중환자실발열환자에서감염성과비감염성원인의감별을위한혈청 Procalcitonin 의측정 경상대학교의과대학내과학교실김호철, 김광민, 이상민, 이승준, 함현석, 조유지, 정이영, 이종덕, 황영실 Measuring Serum Procalcitonin in Patients with Fever in the ICU to Differentiate Infectious Causes from Non-Infectious Causes Ho Cheol Kim, M.D., Kwang Min Kim, M.D., Sang Min Lee, M.D., Seung Jun Lee, M.D., Hyun Seok Ham, M.D., Yu Ji Cho, M.D., Yi Yeong Jeong M.D., Jong Deok Lee M.D., Young Sil Hwang M.D. Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju Background: Although fever is one of the most common and challenging problem in intensive care medicine(icu), it is difficult to distinguish between infectious and non-infectious causes. Procalcitonin(PCT) has recently been reported to be an indicator of various infectious diseases. This study examined whether or not measuring the serum PCT level in patients with fever in the ICU can help distinguish fevers with infectious causes from those with non-infectious causes. Methods: ICU patients with fever at 38 C or over from March to August 2005 were prospectively enrolled. The cause of the fever was identified by the culture results and clinical course. The leukocytes, CRP, PCT, IL-6, and TNF-α in the fever patients with infectious and non-infectious causes were compared, and the PCT level in the patients with fever in the ICU were compared with those without fever. Results: 1) 42 patients were enrolled and 46 cases of fever were analyzed. 26 cases were considered to be infectious, while 13 cases were considered to be non-infectious. 7 cases were found to have no clear causes. 2) There were no significant differences in the degree of fever, leukocytes count, CRP, IL-6, and TNF-α levels in the patiemts with infectious and non-infectious causes. 3) The serum PCT level was higher in those with infectious causes than in those with non-infectious causes (15.1±32.57ng/mL vs 2.68±3.63ng/mL) but there was no statistical significance (p=0.06). 4) The serum PCT level of the ICU patients with fever was significantly higher than in those without fever (10.94± 27.15ng/mL vs 0.45±0.49ng/mL) (p=0.02). Conclusion: The serum PCT cannot be used to distinguish the fever in ICU patients with infectious causes from that with non-infectious causes. (Tuberc Respir Dis 2006; 61: 20-25) Key words : Procalcitonin, Fever, ICU. 서 중환자실환자에서발열은가장흔히경험하는임상상황으로원인을규명하기위해불필요한침습적검사를시행하게되고항생제의사용을증가시킨다 1. 론 Acknowledgement : This study was supported by Gyeongsang National University Hospital Research Funds in 2005. Address for correspondence : Ho Cheol Kim, M.D. Department of Internal Medicine, College of Medicine, Gyeongsang National University. 92 Chilam Dong, Jinju, 660-751, Korea. Phone: 055-750-8684 Fax : 055-758-9122 E-mail : hochkim@gshp.gsnu.ac.kr Received : Feb. 21. 2006 Accepted : Jun. 29. 2006 중환자실환자에서는다양한감염성및비감염성질환이원인 1 이될수있으며발열의원인을감염성과비감염성질환으로구별하는것은적절한치료와예후측면에서매우중요하다. 일반적으로발열의정도, 백혈구수, C-reactive protein(crp) 등을측정하는것이도움이될수있지만그유용성에는한계가있다 1,2. Procalcitonin(PCT) 는갑상샘에서생성되는 calcitonin의전구물질로최근많은연구를통해여러감염성질환의뛰어난표식자로알려져있다 2-6. 건강정상인의혈청에서는매우낮거나검출이되지않으며 3 전신증상이동반된중증의세균감염에서증가하게된다 4,5. 또한바이러스감염이나국소적인세균감염, 비감염성원인에의한염증반응에서는증가하지않 20
Tuberculosis and Respiratory Diseases Vol. 61. No.1, Jul. 2006 거나증가하더라도그정도가높지않은것으로보고되고있다 5. 그러나전신염증반응증후군 (systemic inflammatory response syndrome) 이흔한중환자실환자에서 PCT의측정이패혈증이나감염성질환의진단에도움이되는지에대해서는이견이있다 7-11. 이에연구자등은중환자실발열환자에서혈청 PCT의측정이감염성과비감염성원인을감별하는데도움이되는지알아보기위해다음과같은연구를시행하였다. 대상및방법 1. 대상환자및방법 있는상황에서설사또는그와관련된증상이있고대변에서 Clostridium difficile 독소분석이양성으로나온경우또는대장내시경상특징적인소견이관찰된경우에진단하였다. 카테터관련혈행성감염의진단 14 은말초혈액배양검사에서적어도한번이상균이동정되고카테터팁이나주위조직, 농배양에서동일한균이배양되는경우에진단하였고, 요도감염의진단 15 은 38 이상의발열이있으면서요정량적배양에서 10 5 cfu/ml이상균이배양되고다른규명된감염의원인이없는경우에진단하였다. 감염성발열환자의 CRP, PCT, IL-6, TNF-α, PCT 값은비감염성발열환자, 발열이없는중환자, 정상성인과비교하였다. 2005년 3월부터 8월까지경상대학교병원내과중환자실에서치료받은환자를대상으로하여액와부에서 2번이상측정한체온이 38 C 이상인경우를전향적으로조사하였다. 대상환자는발열의원인을규명하기위해서이학적검사, 흉부단순촬영, 정맥혈배양검사 2회, 소변그램염색및배양검사, 기도흡인물배양검사, 중심정맥카테터을하고있는경우는카테터팁이나주위조직또는농양의그람염색및배양, 설사가있는경우에는대변백혈구와 Clostridium difficile 독소검사등을시행하였다. 대상환자의혈액을채취하여백혈구수를측정하였고 CRP, PCT, IL-6, TNF-α를측정하기위해혈청을분리하여 -70 C 냉장고도보관하였다. 혈청의 IL-6와 TNF-α 값은제조사의지시에따라 ELISA(R & D Systems, Abington, UK) 로측정하였으며, PCT는 immunoluminometric assay(lumitest PCT, Brahma Diagnostica, Berlin, Germany) 로측정하였고측정범위는 0.08mg-500ng/ml 이었다. 감염성과비감염성원인의감별은각환자의배양검사결과와임상경과에의존해판단하였다. 기계호흡기관련폐렴의진단12 은흉부방사선촬영에서침윤이있으면서백혈구가 12 x 10 9 /ml 이상, 38.3 C 이상의발열, 화농성기관지분비물의존재중적어도하나가있으면임상적으로진단하였으며, Clostridium difficile 대장염의진단 13 은항생제를투여받고 2. 자료의분석각각의값은평균 ± 표준편차로표시하였고각군간의비교는일원배치분산분석을이용해서 p값이 0.05이하인경우유의한것으로판정하였다. 통계분석은윈도우용 SPSS 프로그램 (SPSS 10.0 SPSS inc; Chicago, IL, USA) 을이용하였다. 결과 1. 발열의원인총 42명의환자를대상으로 46예의발열에대해평 Table 1. Infectious cause of fever (n=26) Cause of fever Number Ventilator associated pneumonia 6 Community acquired pneumonia 5 Sepsis 6 Urinary tract infection 2 Catheter-related blood stream infection 2 Pseudomembranous colitis 1 Meningitis 1 Tuberculous pleurisy 1 Tuberculous pneumonia 1 Empyema 1 21
HC Kim et al. : Procalcitonin in patients with fever in the ICU Table 2. Non-infectious cause of fever (n=13) Cause of fever Number Posttransfusion fever 2 Hypersensitivity reaction by anti-tuberculous drug 1 Acute cerebral hemorrhage 1 Myocardial infarction 1 Acute pancreatitis 1 Aspiration due to noninvasive ventilation 1 Undefined, but clinical decision alone 6 가하였다. 감염성원인으로생각된경우는 26예, 비감염성원인은 13예, 7예는원인이명확하지않았다. 비감염성원인중에서 6예는발열은있지만모든배양검사와흉부방사선소견에서특이사항이없었고항생제를사용하지않은상태에서발열이자연적으로호전을보인경우로원인이규명되지는않았지만비감염성원인으로분류하였다. 배양검사에서이상은없으나항생제를사용한후호전을보인경우는원인이명확하지않아대상환자에서제외하였다. 감염성과비감염성원인질환은다음과같다 (Table 1, 2). 2. 발열의정도, 백혈구수, CRP, IL-6, TNF-α, PCT 차이감염성원인과비감염성원인의발열의정도는각각 38.4±0.39 C, 38.3±0.27 C이었고백혈구수는 14.6± 0.72 x 10 3 /mm 3, 12.7±0.56 x 10 3 /mm 3, CRP는 115.1± 54.91mg/L, 80.4±62.4mg/L, IL-6 는 216.5±216.34pg /ml, 123.1±153.2pg/ml, TNF-α는 34.45±38.63μg/ml, 25.8±21.76μg/ml으로유의한차이가없었다 (p>0.05). 감염성과비감염성원인의혈청 PCT는각각 15.1± 32.57ng/mL, 2.68±3.63ng/mL로감염성원인이높았으나통계적인유의성은없었다 (p=0.06). 발열이있는환자의혈청 PCT는 10.94±27.15ng/mL로, 발열이없는중환자의 0.45±0.49ng/mL, 정상성인의 0.11±0.04ng /ml에비해의미있게높았다 (p=0.02)(table 3). 고찰본연구에서는내과중환자실환자에서발열의원인을감염성과비감염성으로구별하여혈청 PCT를비교하였을때유의한차이를보이지않아본연구의결과로는중환자실의발열환자에서혈청 PCT의측정이감염성과비감염성의감별에유용하지않으며백혈구나 CRP 등에비해이점도없는것으로판단된다. 그러나감염성원인에의한발열환자의혈청 PCT는발열이없는중환자에비해의미있게증가되어있어발열이있는중환자의감염성질환의지표로는사용될수있을것으로판단된다. PCT는여러연구를통해중증의세균감염과패혈증의유용한표식자로알려져왔다 2-6. 장기이식 16 이나후천성면역결핍증환자 17, 백혈구감소증이있는환자 18 에서발열의감별진단에유용하며, 패혈증의진단에 CRP, lactate, 전염증성시토카인, 백혈구및발열의정도에비해더유용한지표로알려져있다 2,5,6,19. 그러나다발성외상이나수술 20, 심장폐우회로 (cardiopulmonary bypass) 21, 악성종양이있는환자 22 Table 3. Temperature, WBC count, CRP, IL-6 and TNF- α in different study population Infectious Causes with Fever (n=26) Non-infectious Causes with Fever (n=13) Critical-illness without Fever (n=14) Healthy Control (n=12) Temperature( C) 38.4±0.39 38.3±0.27 36.2±0.26 WBC count x 109/L 14.6±0.72* 12.7±0.56 10.7±0.34 6.4±0.17 CRP(mg/l) 115.1±54.91* 80.4±62.4 46.3±50.57 4.0±2.52 IL-6(pg/ml) 216.5±216.34** 123.1±153.2** 15.4±18.33 12.2±15.7 TNF-α(μg/ml) 34.45±38.63* 25.8±21.76 14.0±10.00 16.5±15.68 PCT(ng/ml) 15.1±32.57** 2.6±3.63** 0.4±0.49 0.1±0.04 Values are expressed as mean ± standard deviation. WBC = White blood cell; CRP = C-reactive protein; IL = Interleukin; TNF = tumor necrosis factor, PCT = procalcitonin * ** p<0.05 compared to critically ill patients without fever. 22
Tuberculosis and Respiratory Diseases Vol. 61. No.1, Jul. 2006 에서감염의증거가없이증가되어있고전신염증반응증후군 (systemic inflammatory response syndrome) 이흔한중환자실환자에서 PCT의측정이패혈증이나감염성질환의진단에도움이되는지에대해서는아직많은연구가시행되지는않았으며그유용성에대해서는이견이있다 7-11. 동일한감염성질환이확인된경우에도혈청PCT 값은다양한범주를보이는데일반적으로국소적감염보다는전신적인감염이있는경우 4, 장기부전이나균혈증이동반된감염성질환이있는경우에휠씬높은경향을보여 10,23,24 감염질환의중등도와상관이있을것으로보인다 10,25. 본연구에서도감염성질환으로확인된환자에서 PCT 값은상당한차이를보이는경향이있었는데이런경향으로보아 PCT값자체만으로감염성과비감염성을구별하는데는제한점이있을것으로보이며감염의중등도또는균혈증의유무를판단하는데도움이될것으로생각된다 10,23-25. PCT는전신백혈구세포에서생성되는것이아니라단핵구나지방조직에서생성되는데단핵구에서생성되는것은초기몇시간만지속되고이후에는지방조직에서분비된다 26. 심한외상에의해 PCT가증가되고바이러스감염이나자가면역질환에서 PCT가생성되지않는것은외상에의해서는단핵구가활성화되고자가면역질환은림프구나 T-세포에의한반응이주를이루기때문인것으로생각하고있다 6. 본연구에서는발열의기준을 38 C 이상으로하였으며이는미국중환자학회의중환자실발열의기준 27 인 38.2 C 이상과는차이가있다. 이는임상적으로 38 C 정도의발열이가장흔하고원인을규명하는데문제가되므로이를기준으로하였다. 본연구에서감염성원인과비감염성원인의발열정도는차이가없었으며비감염성원인으로 38.8 C 이상의발열이생긴경우는약제의과민반응에의한것이었으며일반적으로약제나수혈에의한발열은 38.8 C 이상나타날수있는것으로알려져있다 1. 본연구에서발열의원인을여러배양검사결과와임상경과를통해감염성과비감염성으로구별하였다. 그러나비감염성으로생각했던 13예중 6예에서원인을정확히규명하지못하였고임상경과와배양 검사결과에의존해비감염성으로판단하여일부분의환자에서는감염성원인의가능성을완전배제하기는힘든상황이다. 또한구강을통한기관내삽관을시행한환자에서부비동염은기계호흡기환자에서임상적으로의미있는발열의원인일가능성은낮지만, 최근연구결과 28 에따르면구강기관지삽관을시행한환자에서도부비동염이발열의중요한원인으로보고되었고본연구에서는발열의원인으로부비동염을확인할수없었다는단점이있다. 요도감염의진단에서도배양된균수가 10 5 cfu/ml 이상으로나온경우에도이것이실제적인감염을의미하는지집락을의미하는지임상적으로명확하게구별하기힘든경우가많았다. 결론적으로본연구의결과로는중환자실발열환자에서혈청 PCT의측정은감염성질환과비감염성질환을감별하는데도움이되지않을것으로사료된다. 요약배경 : 중환자실에서발열은가장흔한임상상황이며그원인을감염성또는비감염성으로감별하는것은적절한치료와예후측면에서매우중요하다. Procalcitonin(PCT) 는최근여러감염질환의뛰어난표식자로보고되고있다. 연구자등은중환자실발열환자에서혈청 PCT의측정이감염성과비감염성원인을감별하는데도움이되는지알아보기위해연구를시행하였다. 방법 : 2005년 3월부터 8월까지내과중환자실에서치료받은환자중 38 C 이상의발열이있는환자를대상으로백혈구, CRP, PCT, IL-6, TNF-α를측정하였고원인을규명하기위한검사를시행하였다. 감염성과비감염성원인의감별은배양검사결과와임상적인경과에의존해판단하였다. 감염성발열환자, 비감염성발열환자, 발열이없는중환자및건강성인에서각각의값을비교하였다. 결과 : 1) 총 42명의환자를대상으로 46 예의발열에대해평가하였다. 감염성으로생각된경우는 26 예, 비감염성은 13 예, 7예는원인이명확하지않았다. 23
HC Kim et al. : Procalcitonin in patients with fever in the ICU 2) 감염성과비감염성원인의발열의정도, 백혈구수, CRP, IL-6, TNF-α는유의한차이가없었다. 3) 감염성원인과비감염성원인의혈청 PCT는각각 15.1±32.57ng/mL, 2.68±3.63ng/mL로감염성원인이높았으나통계적인유의성은없었다 (p=0.06). 4) 발열이있는환자의혈청 PCT은 10.94±27.15ng/mL 로, 발열이없는중환자의 0.45±0.49ng/mL 에비해의미있게높았다 (p=0.02). 결론 : 중환자실발열환자에서혈청 PCT의측정은감염성원인과비감염성원인을감별하는데도움이되지않을것으로사료된다. 참고문헌 1. Marik PE. Fever in the ICU. Chest 2000;117:855-69. 2. Hatherill M, Tibby SM, Sykes K, Turner C, Murdoch IA. Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count. Arch Dis Child 1999;81:417-21. 3. Karzai W, Oberhoffer M, Meier-Hellmann A, Reinhart K. Procalcitonin: a new indicator of the systemic response to severe infections. Infection 1997;25:329-34. 4. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993;341:515-8. 5. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004;39:206-17. 6. Meisner M. Biomarkers of sepsis: clinically useful? Curr Opin Crit Care 2005;11:473-80. 7. BalcI C, Sungurtekin H, Gurses E, Sungurtekin U, Kaptanoglu B. Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care 2003;7:85-90. 8.Ugarte H, Silva E, Mercan D, de Mendonca A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med 1999;27:498-504. 9. Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, immerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000;28:977-83. 10. Suprin E, Camus C, Gacouin A, le Tulzo Y, Lavoue S, Feuillu A, et al. Procalcitonin: a valuable indicator of infection in a medical ICU? Intensive Care Med 2000;26:1232-8. 11. Giamarellos-Bourboulis EJ, Mega A, Grecka P, Scarpa N, Koratzanis G, Thomopoulos G, et al. Procalcitonin: a marker to clearly differentiate systemic inflammatory response syndrome and sepsis in the critically ill patient? Intensive Care Med 2002; 28:1351-6. 12. Johanson WG Jr, Pierce AK, Sanford JP, Thomas GD. Nosocomial respiratory infections with gramnegative bacilli: the significance of colonization of the respiratory tract. Ann Intern Med 1972;77:701-6. 13. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994;330:257-62. 14. Raad I. Intravascular-catheter-related infections. Lancet 1998;351:893-8. 15. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128-40. 16. Boeken U, Feindt P, Micek M, Petzold T, Schulte HD, Gams E. Procalcitonin (PCT) in cardiac surgery: diagnostic value in systemic inflammatory response syndrome (SIRS), sepsis and after heart transplantation (HTX). Cardiovasc Surg 2000;8:550-4. 17. Gerard Y, Hober D, Assicot M, Alfandari S, Ajana F, Bourez JM, et al. Procalcitonin as a marker of bacterial sepsis in patients infected with HIV-1. J Infect 1997;35:41-6. 18. Bernard L, Ferriere F, Casassus P, Malas F, Leveque S, Guillevin L, et al. Procalcitonin as an early marker of bacterial infection in severely neutropenic febrile adults. Clin Infect Dis 1998;27:914-5. 19. Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, et al. Diagnostic value of procalcitonin, interleukin-6 and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001;164:396-402. 20. Meisner M, Tschaikowsky K, Hulzler A, Schick C, Schuttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med 1998;24:680-4. 21. Hensel M, Volk T, Docke WD, Kern F, Tschirna D, Egerer K, et al. Hyperprocalcitoninemia in patients with non-infectious SIRS and pulmonary dysfunction associated with cardiopulmonary bypass. Anesthesiology 1998;89:93-104. 22. Ghillani P, Motte P, Troalen F, Julienne A, Gardet P, le Chevalier T, et al. Identification and measurement of calcitonin precursors in serum of patients with malignant diseases. Cancer Res 1989;49:6845-51. 23. Bell K, Wattie M, Byth K, Silvestrini R, Clark P, Stachowski E, et al. Procalcitonin: a marker of 24
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