Determining Serum Asymmetric Dimethylarginine (ADMA) level in Covid-19 Pneumonia and its relation with thrombosis and mortality
Yıl 2025,
Cilt: 5 Sayı: 1, 1 - 11, 30.04.2025
Tuğba Çetintepe
,
Uğur Bayram Korkmaz
,
Leyla Demir
,
Salih Atakan Nemli
,
Tuğba Öncel Van
,
Lütfi Cetintepe
,
Serıfe Solmaz
,
Ahmet Alacacıoğlu
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.
Kaynakça
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
Covid-19 Pnömonisinde Serum Asimetrik Dimetilarjinin (ADMA) Düzeyinin Tespiti ve Tromboz, Mortalite ile İlişkisinin Belirlenmesi
Yıl 2025,
Cilt: 5 Sayı: 1, 1 - 11, 30.04.2025
Tuğba Çetintepe
,
Uğur Bayram Korkmaz
,
Leyla Demir
,
Salih Atakan Nemli
,
Tuğba Öncel Van
,
Lütfi Cetintepe
,
Serıfe Solmaz
,
Ahmet Alacacıoğlu
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.
Etik Beyan
This study was submitted to the Izmir Katip Celebi University Hospital Non-Interventional Scientific Research Ethics Committee and approved by the decision dated 22.04.2021 and numbered 2021-48
Kaynakça
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.