Determining Serum Asymmetric Dimethylarginine (ADMA) level in Covid-19 Pneumonia and its relation with thrombosis and mortality

Öz

Purpose: Covid-19 can cause widespread inflammation in the endothelial cell. Asymmetric dimethylarginine (ADMA) is a molecule recognized as one of the important markers of vascular endothelial dysfunction. The aim of this study was to determine serum ADMA level during the course of Covid pneumonia, and to determine the relationship between serum ADMA level and susceptibility to thrombosis and mortality. An other purpose of this study is to identify mortality-associated risk factors, and to investigate the effectiveness of different sepsis scores, laboratory measurements and prognostic markers. Materials and Methods: The data of 60 patients with the diagnosis of Covid-19 pneumonia were analyzed. Blood samples for ADMA were taken in the morning in the first 3 days after symptom onset from Covid-19 pneumonia, and 60 healthy volunteers. Results: Mean serum ADMA level of inpatients with Covid pneumonia was 95.35±223.8 ng/mL. Mean serum ADMA level measured in the control group was 266.56±606.14 ng/mL. ADMA value measured in Covid patients was found to be significantly lower with respect to the control group.(p₌0.042) The inpatient mortality rate was 21%. Mortality was significantly associated with higher SOFA, qSOFA, on admission. Conclusion: The serum ADMA concentration measured in the early period of hospitalization was found to be significantly lower in patients with Covid-19 pneumonia with respect to the control group. It must be kept in mind that cases with a SOFA score≥3, qSOFA score≥1, CRP/Albumin ratio≥30 and Neutrophil/Lymphocyte Ratio≥5 have a high risk of mortality and require early intervention.

Anahtar Kelimeler

• Covid-19 pneumonia
• Asymmetric dimethylarginine
• ADMA
• SOFA
• qSOFA
• Neutrophil/Lymphocyte ratio
• CRP/albümin ratio

Covid-19 Pnömonisinde Serum Asimetrik Dimetilarjinin (ADMA) Düzeyinin Tespiti ve Tromboz, Mortalite ile İlişkisinin Belirlenmesi

Öz

Amaç: Covid-19, endotel hücrelerinde yaygın inflamasyona neden olabilir. Asimetrik dimetilarjinin (ADMA), vasküler endotel disfonksiyonunun önemli belirteçlerinden olarak kabul edilen bir moleküldür. Bu çalışmanın amacı, Covid pnömonisinin seyri sırasında serum ADMA düzeyini saptayıp, serum ADMA düzeyi ile tromboza yatkınlık ve mortalite arasındaki ilişkiyi belirlemektir. Çalışmanın diğer bir amacı da mortaliteyle ilişkili risk faktörlerini belirlemek ve farklı sepsis skorlarının, laboratuvar ölçümlerinin ve prognostik belirteçlerin etkinliğini araştırmaktır. Gereç ve Yöntemler: Covid-19 pnömonisi tanısı alan 60 hastanın verileri analiz edildi. ADMA için kan örnekleri, pnömonisi olan hastalarda semptom başlangıcından sonraki ilk 3 gün sabah saatlerinde ve 60 sağlıklı gönüllüden alındı. Bulgular: Hastaneye yatan covid pnömonili hastaların ortalama serum ADMA düzeyi 95,35±223,8 ng/mL idi. Kontrol grubunda ölçülen ortalama serum ADMA düzeyi 266,56±606,14 ng/mL idi. Covid hastalarında ölçülen ADMA değerinin kontrol grubuna göre anlamlı derecede düşük olduğu görüldü. (p₌0,042) Yatan hastalardaki ölüm oranı %21 idi. Ölüm oranı, başvuru anında daha yüksek düzeyde saptanan SOFA ve qSOFA düzeyleri ile ilişkiliydi. Sonuç: Hastaneye yatışın erken döneminde ölçülen serum ADMA konsantrasyonunun Covid-19 pnömonisi olan hastalarda kontrol grubuna göre anlamlı derecede düşük olduğu belirlendi. SOFA skoru≥3, qSOFA skoru≥1, CRP/Albümin oranı≥30 ve Nötrofil/Lenfosit Oranı ≥5 olan vakaların mortalite riskinin yüksek olduğu ve erken müdahale gerektirdiği unutulmamalıdır.

Anahtar Kelimeler

• Covid-19 pnömonisi
• Asimetrik dimetilarjinin
• ADMA
• SOFA
• qSOFA
• Nötrofil/Lenfosit oranı
• CRP/albümin oranı

Kaynakça

1. Wu C., Chen X., Cai Y., et al. Risk Factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180(7):934-43. Doi: 10.1001/ jamainternmed.2020.0994.
2. Hamming I., Bulthuis M.L.C., Lely A.T. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2014; 203(2):631–7. Doi:10.1002/path.1570.
3. Guan Wei-jie., Zheng-Yi N., Yu Hu., et al. Clinical characteristics of coronavirus disease2019 in China. New Engl J Med 2020; 382(18):1708–20. Doi:10.1056/NEJMoa2002032.
4. Varga Z., Flammer AJ., Steiger P., et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395(10234):1417-8. Doi:10.1016/ S0140-6736(20)30937-5.
5. Dowsett L., Higgins E., Alanazi S., Alshuwayer N.A., Leiper F.C., Leiper J. ADMA: A key player in the relationship between vascular dysfunction and inflammation in atherosclerosis. J Clin Med 2020; 9(9):3026. Doi:10.3390/jcm9093026.
6. Kang S., Tanaka T., Narazaki M. Targeting interleukin-6 signaling in clinic. Immunity 2019; 50(4):1007-23. Doi:10.1016/j. immuni.2019.03.026.
7. Freund Y., Lemachatti N., Krastinova E., et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA 2017; 317(3):301–8. Doi:10.1001/jama.2016.20329.
8. Vincent JL., Mendonça A., Cantraine F., et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of amulticenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26(11):1793–800. Doi:10.1097/00003246-199811000-00016.

9. Docherty AB., Harrison EM., Green CA., et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study. BMJ 2020; 369(22):1985. Doi:10.1136/bmj.m1985.
10. Willeit P., Freitag DF., Laukkanen JA., et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc 2015; 4(6):e001833. Doi:10.1161/JAHA.115.001833.
11. Koch A., Weiskirchen R., Kunze J., et al. Elevated asymmetric dimethylarginine levels predict short- and long-term mortality risk in critically ill patients. J Crit Care 2013; 28(6):947- 53. Doi:10.1016/j.jcrc.2013.05.016.
12. Vögeli A., Ottiger M., Meier MA., et al. Admission levels of asymmetric and symmetric dimethylarginine predict long-term outcome in patients with community-acquired pneumonia. Respir Res 2017 ;18(1):25. Doi:10.1186/ s12931-017-0502-4.
13. Scott J.A., Duongh M., Young A.W., Subbarao P., Gauvreau G.M., Grasemann H. Asymmetric dimethylarginine in chdavironic obstructive pulmonary disease (ADMA in COPD). Int J Mol Sci 2014; 15(4):6062-71. Doi:10.3390/ ijms15046062.
14. Hannemann J., Balfanz P., Schwedhelm E., et al. Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients. Sci Rep 2021; 11(1):9895. Doi:10.1038/s41598-021- 89180-w.
15. Robert J.N., Tom T., Coen van G., et al. Handling of asymmetrical dimethylarginine and symmetrical dimethylarginine by the rat kidney under basal conditions and during endotoxaemia. Nephrol Dial Transplant 2003; 18(12):2542-50. Doi:10.1093/ ndt/gfg452.
16. Mittermayer F., Namiranian K., Pleiner J., Schaller G., Wolzt M. Acute escherichia coli endotoxaemia decreases the plasma l-arginine/asymmetrical dimethylarginine ratio in humans. Clin Sci (Lond) 2004; 106(6):577–81. Doi:10.1042/ CS20030363.
17. Winkler MS., Nierhaus A., Rösler G., et al. Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: high plasma levels as combined risk markers for sepsis survival. Crit Care 2018; 22(1):216. Doi:10.1186/ s13054-018-2090-1.
18. Visser M., Vermeulen MA., Richir MC., et al. Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients. Br J Nutr 2012; 107(10):1458- 65. Doi:10.1017/S0007114511004648.
19. Weiss S.L., Haymond S., Ralay Ranaivo H., et al. Evaluation of asymmetric dimethylarginine, arginine, and carnitine metabolism in pediatric sepsis. Pediatr Crit Care Med 2012; 13(4):e210- 8. Doi:10.1097/PCC.0b013e318238b5cd. Volume: 5 - Issue: 1 Nisan|April 2025 11 Cetintepe et al.
20. Terpos E., Ntanasis-Stathopoulos I., Elalamy I., et al. Hematological findings and complications of COVID-19. Am J Hematol 2020; 95(7):834- 47. Doi:10.1002/ajh.25829.
21. Ruan Q., Yang, K., Wang, W., et al. Clinical predictors of mortality due to COVID‐19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 40(5):846–8. Doi:10.1007/s00134-020-06028-z.
22. Cetintepe T., Cetintepe L., Solmaz S., et al. Determination of the relationship between mortality and SOFA, qSOFA, MASCC scores in febrile neutropenic patients monitored in the intensive care unit. Support Care Cancer 2021; 29(7):4089-94. Doi:10.1007/s00520-020- 05924-w.
23. Vaquero-Roncero LM., Sánchez-Barrado E., Escobar-Macias D., et al. C-Reactive protein and SOFA scale: A simple score as early predictor of critical care requirement in patients with COVID-19 pneumonia in Spain. Rev Esp Anestesiol Reanim (Engl Ed) 2021; 68(9):513-22. Doi:10.1016/j.redare.2020.11.008.
24. Yang Z., Hu Q., Huang F., Xiong S., Sun Y. The prognostic value of the SOFA score in patients with COVID-19: A retrospective, observational study. Medicine (Baltimore) 2021; 13:100(32):e26900. Doi:10.1097/MD.0000000000026900.
25. Raschke RA., Agarwal S., Rangan P., Heise C.W., Curry S.C. Discriminant accuracy of the SOFA score for determining the probable mortality of patients with COVID-19 pneumonia requiring mechanical ventilation. JAMA 2021; 325(14):1469-70. Doi:10.1001/jama.2021.1545.
26. Liu S., Yao N., Qiu Y., He C. Predictive performance of SOFA and qSOFA for in-hospital mortality in severe novel coronavirus disease. Am J Emerg Med 2020; 38(10):2074–80. Doi:10.1016/j. ajem.2020.07.019.
27. Tan C., Huang Y., Shi F., et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol 2020; 92(7):856-62. Doi:10.1002/jmv.25871.
28. Karakoyun I., Colak A., Turken M., et al. Diagnostic utility of C-reactive protein to albumin ratio as an early warning sign in hospitalized severe COVID-19 patients. Int Immunopharmacol 2021; 91:107285. Doi:10.1016/j.intimp.2020.107285.
29. Shang W., Dong J., Ren Y., et al. The value of clinical parameters in predicting the severity of COVID-19. J Med Virol 2020; 92(10):2188-92. Doi:10.1002/jmv.26031.
30. Calim A., Yanic U., Halefoglu A.M., et al. Is there a relationship between epicardial adipose tissue, inflammatory markers, and the severity of COVID-19 pneumonia? Sisli Etfal Hastan Tip Bul 2023; 57(3):387-96. Doi: 10.14744/ SEMB.2023.99582.
31. Ozkarafakili MA., Kara ZMY., Serin E. Asymmetric dimethylarginine in COPD Exacerbation. Med Bull Sisli Etfal Hosp 2022; 56(4):536-42. Doi:10.14744/SEMB.2022.23682.