Обоснование. Бактериальная пневмония является частым осложнением ишемического инсульта на госпитальном этапе. Поиск прогностических лабораторных маркеров пневмонии остается актуальной задачей, поскольку позволит индивидуализировать подход к лечению и реабилитации пациентов. Цель. Изучить прогностическую значимость белков острой фазы воспаления и произвести их оценку в качестве ранних предикторов развития пневмонии у пациентов с ишемическим инсультом. Материалы и методы. В проспективное исследование были включены 302 пациента в остром периоде ишемического инсульта. Всем пациентам в 1-е сутки болезни методом иммуноферментного анализа определяли С-реактивный белок (СРБ), фактор некроза опухоли α, интерлейкин-6 (ИЛ-6), нейтрофильную эластазу, неоптерин, сывороточный амилоид А (SAA), секретируемую фосфолипазу А2 (sPLA2). Статистическая обработка данных произведена при помощи программного обеспечения SPSS и Microsoft Excel (США). Результаты. На госпитальном этапе пневмония развилась у 82 из 302 пациентов (27,2%; 95% доверительный интервал 22,3–32,3%). По наличию и отсутствию пневмонии значимо различались уровни СРБ, ИЛ-6, sPLA2, SAA и неоптерина. Пошаговый логистический регрессионный анализ выявил значимость в прогнозе развития пневмонии концентрации ИЛ-6 и СРБ. Пороговое значение концентрации ИЛ-6 составило 3,45 пг/мл (чувствительность – 82,4%, специфичность – 66,7%). Прогностическая ценность положительного результата (ПЦПР) в прогнозе развития пневмонии составила 40%, отрицательного результата (ПЦОР) – 92%. Пороговое значение СРБ составило 1640 мг/л с чувствительностью 65,8% и специфичностью 74,8%. ПЦПР порогового значения концентрации СРБ была равна 45%, ПЦОР – 80%. Заключение. Измерение концентрации ИЛ-6 и СРБ в 1-е сутки развития ишемического инсульта позволяет определить пациентов с наибольшим риском развития пневмонии на госпитальном этапе. Результаты работы свидетельствуют о необходимости включения показателей СРБ и ИЛ-6 в перечень обязательных лабораторных исследований, которые должны проводиться каждому пациенту с ишемическим инсультом в 1-е сутки от начала болезни.
Background. Bacterial pneumonia is a frequent complication of ischemic stroke at the hospital stage. The search for prognostic laboratory markers of pneumonia remains an urgent task, as it will allow to individualize the approach to the treatment and rehabilitation of such patients. Aim. To investigate the prognostic significance of proteins of the acute phase of inflammation, as well as to evaluate them as early predictors of the development of pneumonia in patients with ischemic stroke. Materials and methods. The study included 302 patients in the acute period of ischemic stroke. C-reactive protein (CRP), tumor necrosis factor α, interleukin-6 (IL-6), neutrophil elastase, neopterin, serum amyloid A (SAA), secreted phospholipase type 2 (sPLA2) were determined in all patients on the first day by enzyme immunoassay. Statistical data processing was carried out using SPSS and Microsoft Excel software (USA). Results. At the hospital stage, pneumonia developed in 82/302 patients (27.2%; 95% confidence interval 22.3–32.3%). The levels of CRP, IL-6, sPLA2, SAA and neopterin significantly differed in the presence and absence of pneumonia. Step-by-step logistic regression analysis revealed the significance of IL-6 and CRP concentrations in the prognosis of pneumonia. The threshold value of IL-6 concentration was 3.45 pg/ml (sensitivity – 82.4%, specificity – 66.7%). The prognostic value of a positive result (PPR) in the prognosis of pneumonia was 40%, a negative result (PNR) – 92%. The threshold value of CRP was 1640 mg/l with a sensitivity of 65.8% and a specificity of 74.8%. The PPR of the threshold value of the concentration of CRP was 45%, PNR – 80%. Conclusion. The measurement of the concentration of IL-6 and CRP on the first day of ischemic stroke makes it possible to identify patients with the greatest risk of pneumonia at the hospital stage. The results of the work indicate the necessity to include CRP and IL-6 in the list of mandatory laboratory tests that should be carried out for each patient with ischemic stroke on the first day from the onset of the disease.
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2. Кутлубаев М.А. Инфекционно-воспалительные осложнения церебрального инсульта. Клиническая медицина. 2014;10:66-72 [Kutlubaev MA. Infectious-inflammatory complications of cerebral insulitis. Clinical Medicine (Russian Journal). 2014;10:66-72 (in Russian)].
3. Попова Е.А., Орлов С.В., Позднякова М.А., и др. Профилактика и интенсивная терапия пневмоний у больных с ишемическим инсультом. Сибирский медицинский журнал (Иркутск). 2007;2:41-4 [Popova EA, Orlov SV, Pozdnjakova MA, et al. Preventive maintenance and intensive therapy of pneumonias in patients with ischemic insult. Siberian Medical Journal (Irkutsk). 2007;2:41-4 (in Russian)].
4. Hannawi Y, Hannawi B, Rao CPV. Stroke-associated pneumonia: Major advances and obstacles. Cerebrovasc Dis. 2013;35(5):430-43. DOI:10.1159/000350199
5. Singh P, Singh M, Singh NH, et al. A novel haplotype within C-reactive protein gene influences CRP levels and coronary heart disease risk in Northwest Indians. Mol Biol Rep. 2014;41(9):5851-62. DOI:10.1007/s11033-014-3459-0
6. Dawood FZ, Judd S, Howard V, et al. High-Sensitivity C-Reactive Protein and Risk of Stroke in Atrial Fibrillation (from the Reasons for Geographic and Racial Differences in Stroke Study). Am J Cardiol. 2016;118(12):1826-30. DOI:10.1016/j.amjcard.2016.08.069
7. Schulz S, Ludike H, Lierath M, Schlitt A. C-reactive protein levels and genetic variants of CRP as prognostic markers for combined cardiovascular endpoint (cardiovascular death, death from stroke, myocardial infarction, and stroke/TIA). Cytokine. 2016;88:71-6. DOI:10.1016/j.cyto.2016.08.021
8. Hutanu A, Iancu M, Balasa R. Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array. Acta Pharmacol Sin. 2018;39(7):1228-36. DOI:10.1038/aps.2018.26
9. Mazaheri S, Reisi E, Poorolajal J, Ghiasian M. C-Reactive Protein Levels and Clinical Outcomes in Stroke Patients: A Prospective Cohort Study. Arch Iran Med. 2018;21(1):8-12.
10. Matsuo R, Ago T, Hata J. Plasma C-Reactive Protein and Clinical Outcomes after Acute Ischemic Stroke: A Prospective Observational Study. PLoS One. 2016;11(6):e0156790. DOI:10.1371/journal.pone.0156790
11. Anrather J, Iadecola C. Inflammation and Stroke: An Overview. Neurotherapeutics. 2016;13(4):661-70. DOI:10.1007/s13311-016-0483-x
12. Rayasam A, Hsu M, Hernandez G, et al. Contrasting roles of immune cells in tissue injury and repair in stroke: The dark and bright side of immunity in the brain. Neurochem Int. 2017;107:104-16. DOI:10.1016/j.neuint.2017.02.009
13. Pusch G, Debrabant B, Molnar T, Gergely F. Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke. J Stroke Cerebrovasc Dis. 2015;24(8):1938-47. DOI:10.1016/j.jstrokecerebrovasdis.2015.05.005
14. Fahmi RM, Elsaid AF, Ahmed F. Infarction Size, Interleukin-6, and Their Interaction Are Predictors of Short-Term Stroke Outcome in Young Egyptian Adults. J Stroke Cerebrovasc Dis. 2016;25(10):2475-81. DOI:10.1016/j.jstrokecerebrovasdis.2016.06.021
15. Murr С, Widner B, Wirleitner B, Fuchs D. Neopterin as a Marker for Immune System Activation. Curr Drug Metab. 2002;3(2):175-87. DOI:10.2174/1389200024605082
16. Zeng X, Zhang G, Yang B, et al. Neopterin as a Predictor of Functional Outcome and Mortality in Chinese Patients with Acute Ischemic Stroke. Mol Neurobiol. 2016;53(6):3939-47. DOI:10.1007/s12035-015-9310-3
17. Vogelgesang A, Lange C, Blumke L, et al. Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function. J Neuroinflammation. 2017;14(1):140. DOI:10.1186/s12974-017-0914-6
18. Shang J, Yamashita T, Fukui Y. Different Associations of Plasma Biomarkers in Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, and Ischemic Stroke. J Clin Neurol. 2018;14(1):29-34. DOI:10.3988/jcn.2018.14.1.29
19. Azurmendi L, Lapierre-Fetaud V. Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection: a pilot study. Clin Proteomics. 2017;14:27. DOI:10.1186/s12014-017-9162-0
20. Каминный А.И., Павлунина Т.О., Шувалова Ю.А., Коротаева А.А. Роль секреторной фосфолипазы А2 в развитии атеросклероза. Атеросклероз и дислипидемии. 2012;4(9):63-8 [Kaminnyi AI, Pavlunina TO, Shuvalova JuA, Korotaeva AA. Secretory phospholipase A2 and the development of atherosclerosis. Ateroskleroz i dislipidemii. 2012;4(9):63-8 (in Russian)].
21. Hoda MN, Singh I, Singh AK, Khan M. Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat. J Neuroinflammation. 2009;6:21. DOI:10.1186/1742-2094-6-21
22. Ji R, Wang D, Shen H, et al. Interrelationship among common medical complications after acute stroke: pneumonia plays an important role. Stroke. 2013;44(12):3436-44. DOI:10.1161/STROKEAHA.113.001931
23. Pepe MS. The statistical evaluation of medical tests for classification and prediction. New York, NY: Oxford University Press, 2004.
________________________________________________
1. Insul't: Rukovodstvo dlya vrachei. Pod red. LV Stakhovskoi, SV Kotova. Moscow: MIA, 2014 (in Russian).
2. Kutlubaev MA. Infectious-inflammatory complications of cerebral insulitis. Clinical Medicine (Russian Journal). 2014;10:66-72 (in Russian).
3. Popova EA, Orlov SV, Pozdnjakova MA, et al. Preventive maintenance and intensive therapy of pneumonias in patients with ischemic insult. Siberian Medical Journal (Irkutsk). 2007;2:41-4 (in Russian).
4. Hannawi Y, Hannawi B, Rao CPV. Stroke-associated pneumonia: Major advances and obstacles. Cerebrovasc Dis. 2013;35(5):430-43. DOI:10.1159/000350199
5. Singh P, Singh M, Singh NH, et al. A novel haplotype within C-reactive protein gene influences CRP levels and coronary heart disease risk in Northwest Indians. Mol Biol Rep. 2014;41(9):5851-62. DOI:10.1007/s11033-014-3459-0
6. Dawood FZ, Judd S, Howard V, et al. High-Sensitivity C-Reactive Protein and Risk of Stroke in Atrial Fibrillation (from the Reasons for Geographic and Racial Differences in Stroke Study). Am J Cardiol. 2016;118(12):1826-30. DOI:10.1016/j.amjcard.2016.08.069
7. Schulz S, Ludike H, Lierath M, Schlitt A. C-reactive protein levels and genetic variants of CRP as prognostic markers for combined cardiovascular endpoint (cardiovascular death, death from stroke, myocardial infarction, and stroke/TIA). Cytokine. 2016;88:71-6. DOI:10.1016/j.cyto.2016.08.021
8. Hutanu A, Iancu M, Balasa R. Predicting functional outcome of ischemic stroke patients in Romania based on plasma CRP, sTNFR-1, D-Dimers, NGAL and NSE measured using a biochip array. Acta Pharmacol Sin. 2018;39(7):1228-36. DOI:10.1038/aps.2018.26
9. Mazaheri S, Reisi E, Poorolajal J, Ghiasian M. C-Reactive Protein Levels and Clinical Outcomes in Stroke Patients: A Prospective Cohort Study. Arch Iran Med. 2018;21(1):8-12.
10. Matsuo R, Ago T, Hata J. Plasma C-Reactive Protein and Clinical Outcomes after Acute Ischemic Stroke: A Prospective Observational Study. PLoS One. 2016;11(6):e0156790. DOI:10.1371/journal.pone.0156790
11. Anrather J, Iadecola C. Inflammation and Stroke: An Overview. Neurotherapeutics. 2016;13(4):661-70. DOI:10.1007/s13311-016-0483-x
12. Rayasam A, Hsu M, Hernandez G, et al. Contrasting roles of immune cells in tissue injury and repair in stroke: The dark and bright side of immunity in the brain. Neurochem Int. 2017;107:104-16. DOI:10.1016/j.neuint.2017.02.009
13. Pusch G, Debrabant B, Molnar T, Gergely F. Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke. J Stroke Cerebrovasc Dis. 2015;24(8):1938-47. DOI:10.1016/j.jstrokecerebrovasdis.2015.05.005
14. Fahmi RM, Elsaid AF, Ahmed F. Infarction Size, Interleukin-6, and Their Interaction Are Predictors of Short-Term Stroke Outcome in Young Egyptian Adults. J Stroke Cerebrovasc Dis. 2016;25(10):2475-81. DOI:10.1016/j.jstrokecerebrovasdis.2016.06.021
15. Murr С, Widner B, Wirleitner B, Fuchs D. Neopterin as a Marker for Immune System Activation. Curr Drug Metab. 2002;3(2):175-87. DOI:10.2174/1389200024605082
16. Zeng X, Zhang G, Yang B, et al. Neopterin as a Predictor of Functional Outcome and Mortality in Chinese Patients with Acute Ischemic Stroke. Mol Neurobiol. 2016;53(6):3939-47. DOI:10.1007/s12035-015-9310-3
17. Vogelgesang A, Lange C, Blumke L, et al. Ischaemic stroke and the recanalization drug tissue plasminogen activator interfere with antibacterial phagocyte function. J Neuroinflammation. 2017;14(1):140. DOI:10.1186/s12974-017-0914-6
18. Shang J, Yamashita T, Fukui Y. Different Associations of Plasma Biomarkers in Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, and Ischemic Stroke. J Clin Neurol. 2018;14(1):29-34. DOI:10.3988/jcn.2018.14.1.29
19. Azurmendi L, Lapierre-Fetaud V. Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection: a pilot study. Clin Proteomics. 2017;14:27. DOI:10.1186/s12014-017-9162-0
20. Kaminnyi AI, Pavlunina TO, Shuvalova JuA, Korotaeva AA. Secretory phospholipase A2 and the development of atherosclerosis. Ateroskleroz i dislipidemii. 2012;4(9):63-8 (in Russian).
21. Hoda MN, Singh I, Singh AK, Khan M. Reduction of lipoxidative load by secretory phospholipase A2 inhibition protects against neurovascular injury following experimental stroke in rat. J Neuroinflammation. 2009;6:21. DOI:10.1186/1742-2094-6-21
22. Ji R, Wang D, Shen H, et al. Interrelationship among common medical complications after acute stroke: pneumonia plays an important role. Stroke. 2013;44(12):3436-44. DOI:10.1161/STROKEAHA.113.001931
23. Pepe MS. The statistical evaluation of medical tests for classification and prediction. New York, NY: Oxford University Press, 2004.
1 АНО ДПО «Институт лабораторной медицины», Москва, Россия;
2 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия;
3 ФГАОУ ВО «Российский университет дружбы народов», Москва, Россия;
4 ФГБУ «Федеральный центр мозга и нейротехнологий» ФМБА России, Москва, Россия
*ag_kochetov@dpo-ilm.ru
________________________________________________
Anatoly G. Kochetov*1,2, Olga V. Lyang3,4, Irina A. Zhirova3, Oleg O. Ivoylov3, Rita R. Politidis3, Yulia V. Novozhenova3
1 Institute of Laboratory Medicine, Moscow, Russia;
2 Pirogov Russian National Research Medical University, Moscow, Russia;
3 People’s Friendship University of Russia (RUDN University), Moscow, Russia;
4 Federal Center of Brain Research and Neurotechnologies, Moscow, Russia
*ag_kochetov@dpo-ilm.ru