** |
Severity | CMV IgG Status | Frequency |
---|---|---|
ICU | Negative | 1 |
Non-ICU | Negative | 24 |
ICU | Positive | 51 |
Non-ICU | Positive | 134 |
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Pius-Sadowska, E.; Niedźwiedź, A.; Kulig, P.; Baumert, B.; Sobuś, A.; Rogińska, D.; Łuczkowska, K.; Ulańczyk, Z.; Wnęk, S.; Karolak, I.; et al. CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course. Int. J. Mol. Sci. 2022, 23, 11338. https://doi.org/10.3390/ijms231911338
Pius-Sadowska E, Niedźwiedź A, Kulig P, Baumert B, Sobuś A, Rogińska D, Łuczkowska K, Ulańczyk Z, Wnęk S, Karolak I, et al. CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course. International Journal of Molecular Sciences. 2022; 23(19):11338. https://doi.org/10.3390/ijms231911338
Chicago/Turabian StylePius-Sadowska, Ewa, Anna Niedźwiedź, Piotr Kulig, Bartłomiej Baumert, Anna Sobuś, Dorota Rogińska, Karolina Łuczkowska, Zofia Ulańczyk, Szymon Wnęk, Igor Karolak, and et al. 2022. "CXCL8, CCL2, and CMV Seropositivity as New Prognostic Factors for a Severe COVID-19 Course" International Journal of Molecular Sciences 23, no. 19: 11338. https://doi.org/10.3390/ijms231911338