Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Collection of Serum Samples and Patient Data
4.3. Measurement of Each Biomarker
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Verity, R.; Okell, L.C.; Dorigatti, I.; Winskill, P.; Whittaker, C.; Imai, N.; Cuomo-Dannenburg, G.; Thompson, H.; Walker, P.G.T.; Fu, H.; et al. Estimates of the severity of coronavirus disease 2019: A model-based analysis. Lancet Infect. Dis. 2020, 20, 669–677. [Google Scholar] [CrossRef] [PubMed]
- Long, B.; Carius, B.M.; Chavez, S.; Liang, S.Y.; Brady, W.J.; Koyfman, A.; Gottlieb, M. Clinical update on COVID-19 for the emergency clinician: Presentation and evaluation. Am. J. Emerg. Med. 2022, 54, 46–57. [Google Scholar] [CrossRef] [PubMed]
- Yegiazaryan, A.; Abnousian, A.; Alexander, L.J.; Badaoui, A.; Flaig, B.; Sheren, N.; Aghazarian, A.; Alsaigh, D.; Amin, A.; Mundra, A.; et al. Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19. Int. J. Mol. Sci. 2022, 23, 9297. [Google Scholar] [CrossRef] [PubMed]
- Biancolella, M.; Colona, V.L.; Mehrian-Shai, R.; Watt, J.L.; Luzzatto, L.; Novelli, G.; Reichardt, J.K.V. COVID-19 2022 update: Transition of the pandemic to the endemic phase. Hum. Genom. 2022, 16, 19. [Google Scholar] [CrossRef] [PubMed]
- Song, P.; Li, W.; Xie, J.; Hou, Y.; You, C. Cytokine storm induced by SARS-CoV-2. Clin. Chim. Acta 2020, 509, 280–287. [Google Scholar] [CrossRef] [PubMed]
- Nazerian, Y.; Ghasemi, M.; Yassaghi, Y.; Nazerian, A.; Hashemi, S.M. Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: Molecular pathways and potential therapeutic options. Int. Immunopharmacol. 2022, 113, 109428. [Google Scholar] [CrossRef] [PubMed]
- Mehri, F.; Rahbar, A.H.; Ghane, E.T.; Souri, B.; Esfahani, M. Changes in oxidative markers in COVID-19 patients. Arch. Med. Res. 2021, 52, 843–849. [Google Scholar] [CrossRef] [PubMed]
- Higashi, Y. Roles of Oxidative Stress and Inflammation in Vascular Endothelial Dysfunction-Related Disease. Antioxidants 2022, 11, 1958. [Google Scholar] [CrossRef] [PubMed]
- Tay, M.Z.; Poh, C.M.; Rénia, L.; MacAry, P.A.; Ng, L.F.P. The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 2020, 20, 363–374. [Google Scholar] [CrossRef]
- Kosanovic, T.; Sagic, D.; Djukic, V.; Pljesa-Ercegovac, M.; Savic-Radojevic, A.; Bukumiric, Z.; Lalosevic, M.; Djordjevic, M.; Coric, V.; Simic, T. Time Course of Redox Biomarkers in COVID-19 Pneumonia: Relation with Inflammatory, Multiorgan Impairment Biomarkers and CT Findings. Antioxidants 2021, 10, 1126. [Google Scholar] [CrossRef]
- Tavassolifar, M.J.; Aghdaei, H.A.; Sadatpour, O.; Maleknia, S.; Fayazzadeh, S.; Mohebbi, S.R.; Montazer, F.; Rabbani, A.; Zali, M.R.; Izad, M.; et al. New insights into extracellular and intracellular redox status in COVID-19 patients. Redox Biol. 2023, 59, 102563. [Google Scholar] [CrossRef] [PubMed]
- Dominic, P.; Ahmad, J.; Bhandari, R.; Pardue, S.; Solorzano, J.; Jaisingh, K.; Watts, M.; Bailey, S.R.; Orr, A.W.; Kevil, C.G.; et al. Decreased availability of nitric oxide and hydrogen sulfide is a hallmark of COVID-19. Redox Biol. 2021, 43, 101982. [Google Scholar] [CrossRef] [PubMed]
- Montiel, V.; Lobysheva, I.; Gérard, L.; Vermeersch, M.; Perez-Morga, D.; Castelein, T.; Mesland, J.B.; Hantson, P.; Collienne, C.; Gruson, D.; et al. Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients. EBioMedicine 2022, 77, 103893. [Google Scholar] [CrossRef] [PubMed]
- Mandal, S.M. Nitric oxide mediated hypoxia dynamics in COVID-19. Nitric Oxide 2023, 133, 18–21. [Google Scholar] [CrossRef] [PubMed]
- Prediletto, I.; D’Antoni, L.; Carbonara, P.; Daniele, F.; Dongilli, R.; Flore, R.; Pacilli, A.M.G.; Pisani, L.; Tomsa, C.; Vega, M.L.; et al. Standardizing PaO2 for PaCO2 in P/F ratio predicts in-hospital mortality in acute respiratory failure due to Covid-19: A pilot prospective study. Eur. J. Intern. Med. 2021, 92, 48–54. [Google Scholar] [CrossRef] [PubMed]
- Zaccagnini, G.; Berni, A.; Pieralli, F. Correlation of non-invasive oxygenation parameters with paO2/FiO2 ratio in patients with COVID-19 associated ARDS. Eur. J. Intern. Med. 2022, 96, 117–119. [Google Scholar] [CrossRef] [PubMed]
- Pipitone, G.; Camici, M.; Granata, G.; Sanfilippo, A.; Di Lorenzo, F.; Buscemi, C.; Ficalora, A.; Spicola, D.; Imburgia, C.; Alongi, I.; et al. Alveolar-Arterial Gradient Is an Early Marker to Predict Severe Pneumonia in COVID-19 Patients. Infect. Dis. Rep. 2022, 14, 470–478. [Google Scholar] [CrossRef] [PubMed]
- Galván-Román, J.M.; Rodríguez-García, S.C.; Roy-Vallejo, E.; Marcos-Jiménez, A.; Sánchez-Alonso, S.; Fernández-Díaz, C.; Alcaraz-Serna, A.; Mateu-Albero, T.; Rodríguez-Cortes, P.; Sánchez-Cerrillo, I.; et al. IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study. J. Allergy Clin. Immunol. 2021, 147, 72–80.e78. [Google Scholar] [CrossRef]
- Veenith, T.; Martin, H.; Le Breuilly, M.; Whitehouse, T.; Gao-Smith, F.; Duggal, N.; Lord, J.M.; Mian, R.; Sarphie, D.; Moss, P. High generation of reactive oxygen species from neutrophils in patients with severe COVID-19. Sci. Rep. 2022, 12, 10484. [Google Scholar] [CrossRef] [PubMed]
- Bastin, A.; Abbasi, F.; Roustaei, N.; Abdesheikhi, J.; Karami, H.; Gholamnezhad, M.; Eftekhari, M.; Doustimotlagh, A. Severity of oxidative stress as a hallmark in COVID-19 patients. Eur. J. Med. Res. 2023, 28, 558. [Google Scholar] [CrossRef]
- Djordjevic, J.; Ignjatovic, V.; Vukomanovic, V.; Vuleta, K.; Ilic, N.; Slovic, Z.; Stanojevic Pirkovic, M.; Mihaljevic, O. Laboratory Puzzle of Oxidative Stress, Parameters of Hemostasis and Inflammation in Hospitalized Patients with COVID-19. Biomedicines 2024, 12, 636. [Google Scholar] [CrossRef] [PubMed]
- Petrushevska, M.; Zendelovska, D.; Atanasovska, E.; Eftimov, A.; Spasovska, K. Presentation of cytokine profile in relation to oxidative stress parameters in patients with severe COVID-19: A case-control pilot study. F1000Research 2021, 10, 719. [Google Scholar] [CrossRef] [PubMed]
- Osredkar, J.; Pucko, S.; Lukić, M.; Fabjan, T.; Alič, E.B.; Kumer, K.; Rodriguez, M.M.; Jereb, M. The Predictive Value of Oxidative Stress Index in Patients with Confirmed SARS-COV-2 Infection. Acta Chim. Slov. 2022, 69, 564–570. [Google Scholar] [CrossRef] [PubMed]
- Ciacci, P.; Paraninfi, A.; Orlando, F.; Rella, S.; Maggio, E.; Oliva, A.; Cangemi, R.; Carnevale, R.; Bartimoccia, S.; Cammisotto, V.; et al. Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards. Microvasc. Res. 2023, 149, 104557. [Google Scholar] [CrossRef] [PubMed]
- Ahmed, S.A.; Alahmadi, Y.M.; Abdou, Y.A. The Impact of Serum Levels of Reactive Oxygen and Nitrogen Species on the Disease Severity of COVID-19. Int. J. Mol. Sci. 2023, 24, 8973. [Google Scholar] [CrossRef] [PubMed]
- Gjorgjievska, K.; Petrushevska, M.; Zendelovska, D.; Atanasovska, E.; Spasovska, K.; Stevanovikj, M.; Grozdanovski, K. Hematological Findings and Alteration of Oxidative Stress Markers in Hospitalized Patients with SARS-COV-2. Prilozi 2022, 43, 5–13. [Google Scholar] [CrossRef]
- Gadotti, A.C.; Lipinski, A.L.; Vasconcellos, F.T.; Marqueze, L.F.; Cunha, E.B.; Campos, A.C.; Oliveira, C.F.; Amaral, A.N.; Baena, C.P.; Telles, J.P.; et al. Susceptibility of the patients infected with Sars-Cov2 to oxidative stress and possible interplay with severity of the disease. Free Radic. Biol. Med. 2021, 165, 184–190. [Google Scholar] [CrossRef] [PubMed]
- Draxler, A.; Blaschke, A.; Binar, J.; Weber, M.; Haslacher, M.; Bartak, V.; Bragagna, L.; Mare, G.; Maqboul, L.; Klapp, R.; et al. Age-related influence on DNA damage, proteomic inflammatory markers and oxidative stress in hospitalized COVID-19 patients compared to healthy controls. Redox Biol. 2023, 67, 102914. [Google Scholar] [CrossRef] [PubMed]
- Wu, D.; Shu, T.; Yang, X.; Song, J.X.; Zhang, M.; Yao, C.; Liu, W.; Huang, M.; Yu, Y.; Yang, Q.; et al. Plasma metabolomic and lipidomic alterations associated with COVID-19. Natl. Sci. Rev. 2020, 7, 1157–1168. [Google Scholar] [CrossRef]
- Thomas, T.; Stefanoni, D.; Reisz, J.A.; Nemkov, T.; Bertolone, L.; Francis, R.O.; Hudson, K.E.; Zimring, J.C.; Hansen, K.C.; Hod, E.A.; et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight 2020, 5, e140327. [Google Scholar] [CrossRef]
- Kimhofer, T.; Lodge, S.; Whiley, L.; Gray, N.; Loo, R.L.; Lawler, N.G.; Nitschke, P.; Bong, S.H.; Morrison, D.L.; Begum, S.; et al. Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection. J. Proteome Res. 2020, 19, 4442–4454. [Google Scholar] [CrossRef] [PubMed]
- D’Alessandro, A.; Thomas, T.; Akpan, I.J.; Reisz, J.A.; Cendali, F.I.; Gamboni, F.; Nemkov, T.; Thangaraju, K.; Katneni, U.; Tanaka, K.; et al. Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19. Cells 2021, 10, 2293. [Google Scholar] [CrossRef] [PubMed]
- Ansone, L.; Briviba, M.; Silamikelis, I.; Terentjeva, A.; Perkons, I.; Birzniece, L.; Rovite, V.; Rozentale, B.; Viksna, L.; Kolesova, O.; et al. Amino Acid Metabolism is Significantly Altered at the Time of Admission in Hospital for Severe COVID-19 Patients: Findings from Longitudinal Targeted Metabolomics Analysis. Microbiol. Spectr. 2021, 9, e0033821. [Google Scholar] [CrossRef] [PubMed]
- Ming, S.; Qu, S.; Wu, Y.; Wei, J.; Zhang, G.; Jiang, G.; Huang, X. COVID-19 Metabolomic-Guided Amino Acid Therapy Protects from Inflammation and Disease Sequelae. Adv. Biol. 2023, 7, e2200265. [Google Scholar] [CrossRef] [PubMed]
- Uzzan, M.; Soudan, D.; Peoc’h, K.; Weiss, E.; Corcos, O.; Treton, X. Patients with COVID-19 present with low plasma citrulline concentrations that associate with systemic inflammation and gastrointestinal symptoms. Dig. Liver Dis. 2020, 52, 1104–1105. [Google Scholar] [CrossRef] [PubMed]
- Rees, C.A.; Rostad, C.A.; Mantus, G.; Anderson, E.J.; Chahroudi, A.; Jaggi, P.; Wrammert, J.; Ochoa, J.B.; Ochoa, A.; Basu, R.K.; et al. Altered amino acid profile in patients with SARS-CoV-2 infection. Proc. Natl. Acad. Sci. USA 2021, 118, e2101708118. [Google Scholar] [CrossRef] [PubMed]
- Dean, M.J.; Ochoa, J.B.; Sanchez-Pino, M.D.; Zabaleta, J.; Garai, J.; Del Valle, L.; Wyczechowska, D.; Baiamonte, L.B.; Philbrook, P.; Majumder, R.; et al. Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells. Front. Immunol. 2021, 12, 695972. [Google Scholar] [CrossRef] [PubMed]
- Durante, W. Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy. Metabolites 2022, 12, 240. [Google Scholar] [CrossRef] [PubMed]
- Tosato, M.; Calvani, R.; Picca, A.; Ciciarello, F.; Galluzzo, V.; Coelho-Júnior, H.J.; Di Giorgio, A.; Di Mario, C.; Gervasoni, J.; Gremese, E.; et al. Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial. Nutrients 2022, 14, 4984. [Google Scholar] [CrossRef] [PubMed]
- Lawler, N.G.; Gray, N.; Kimhofer, T.; Boughton, B.; Gay, M.; Yang, R.; Morillon, A.C.; Chin, S.T.; Ryan, M.; Begum, S.; et al. Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses. J. Proteome Res. 2021, 20, 2796–2811. [Google Scholar] [CrossRef]
- D’Amora, P.; Silva, I.D.C.G.; Budib, M.A.; Ayache, R.; Silva, R.M.S.; Silva, F.C.; Appel, R.M.; Sarat, S., Jr.; Pontes, H.B.D.; Alvarenga, A.C.; et al. Towards risk stratification and prediction of disease severity and mortality in COVID-19: Next generation metabolomics for the measurement of host response to COVID-19 infection. PLoS ONE 2021, 16, e0259909. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Gómez, L.E.; Ibarra-González, I.; Fernández-Lainez, C.; Tusie, T.; Moreno-Macías, H.; Martinez-Armenta, C.; Jimenez-Gutierrez, G.E.; Vázquez-Cárdenas, P.; Vidal-Vázquez, P.; Ramírez-Hinojosa, J.P.; et al. Metabolic Reprogramming in SARS-CoV-2 Infection Impacts the Outcome of COVID-19 Patients. Front. Immunol. 2022, 13, 936106. [Google Scholar] [CrossRef] [PubMed]
- Albóniga, O.E.; Jiménez, D.; Sánchez-Conde, M.; Vizcarra, P.; Ron, R.; Herrera, S.; Martínez-Sanz, J.; Moreno, E.; Moreno, S.; Barbas, C.; et al. Metabolic Snapshot of Plasma Samples Reveals New Pathways Implicated in SARS-CoV-2 Pathogenesis. J. Proteome Res. 2022, 21, 623–634. [Google Scholar] [CrossRef] [PubMed]
- Canzano, P.; Brambilla, M.; Porro, B.; Cosentino, N.; Tortorici, E.; Vicini, S.; Poggio, P.; Cascella, A.; Pengo, M.F.; Veglia, F.; et al. Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients. JACC Basic Transl. Sci. 2021, 6, 202–218. [Google Scholar] [CrossRef] [PubMed]
- Reizine, F.; Lesouhaitier, M.; Gregoire, M.; Pinceaux, K.; Gacouin, A.; Maamar, A.; Painvin, B.; Camus, C.; Le Tulzo, Y.; Tattevin, P.; et al. SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage. J. Clin. Immunol. 2021, 41, 515–525. [Google Scholar] [CrossRef] [PubMed]
- Sacchi, A.; Grassi, G.; Notari, S.; Gili, S.; Bordoni, V.; Tartaglia, E.; Casetti, R.; Cimini, E.; Mariotti, D.; Garotto, G.; et al. Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection. Cells 2021, 10, 2111. [Google Scholar] [CrossRef]
- Hannemann, J.; Balfanz, P.; Schwedhelm, E.; Hartmann, B.; Ule, J.; Müller-Wieland, D.; Dahl, E.; Dreher, M.; Marx, N.; Böger, R. Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients. Sci. Rep. 2021, 11, 9895. [Google Scholar] [CrossRef] [PubMed]
- Caterino, M.; Gelzo, M.; Sol, S.; Fedele, R.; Annunziata, A.; Calabrese, C.; Fiorentino, G.; D’Abbraccio, M.; Dell’Isola, C.; Fusco, F.M.; et al. Dysregulation of lipid metabolism and pathological inflammation in patients with COVID-19. Sci. Rep. 2021, 11, 2941. [Google Scholar] [CrossRef]
- Karu, N.; Kindt, A.; van Gammeren, A.J.; Ermens, A.A.M.; Harms, A.C.; Portengen, L.; Vermeulen, R.C.H.; Dik, W.A.; Langerak, A.W.; van der Velden, V.H.J.; et al. Severe COVID-19 Is Characterised by Perturbations in Plasma Amines Correlated with Immune Response Markers, and Linked to Inflammation and Oxidative Stress. Metabolites 2022, 12, 618. [Google Scholar] [CrossRef]
- Yang, Z.; Ming, X.F. Arginase: The emerging therapeutic target for vascular oxidative stress and inflammation. Front. Immunol. 2013, 4, 149. [Google Scholar] [CrossRef]
- Bouras, G.; Deftereos, S.; Tousoulis, D.; Giannopoulos, G.; Chatzis, G.; Tsounis, D.; Cleman, M.W.; Stefanadis, C. Asymmetric Dimethylarginine (ADMA): A promising biomarker for cardiovascular disease? Curr. Top. Med. Chem. 2013, 13, 180–200. [Google Scholar] [CrossRef] [PubMed]
- Ware, L.B.; Magarik, J.A.; Wickersham, N.; Cunningham, G.; Rice, T.W.; Christman, B.W.; Wheeler, A.P.; Bernard, G.R.; Summar, M.L. Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis. Crit. Care 2013, 17, R10. [Google Scholar] [CrossRef] [PubMed]
- Ivanovski, N.; Wang, H.; Tran, H.; Ivanovska, J.; Pan, J.; Miraglia, E.; Leung, S.; Posiewko, M.; Li, D.; Mohammadi, A.; et al. L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats. Pediatr. Res. 2023, 94, 1684–1695. [Google Scholar] [CrossRef] [PubMed]
- Ichihara, E.; Hasegawa, K.; Kudo, K.; Tanimoto, Y.; Nouso, K.; Oda, N.; Mitsumune, S.; Yamada, H.; Takata, I.; Hagiya, H.; et al. A randomized controlled trial of teprenone in terms of preventing worsening of COVID-19 infection. PLoS ONE 2023, 18, e0287501. [Google Scholar] [CrossRef] [PubMed]
- Tsukahara, H.; Ohta, N.; Tokuriki, S.; Nishijima, K.; Kotsuji, F.; Kawakami, H.; Ohta, N.; Sekine, K.; Nagasaka, H.; Mayumi, M. Determination of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, in umbilical blood. Metabolism 2008, 57, 215–220. [Google Scholar] [CrossRef] [PubMed]
- Nagasaka, H.; Morioka, I.; Takuwa, M.; Nakacho, M.; Yoshida, M.; Ishida, A.; Hirayama, S.; Miida, T.; Tsukahara, H.; Yorifuji, T.; et al. Blood asymmetric dimethylarginine and nitrite/nitrate concentrations in short-stature children born small for gestational age with and without growth hormone therapy. J. Int. Med. Res. 2018, 46, 761–772. [Google Scholar] [CrossRef] [PubMed]
- Tsuge, M.; Uda, K.; Eitoku, T.; Matsumoto, N.; Yorifuji, T.; Tsukahara, H. Roles of Oxidative Injury and Nitric Oxide System Derangements in Kawasaki Disease Pathogenesis: A Systematic Review. Int. J. Mol. Sci. 2023, 24, 15450. [Google Scholar] [CrossRef]
- Ogino, K.; Obase, Y.; Takahashi, N.; Shimizu, H.; Takigawa, T.; Wang, D.H.; Ouchi, K.; Oka, M. High serum arginase I levels in asthma: Its correlation with high-sensitivity C-reactive protein. J. Asthma 2011, 48, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Nakatsukasa, Y.; Tsukahara, H.; Tabuchi, K.; Tabuchi, M.; Magami, T.; Yamada, M.; Fujii, Y.; Yashiro, M.; Tsuge, M.; Morishima, T. Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: Relation to maternal and neonatal characteristics. J. Clin. Biochem. Nutr. 2013, 52, 27–31. [Google Scholar] [CrossRef] [PubMed]
- Kaneko, K. Rapid Diagnostic Tests for Oxidative Stress Status. In Studies on Pediatric Disorders; Tsukahara, H., Kaneko, K., Eds.; Springer: New York, NY, USA, 2014; pp. 137–148. [Google Scholar]
- Ezaki, S.; Suzuki, K.; Kurishima, C.; Miura, M.; Weilin, W.; Hoshi, R.; Tanitsu, S.; Tomita, Y.; Takayama, C.; Wada, M.; et al. Resuscitation of preterm infants with reduced oxygen results in less oxidative stress than resuscitation with 100% oxygen. J. Clin. Biochem. Nutr. 2009, 44, 111–118. [Google Scholar] [CrossRef]
Biomarkers | Lung Infiltration (n = 29) | No Infiltration (n = 63) | p-Value |
---|---|---|---|
Saturation of percutaneous oxygen (%) | 95 (91–96) | 97 (95–98) | <0.001 |
Lymphocyte counts (/µL) | 925 (530–1184) | 1150 (828–1450) | 0.025 |
Lactate dehydrogenase (U/L) | 362 (293–446) | 218 (180–284) | <0.001 |
KL-6 (U/mL) | 291 (229–443) | 205 (163–268) | 0.10 |
Ferritin (ng/mL) | 1049 (717–2501) | 607 (258–985) | 0.38 |
D-dimer (μg/mL) | 1.2 (0.7–2.0) | 0.5 (0.0–1.0) | <0.001 |
C-reactive protein (mg/dL) | 7.9 (5.0–14.2) | 1.4 (0.3–3.4) | <0.001 |
Interleukin-6 (pg/mL) | 62 (26–93) | 23 (15–45) | 0.001 |
Hydroperoxides (mg/dL) | 32 (29–36) | 30 (21–33) | 0.031 |
Nitrite/nitrate (µmol/L) | 28 (16–37) | 28 (21–35) | 0.47 |
Asymmetric dimethylarginine (µmol/L) | 0.23 (0.04–0.32) | 0.26 (0.09–0.44) | 0.072 |
Arginine (nmol/mL) | 134 (112–154) | 135 (111–145) | 0.94 |
Ornithine (nmol/mL) | 83 (75–106) | 80 (61–100) | 0.68 |
Citrulline (nmol/mL) | 15 (13–20) | 25 (18–31) | 0.002 |
Ammonia (nmol/mL) | 117 (100–145) | 118 (104–139) | 0.42 |
Arginase-1 (ng/mL) | 152 (101–241) | 157 (123–228) | 0.38 |
Biomarkers | Oxygen Inhalation on Admission (n = 42) | No Inhalation on Admission (n = 58) | p-Value |
---|---|---|---|
Saturation of percutaneous oxygen (%) | 95 (93–97) | 97 (95–98) | <0.001 |
Lymphocyte counts (/µL) | 910 (643–1219) | 1151 (835–1450) | 0.037 |
Lactate dehydrogenase (U/L) | 334 (281–409) | 209 (179–249) | <0.001 |
KL-6 (U/mL) | 266 (202–374) | 210 (173–274) | 0.28 |
Ferritin (ng/mL) | 738 (434–1083) | 588 (220–65,250) | 0.037 |
D-dimer (μg/mL) | 1.1 (0.7–1.4) | 0.5 (0.0–0.8) | <0.001 |
C-reactive protein (mg/dL) | 5.3 (2.1–10.4) | 0.7 (0.2–3.3) | <0.001 |
Interleukin-6 (pg/mL) | 44 (25–93) | 23 (15–40) | 0.004 |
Hydroperoxides (mg/dL) | 31 (28–36) | 30 (25–33) | 0.012 |
Nitrite/nitrate (µmol/L) | 30 (21–36) | 28 (18–40) | 0.59 |
Asymmetric dimethylarginine (µmol/L) | 0.10 (0.04–0.28) | 0.31 (0.21–0.48) | <0.001 |
Arginine (nmol/mL) | 136 (115–149) | 131 (108–145) | 0.91 |
Ornithine (nmol/mL) | 88 (76–118) | 75 (58–96) | 0.16 |
Citrulline (nmol/mL) | 19 (15–25) | 25 (18–31) | <0.001 |
Ammonia (nmol/mL) | 139 (116–170) | 110 (95–125) | 0.035 |
Arginase-1 (ng/mL) | 156 (116–247) | 140 (105–228) | 0.76 |
Biomarkers | Oxygen Inhalation after Admission (n = 16) | No Oxygen Inhalation after Admission (n = 42) | p-Value |
---|---|---|---|
Saturation of percutaneous oxygen (%) | 96 (95–97) | 97 (96–98) | 0.063 |
Lymphocyte counts (/µL) | 1105 (843–1426) | 1172 (839–1506) | 0.78 |
Lactate dehydrogenase (U/L) | 228 (216–304) | 204 (171–238) | 0.013 |
KL-6 (U/mL) | 224 (187–295) | 207 (156–267) | 0.16 |
Ferritin (ng/mL) | 589 (297–153,000) | 481 (179–61,000) | 0.002 |
D-dimer (μg/mL) | 0.6 (0.3–1.1) | 0.0 (0.0–0.7) | 0.063 |
C-reactive protein (mg/dL) | 2.0 (1.2–4.1) | 0.4 (0.2–2.5) | 0.021 |
Interleukin-6 (pg/mL) | 32 (19–51) | 18 (13–36) | 0.16 |
Hydroperoxides (mg/dL) | 32 (29–36) | 28 (25–32) | 0.014 |
Nitrite/nitrate (µmol/L) | 28 (15–42) | 27 (19–36) | 0.53 |
Asymmetric dimethylarginine (µmol/L) | 0.27 (0.20–0.31) | 0.33 (0.22–0.53) | 0.18 |
Arginine (nmol/mL) | 116 (106–136) | 135 (111–147) | 0.056 |
Ornithine (nmol/mL) | 92 (69–102) | 69 (56–87) | 0.52 |
Citrulline (nmol/mL) | 18 (15–27) | 28 (18–31) | 0.031 |
Ammonia (nmol/mL) | 103 (97–115) | 111 (95–129) | 0.056 |
Arginase-1 (ng/mL) | 135 (103–256) | 157 (105–223) | 0.81 |
Comparative Groups | Low Citrulline (<18.0 nmol/mL) | Normo-Citrulline (≥18.0 nmol/mL) | p-Value |
---|---|---|---|
Lung infiltrations on admission/all cases | 15/27 (55.6%) | 11/52 (21.2%) | 0.002 |
Oxygen inhalation on admission/all cases | 14/27 (51.9%) | 21/52 (40.4%) | 0.33 |
Oxygen inhalation after admission/no inhalation on admission | 5/13 (38.5%) | 6/31 (19.4%) | 0.18 |
Biomarkers | Low Citrulline (<18.0 nmol/mL) (n = 27) | Normo-Citrulline (≥18.0 nmol/mL) (n = 52) | p-Value |
---|---|---|---|
Saturation of percutaneous oxygen (%) | 95 (94–96) | 97 (95–98) | 0.008 |
Lymphocyte counts (/µL) | 890 (620–1270) | 1070 (778–1450) | 0.19 |
Lactate dehydrogenase (U/L) | 314 (271–422) | 223 (179–307) | <0.001 |
KL-6 (U/mL) | 247 (215–317) | 202 (163–289) | 0.11 |
Ferritin (ng/mL) | 927 (434–5233) | 730 (241–1937) | 0.41 |
D-dimer (μg/mL) | 0.8 (0.2–1.2) | 0.7 (0.0–1.2) | 0.45 |
C-reactive protein (mg/dL) | 6.4 (4.2–12.0) | 1.2 (0.3–5.1) | <0.001 |
Interleukin-6 (pg/mL) | 49 (27–84) | 25 (15–52) | 0.011 |
Hydroperoxides (mg/dL) | 35 (30–37) | 29 (26–32) | <0.001 |
Nitrite/nitrate (µmol/L) | 21 (18–38) | 28 (21–36) | 0.61 |
Asymmetric dimethylarginine (µmol/L) | 0.24 (0.09–0.32) | 0.27 (0.10–0.48) | 0.14 |
Arginine (nmol/mL) | 121 (108–135) | 140 (119–152) | 0.004 |
Ornithine (nmol/mL) | 77 (59–88) | 88 (67–101) | 0.12 |
Ammonia (nmol/mL) | 115 (100–139) | 124 (104–144) | 0.40 |
Arginase-1 (ng/mL) | 157 (110–234) | 152 (106–231) | 0.97 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Tsuge, M.; Ichihara, E.; Hasegawa, K.; Kudo, K.; Tanimoto, Y.; Nouso, K.; Oda, N.; Mitsumune, S.; Kimura, G.; Yamada, H.; et al. Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients. Int. J. Mol. Sci. 2024, 25, 8370. https://doi.org/10.3390/ijms25158370
Tsuge M, Ichihara E, Hasegawa K, Kudo K, Tanimoto Y, Nouso K, Oda N, Mitsumune S, Kimura G, Yamada H, et al. Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients. International Journal of Molecular Sciences. 2024; 25(15):8370. https://doi.org/10.3390/ijms25158370
Chicago/Turabian StyleTsuge, Mitsuru, Eiki Ichihara, Kou Hasegawa, Kenichiro Kudo, Yasushi Tanimoto, Kazuhiro Nouso, Naohiro Oda, Sho Mitsumune, Goro Kimura, Haruto Yamada, and et al. 2024. "Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients" International Journal of Molecular Sciences 25, no. 15: 8370. https://doi.org/10.3390/ijms25158370