Analysis of Plasma Proteins Involved in Inflammation, Immune Response/Complement System, and Blood Coagulation upon Admission of COVID-19 Patients to Hospital May Help to Predict the Prognosis of the Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Aspects
2.2. Study Design and Patients
2.3. Comparisons and Sampling
2.4. Preparation of the Plasma Samples for Proteomic Analysis
2.5. Proteomic Analysis
2.6. Statistical Analysis
3. Results
3.1. Characterization of the Patients Included in the Study
3.2. Laboratory Findings
3.3. Proteomic Analysis
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | Mild | Severe | Critical |
---|---|---|---|
Median age, years (95% CI) | 51.0 (48.8–56.7) a | 56.5 (51.8–60.4) a | 73.0 (63.7–72.7) b |
Female (n, %) | 41, 53.9% | 30, 53.6% | 11, 35.5% |
Male (n, %) | 35, 46.1% | 26, 46.4% | 20, 64.5% |
Comorbidity | |||
Hypertension | 31.6% | 49.1% | 64.5% |
Diabetes | 21.1% | 41.8% | 32.3% |
Cardiovascular disease | 10.5% | 10.9% | 9.7% |
Obesity | 22.4% | 14.5% | 3.2% |
COPD | 5.3% | 10.9% | 12.9% |
Cancer | 2.6% | 5.5% | 3.2% |
Nephropathy | 3.9% | 5.5% | 16.1% |
Hepatic disease | 1.3% | 0 | 0 |
Stroke | 5.3% | 1.8% | 6.5% |
Autoimmune disease | 0 | 0 | 6.5% |
Characteristics | Mild | Severe | Critical | p |
---|---|---|---|---|
Full blood counts | ||||
Red blood cells, ×106/mm3 | 4.43 ± 0.58 a | 4.24 ± 0.69 a | 4.12 ± 0.79 a | 0.058 ** |
White blood cells, /mm3 | 5930 (5565–6949) a | 8050 (7090–9090) b | 8020 (7349–12024) b | 0.001 ** |
Neutrophil, /mm3 | 4112 (4086–5707) a | 6018 (5553–7628) b | 5849 (5613 –9889) b | 0.005 * |
Lymphocyte, /mm3 | 954 (986–1397) a | 870 (817–1353) a,b | 529 (458–1255) b | 0.003 * |
Hemoglobin, g/dL | 13.0 (12.5–13.8) a | 12.8 (12.2–13.2) a | 12.5 (11.5–13.2) a | 0.217 * |
Eosinophil, /mm3 | 0 (15.4–51.8) a | 0 (11.7–104.6) a | 0 (7.7–61.2) a | 0.848 * |
Platelets, ×103/mm3 | 220 (210–245) a | 220 (207–268) a | 176 (154–245) b | 0.011 * |
Biochemical tests | ||||
Ferritin, µg/L | 417 (511–796) a | 631 (664–1100) a | 931 (883–1474) b | 0.003 * |
Albumin, g/dL | 3.60 (3.42–3.82) a | 3.20 (3.17–3.41) b | 3.1 (2.82–3.23) b | <0.001 * |
TGO, U/L | 29.5 (31.5–50.0) a | 37.0 (36.7–57.1) a | 46.0(40.9–81.5) b | 0.014 * |
TGP, U/L | 29.0 (33.5–51.1) a | 36.0 (37.6–65.6) a | 31.0 (27.8–61.8) a | 0.789 * |
CPK, U/L | 75 (85–138) a | 120 (173–344) b | 124 (140–865) b | 0.001 * |
Ure a, mg/dL | 32.8 (34.3–50.6) a | 33.8 (35.1–54.5) a | 44.0 (43.3–60.9) b | 0.007 * |
Creatinine, mg/dL | 0.80 (1.00–1.99) a | 0.80 (0.86–1.35) a | 1.20 (1.19–4.60) b | 0.001 * |
PCR, mg/L | 46.0 (60.3–93.7) a | 120.6 (92.5–140.0) b | 102.0 (86.5–151.9) a,b | 0.004 * |
LDH, U/L | 213 (221–263) a | 314 (285–363) b | 402 (290–531) b | <0.001 * |
D–dimer, mg/L | 0.73 (0.83–1.32) a | 1.11 (1.55–2.62) b | 2.14 (1.66–6.43) b | <0.001 * |
Plasma Proteomic Findings | Implications for the Course of COVID-19 According to the Literature | Potential Therapies |
---|---|---|
GSN levels were reduced in severe patients compared to those with mild symptoms | Calcium-binding protein that scavenges circulating filamentous actin, thus possessing anti-inflammatory properties. Reduced levels of GELS have been shown in serum [13,15] and plasma [14] of COVID-19 patients with worse outcomes. | GSN supplementation has been suggested as a potential therapy for COVID-19 [13], and a clinical trial of recombinant plasma from GSN is currently being conducted (NCT04358406). |
PON1 levels were reduced in critical patients compared to those with mild symptoms | This enzyme possesses aryadialkylphosphatase activity, as it is involved in the protection of low-density lipoproteins against oxidative damage and the formation of atheroma [40]. It is also important for the innate immune response [56]. In a recent study involving in silico discovery of candidate drugs against COVID-19, it was reported that genes correlated with ACE2 are enriched in aryadialkylphosphatase activity [57]. | Increasing the activity of PON1. |
CFHR1 levels were reduced in critical patients compared to those with mild symptoms | Involved in complement regulation. The variant rs414628 found in CFHR1 was associated with severe COVID-19 in adult Caucasian patients [58] | Regulation of CFHR1. |
AHSG levels were reduced in critical patients compared to those with mild symptoms | Promotes endocytosis and possesses opsonic properties. This protein was reported to be increased in the serum of survivor COVID-19 patients admitted to the respiratory and ICU because of respiratory failure [59]. | Increasing AHSG levels. |
SERPINA3 levels were increased in critical and severe patients compared to those with mild symptoms | Inhibits neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2. The levels of this protein were reported to be reduced in the serum of survivor COVID-19 patients admitted to the respiratory ward and ICU because of respiratory failure [59] and in the plasma of non-severe compared to severe patients [60] | Inhibition of SERPINA3 |
Plasma Proteomic Findings | Implications for the Course of COVID-19 According to the Literature |
---|---|
TF levels were reduced in critical and severe patients compared to those with mild symptoms | High ferritin and low transferrin levels are associated with increased risk for ICU admission and the need for mechanical ventilation in COVID-19 patients [35]. |
APOA1 *, APOA2, APOC1, and APOC2 levels were reduced in critical and/or severe patients compared to those with mild symptoms | Apolipoproteins transport cholesterol from peripheral tissues back to the liver, performing cardioprotective, antiapoptotic, antioxidant, anti-inflammatory, antithrombotic, and anti-infectious functions [36]. Adequate levels of APOA1 were related to protection against mortality in patients hospitalized for COVID-19 [37]. |
CLEC4 levels were increased in critical patients compared to those with severe symptoms | CLEC4 is a C-type lectin receptor that, once triggered by an antigen, is internalized by clathrin-dependent endocytosis and delivers its antigenic cargo into the antigen presentation pathway, thereby promoting expansion of CD8+ T cells and high production of IFN-γ and TNFα. Functional analysis revealed the potential role of CLEC4A in viral infection, including that of COVID-19 [41]. |
CCL24 levels were increased in critical patients compared to those with severe symptoms | Chemotactic for resting T-lymphocytes and eosinophils. COVID-19 patients that will clinically deteriorate have a blunted IFN and an exaggerated CCL24 airway response [42]. |
SAA1 and SAA2 were increased in critical and severe patients compared to those with mild symptoms | SAAs are acute-phase proteins that have been suggested to be predictors of COVID-19 severity [45,46]. |
CFHR1 levels were reduced in critical patients compared to those with mild symptoms | Involved in complement regulation. The variant rs414628 in CFHR1 was associated with severe COVID-19 in adult Caucasian patients [58] |
AHSG levels were reduced in critical patients compared to those with mild symptoms | Promotes endocytosis and possesses opsonic properties. This protein was reported to be increased in the serum of survivor COVID-19 patients admitted to the respiratory and ICU because of respiratory failure [59]. |
SERPINA3 levels were increased in critical and severe patients compared to those with mild symptoms | Inhibits neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2. The levels of this protein were reported to be reduced in the serum of survivor COVID-19 patients admitted to the respiratory and ICU because of respiratory failure [59] and in the plasma of non-severe compared to severe patients [60] |
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di Flora, D.C.; Dionizio, A.; Pereira, H.A.B.S.; Garbieri, T.F.; Grizzo, L.T.; Dionisio, T.J.; Leite, A.d.L.; Silva-Costa, L.C.; Buzalaf, N.R.; Reis, F.N.; et al. Analysis of Plasma Proteins Involved in Inflammation, Immune Response/Complement System, and Blood Coagulation upon Admission of COVID-19 Patients to Hospital May Help to Predict the Prognosis of the Disease. Cells 2023, 12, 1601. https://doi.org/10.3390/cells12121601
di Flora DC, Dionizio A, Pereira HABS, Garbieri TF, Grizzo LT, Dionisio TJ, Leite AdL, Silva-Costa LC, Buzalaf NR, Reis FN, et al. Analysis of Plasma Proteins Involved in Inflammation, Immune Response/Complement System, and Blood Coagulation upon Admission of COVID-19 Patients to Hospital May Help to Predict the Prognosis of the Disease. Cells. 2023; 12(12):1601. https://doi.org/10.3390/cells12121601
Chicago/Turabian Styledi Flora, Daniele Castro, Aline Dionizio, Heloisa Aparecida Barbosa Silva Pereira, Thais Francini Garbieri, Larissa Tercilia Grizzo, Thiago José Dionisio, Aline de Lima Leite, Licia C. Silva-Costa, Nathalia Rabelo Buzalaf, Fernanda Navas Reis, and et al. 2023. "Analysis of Plasma Proteins Involved in Inflammation, Immune Response/Complement System, and Blood Coagulation upon Admission of COVID-19 Patients to Hospital May Help to Predict the Prognosis of the Disease" Cells 12, no. 12: 1601. https://doi.org/10.3390/cells12121601