DOI: 10.4046/trd.2009.67.5.430 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2009;67:430-435 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. Original Article 지역사회획득폐렴환자의중증도평가에서 Procalcitonin 유용성 1 창원파티마병원호흡기내과, 2 대구파티마병원 박훈표 1, 이정수 2, 장예수 2, 김민수 1 Usefulness of Procalcitonin in the Assessing the Severity of Community-Acquired Pneumonia Patient Hun-Pyo Park, M.D. 1, Jung-Soo Lee, M.D. 2, Ye-Su Jang, M.D. 2, Min-Su Kim, M.D. 1 Department of Respiratory Medicine, 1 Changwon Fatima Hospital, Changwon, 2 Daegu Fatima Hospital, Daegu, Korea Background: Thus far, research studies on community-acquired pneumonia (CAP) have focused on its clinical severity. Recently, it has been determined that procalcitonin (PCT) level is correlated with severity of CAP. A retrospective study conducted at our hospital used risk predictability and PCT to determine whether or no PCT is useful in assessing the severity of CAP. Methods: This study covered 92 CAP cases that were admitted to the respiratory department at Changwon Fatima Hospital between July 1, 2008 and June 30, 2009. All enrolled subjects were measured for infection markers and risk predictability. Results: Based on hospital admission data, enrolled subjects had Pneumonia Severity Index (PSI) scores serving as risk predictors showed that both PCT and white blood cell (WBC) were statistically significant as infection markers (p=0.001, 0.037). Thus, this study used ROC curves in PSI for data analysis. As a result, it was determined that the area under curve (AUC) of PCT and WBC was 0.694 and 0.593 respectively, indicating that PCT has a higher test value for WBC, when PCT was higher than 0.745 ng/ml. In addition, it was found that PCT levels higher than 0.745 ng/ml had higher PSI scores than the group with PCT lower than 0.745 ng/ml (p=0.032). Conclusion: In order to predict risk of pneumonia cases admitted due to symptoms of CAP, it is important to consider PCT as well as PSI, and follow-up monitoring of PCT cases. Key Words: Pneumonia; Community-Acquired Infections; Procalcitonin; Severity Illness Index 서 지역사회획득폐렴은적절한항생제사용으로빠른회복을보이기도하나입원한환자의 10 20% 가집중치료실에서치료를받고이들가운데사망률이 20 50% 가될정도로감염으로인한사망중많은부분을차지하는질환이다 1,2. 이러한사망률을감소시키기위해서오래전부터 Address for correspondence: Hun-Pyo Park, M.D. Department of Respiratory Medicine, Changwon Fatima Hospital, 212, Myeonseo-dong, Changwon 641-560, Korea Phone: 82-55-270-1264, Fax: 82-55-265-7766 E-mail: hunpyopark@hanmail.net Received: Sep. 9, 2009 Accepted: Sep. 29, 2009 론 입원초기에폐렴의중증도및위험인자를파악하려는연구가지속되었다. 영국흉부학회에서는호흡수 (30회이상 ), 이완기혈압 (60 mmhg 이하 ), 혈액요소질소 (20 mg/ dl 초과 ) 가사망과관련된인자라고발표하였고 3 이후 Confusion, Uremia, Respiratory rate, Blood pressure (CURB) 점수를개발하였다 4,5. 그리고혈액요소질소를대신하여 65세이상의나이를이용한 Confusion, Respiratory rate, Blood pressure (CRB)-65를사용하기도하였다. 미국에서도 Patients Outcome Research Team (PORT) 의 Pneumonia Severity Index (PSI) 를발표한이후 6 최근의폐렴치료지침에는 PSI와 CURB-65 를폐렴의예후와중증도인자로서입원결정및치료에이용하였다 7. 이런생체징후와관련된인자들외에도체내염증반 430
Tuberculosis and Respiratory Diseases Vol. 67. No. 5, Nov. 2009 응초기에상승하는백혈구를포함한염증지표들이지역사회획득폐렴의예후에영향을미치는지에대한연구가지속되었고그중에서 C-reactive protein (CRP), Procalcitonin (PCT) 가폐렴의중증도평가에좋은예측인자라는보고가있다 8,9. 특히 PCT는건강정상인의혈청또는바이러스감염이나비감염성원인에의한염증반응에서는증가하지않고전형적폐렴균을포함한중증의세균감염과패혈증에서증가하여 PSI 고위험군일수록 PCT가높아폐렴중증도를평가할수있다고한다 10. 그외에도입원초기의 PCT가 CRP, 백혈구와비교하여폐렴의중증도와예후를예측할수있다고하며 11 위험인자와관련없이 PCT가 0.1 ng/ml 미만인군에서 30일사망률이낮았다는보고가있다 12. 이에저자들은기존의지역사회획득폐렴의위험예측도로사용한 PSI, CRB-65, CURB-65 를이용하여백혈구, CRP, PCT의염증지표가폐렴중증도평가에유용한지를후향적으로알아보고자하였다. CURB-65는 0점에서 5점, CRB-65는 0점에서 4점까지주었고 0에서 1까지는저위험군, 2 이상은고위험군으로하였다. PSI는각각점수를계산하여 I군에서 V군으로측정하였고 I, II, III군은저위험군, IV, V는고위험군으로하였다. 혈액에서 CRP 측정은 immunoturbidimetric assay (Modular, Roche, Switzerland), PCT는 enzyme-linked fluorescence assay (VIDAS BRAHMS PCT, France, measurement range, 0.05 200 ng/ml) 법으로하였다. 3. 통계분석윈도우용 SPSS 12.0 (SPSS Inc., Chicago, IL, USA) 을사용하여서로다른두군간의평균값은독립표본 T 검정으로비교하였고세군간은일원배치분산분석법으로비교하였다. 그리고통계학적으로유의한차이를보이는측정값은 receiver operating characteristic (ROC) 곡선분석을하였다. 그리고 p값이 0.05 미만일때통계학적으로유의성이있다고판정하였다. 대상및방법 결 과 1. 대상 2008년 7월 1일부터 2009년 6월 30일까지창원파티마병원호흡기내과에지역사회획득폐렴으로입원하여처음 24시간이내에염증지표와위험예측도를측정한환자를대상으로하였다. 이기간동안폐렴으로호흡기내과에입원하여 PCT를포함한염증지표를측정한환자는 286명이었다. 이중흉부사진상병변이명확하지않는환자 145 명, 최근 1주내타병원에입원한환자 31명, PSI를측정하지않은환자 15명, 추후결핵으로판명된 3명을조사대상에서제외하고지역사회획득폐렴으로위험예측도를측정한환자 92명을대상으로조사하였다. 2. 정의지역사회획득폐렴은입원전호흡기증상 ( 기침, 객담, 발열, 흉통, 호흡곤란 ) 이하나이상있으면서흉부사진상병변이있고청진상수포음이들린경우로하였다. 백혈구, PCT, CRP를염증지표로 CRB-65, CURB-65, PSI를위험예측도로규정하였다. CURB-65는의식혼미, 혈액요소질소 20 mg/dl 초과, 호흡수 30회이상, 수축기혈압 90 mmhg 미만, 이완기혈압 60 mmhg 이하, 65세이상으로하였고 CRB-65는 CURB-65 에서혈액요소질소가없는것이다. 각각에대해해당사항이있으면 1점씩부과하여 1. 환자 평균나이는 63세 (19 92세), 여자 30명이었다 (Table 1). 그리고사망자는 6명 (6.52%) 이었고사망자의평균 PCT는 9.30±12.24 ng/ml이었다. 생존자의평균 PCT는 4.07±8.38 ng/ml이었다. 입원당시객담검사에서세균이배양된경우는 33명 (35.87%), 2가지이상세균이나온경우는 4명이었다. 세균은 klebsiella pneumoniae 10명으로가장많았고 streptococcal pneumoniae, staphylococcus aureus 가각각 8명이었다. PSI 고위험군에는 pseudo- Table 1. Baseline characteristics of the 92 patients Characteristics Age, yr 63.15±15.69 Male sex, n (%) 62 (67.39) PSI, points 85±38.64 PCT, ng/ml 4.41±8.69 CRP, mg/dl 13.23±10.64 WBC, 10 3 /μl 14,275.22±7,857.94 Values are number of patients (percentage) or means (standard deviation, SD). PSI: pneumonia severity index; PCT: procalcitonin; CRP: C-reactive protein; WBC: white blood cell. 431
HP Park et al: Procalcitonin in the community-acquired pneumonia Table 2. Biomarkers and prognostic scales in community-acquired pneumonia N PCT, ng/ml CRP, mg/dl WBC, 10 3 /μl CRB-65 0 1 72 3.80±8.70 13.95±11.15 13,171.53±6,121.50 2 4 20 6.62±8.49 10.66±8.24 18,248.22±11,596.24 (p-value) (0.2) (0.222) (0.01) CURB-65 0 1 56 3.03±7.53 13.22±11.20 12,879.64±5,393.98 2 5 36 6.57±9.97 13.25±9.85 16,446.11±10,337.23 (p-value) (0.056) (0.988) (0.033) PSI I III 61 2.26±4.87 13.42±11.08 13,061.80±5,601.21 IV V 31 8.65±12.69 12.87±9.87 16,662.90±10,754.91 (p-value) (0.001) (0.816) (0.037) Values are means (±SD). PCT: procalcitonin; CRP: C-reactive protein; WBC: white blood cell; CRB: confusion, respiratory rate, blood pressure; CURB: confusion, uremia, respiratory rate, blood pressure; PSI: pneumonia severity index. monas aeruginosa 4명, 저위험군에는 streptococcal pneumoniae 가 6명으로많았다. 2. 지역사회획득폐렴에서염증지표와위험예측도 Table 2는일원배치분산분석법을이용한것으로염증지표측면에서보면 PCT값은위험예측도의고위험군일수록높았다. 그러나통계학적인유의성을보이는것은 PSI 이었다. CRP값은모든위험예측도에서유의성이없었고반대로백혈구는모든위험예측도에서유의성이있었다. 특이한사항은 CRP값이모든위험예측도에서고위험군보다저위험군에서높았다. 위험예측도측면에서보면 CRB- 65, CURB-65 에서는백혈구가유의성을보였고 PSI에서는 PCT, 백혈구가유의성을보였다. 3. PSI에서 PCT값에대한 ROC 곡선 PCT와백혈구측정값이 PSI에서통계학적으로유의성이있게증가하여이에대해 ROC 곡선을분석하였다. Figure 1에서 PCT가곡선하면적이 0.694, 백혈구가곡선하면적이 0.593로 PSI에서 PCT가검사적가치가있다고볼수있겠다. PCT의경우 0.745 ng/ml 보다높을때특이도 70.5%, 민감도 61.3% 를나타내어지역사회획득폐렴의고위험군으로판단하는데도움이될것으로관찰되었다. 4. PCT에따른임상양상 Table 3에서와같이 PCT가 0.745 ng/ml 이상일때 CRP, 백혈구는커졌고혈액요소질소도 20 mg/dl 보다높 Figure 1. Receiver operating characteristic curves comparing WBC, PCT in PSI. WBC: white blood cell; PCT: procalcitonin; PSI: pneumonia severity index. 았으며호흡수도빠르게나타났다. 그리고 PCT가 0.745 ng/ml 미만일때사망자는 2명 (3.57%) 이고그이상인경우는사망자가 4명 (11.11%) 이었다. 고 본연구는지역사회획득폐렴에서기존에알려진위험예측도와염증지표간의상관관계를알아보고자하였고그결과로입원당시의 PCT가높을수록그위험예측도가크다는것을확인하였다. 그리고이연구에서두가지특이할만한점을관찰하였는데첫째는위험예측도에서 찰 432
Table 3. Comparison of clinical characteristics of patients with procalcitonin level Tuberculosis and Respiratory Diseases Vol. 67. No. 5, Nov. 2009 Characteristics PCT <0.75 ng/ml (n=56) PCT 0.75 ng/ml (n=36) p-value Age, yr 61±16.72 66.5±13.48 0.101 WBC, 10 3 /μl 11,731.96±4,681.40 18,231.39±9,982.82 0.000 CRP, mg/dl 10.83±8.59 16.97±12.43 0.006 BUN, mg/dl 18.17±10.85 25.75±12.28 0.003 RR, /min 21.14±4.23 23.03±3.89 0.034 SBP, mmhg 126.61±21.77 111.94±32.41 0.011 DBP, mmhg 76.61±12.94 68.06±18.33 0.010 PSI, points 74.75±32.83 100.94±41.93 0.032 Values are means (±SD). PCT: procalcitonin; WBC: white blood cell; CRP: C-reactive protein; RR: respiratory rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; PSI: pneumonia severity index. PORT 의 PSI 고위험군에서만통계학적으로 PCT가상승된것이유의하였고 CAPNETZ study의 CRB-65 13, CURB-65 에서는유의성이없다는점이다. 이것은동반질환과나이구분이 PSI에있기때문에동반질환이없는젊은성인에서 PSI가사망위험성이낮은환자를잘예측할수있는반면 CURB-65 는중증의사망률이높은환자를보다정확히예측할수있는차이점때문일수도있겠다 14. 둘째는 PCT, 백혈구가위험예측도고위험군에서증가하나 CRP는비록통계학적인유의성은없을지라도저위험군에서증가하였다. 이것은최근폐구균에의한지역사회획득폐렴에서높은 streptococcal pneumoniae urinary antigen titer 에도불구하고 CRP가낮았다는보고와 15 CRP 가위험예측도와일치하지않는다는보고와 16 같은결과이다. 또한 CRP가 PCT보다는중증폐렴환자에서늦게상승하여 17 지역사회획득폐렴의중증도평가에유용성이낮다고할수있겠다. 일반적으로전신감염을확인시 CRP에비해민감성이나특이성이높다고알려진 PCT는 calcitonin 의전구물질서중증의세균성감염시균체내독소 (lipopolysaccharide 포함 ) 혹은시토카인 (interleukin-1β, tumor necrosis factor-α, interleukin-6) 의해 4시간부터증가하여 8 24시간에고점에이르게되지만바이러스에의해유도된사이토카인 (interferon-r) 에의해서는증가가둔화된다 18-20. 이런이유로 PCT는패혈증을동반한심한세균성감염의특이적인표지자역할과 21 응급실에서는전신감염을진단하고사망환자를예측할수있다 22. 그러나중환자실발열환자에서감염성원인을진단하는데도움이되지않는다는연구와 23 PCT 측정값의확정범위에따라민감도및특이도에많은차이가있어 24 추후임상적으로진단이나치료 의방침을적용할수있는기준이요구되는상황이다. 그외에 PCT의유용한역할은감염이있을때추적검사를하면항생제사용기간을줄일수있다는것이다. 지금까지는항생제사용을임상적관찰을통해결정을하였는데최근보고에따르면만성폐쇄성폐질환의급성악화시 PCT를이용한경우는항생제처방률이 40%, 그렇지않는경우는 72% 이었고 25 패혈증환자도 PCT를이용한군이대조군에비해항생제사용기간을 3.5일줄였고 26 지역사회획득폐렴에서도대조군에비해 PCT군이항생제사용기간을 55% 나감소시켰다는연구처럼 27 PCT를추적검사하여항생제중단을결정하면좀더객관적인지표가될뿐만아니라비용측면에서도효과가있을것으로사료된다. 추가적으로 Nyamande 와 Lalloo 28 의보고처럼폐결핵시 PCT가세균성폐렴일때보다낮아서우리나라처럼결핵유병률이높은나라에서폐렴과폐결핵을감별하는데도움이될수있겠다. 본조사는지역사회획득폐렴의위험예측에대한추후전향적인연구를목표한사전조사이기에제한점을많이가지고있다. 첫째, PCT와지역사회획득폐렴의사망자를조사하여중증도와의상관관계를평가할계획이었으나사망자수가적어 PCT와폐렴의증증도를직접비교하지못하여위험예측도를이용하였다. 그러나추후타병원과같이다기관조사를전향적으로하면이런점은개선시킬수있을것으로판단된다. 둘째, 진단적검사로서혈액및객담배양검사, 혈청학적검사를모두시행하지못하여폐렴원인에따른 PCT 차이를확인하지못했다. 비록 PSI 저위험군에국한되지만세균성원인의폐렴시비세균성폐렴에비해 PCT가의미있게증가되었다는보고처럼 11 철저한진단검사를통해원인균주에따른 PCT 차이를 433
HP Park et al: Procalcitonin in the community-acquired pneumonia 확인하는것이필요하겠다. 셋째, PCT가우리나라에서는보험이되지않아비용문제로추적검사를하지못했다. 입원당시의 PCT를측정하여위험예측도에반영하는것도중요하나앞서언급한대로 PCT 의유용성은추적검사하여염증이호전되었을때항생제사용기간을단축하는데더의미가있을수있고이로인해항생제비용을줄여오히려폐렴에대한전체적인경비감소도가져올수있으므로이에대해서는추후논의가필요할것으로판단된다. 결론적으로지역사회획득폐렴으로입원한환자에서의위험도를예측하기위해서는 PSI뿐만아니라 PCT를함께고려해보는것이중요할것으로판단되고이에대한전향적인조사및 PCT의추적관찰이필요하겠다. 참고문헌 1. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA, et al. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA 1996;275:134-41. 2. Kaplan V, Angus DC, Griffin MF, Clermont G, Scott Watson R, Linde-Zwirble WT. Hospitalized community-acquired pneumonia in the elderly: age- and sex-related patterns of care and outcome in the United States. Am J Respir Crit Care Med 2002;165:766-72. 3. The British Thoracic Society Research Committee and The Public Health Laboratory Service. The aetiology, management and outcome of severe community-acquired pneumonia on the intensive care unit. Respir Med 1992;86:7-13. 4. Neill AM, Martin IR, Weir R, Anderson R, Chereshsky A, Epton MJ, et al. Community acquired pneumonia: aetiology and usefulness of severity criteria on admission. Thorax 1996;51:1010-6. 5. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58:377-82. 6. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify lowrisk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-50. 7. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 Suppl 2:S27-72. 8. Hedlund J, Hansson LO. Procalcitonin and C-reactive protein levels in community-acquired pneumonia: correlation with etiology and prognosis. Infection 2000;28: 68-73. 9. Hausfater P, Garric S, Ayed SB, Rosenheim M, Bernard M, Riou B. Usefulness of procalcitonin as a marker of systemic infection in emergency department patients: a prospective study. Clin Infect Dis 2002;34:895-901. 10. Masia M, Gutierrez F, Shum C, Padilla S, Navarro JC, Flores E, et al. Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index. Chest 2005;128:2223-9. 11. Kruger S, Ewig S, Marre R, Papassotiriou J, Richter K, von Baum H, et al. Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes. Eur Respir J 2008;31:349-55. 12. Huang DT, Weissfeld LA, Kellum JA, Yealy DM, Kong L, Martino M, et al. Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia. Ann Emerg Med 2008;52:48-58.e2. 13.Bauer TT, Ewig S, Marre R, Suttorp N, Welte T; CAPNETZ Study Group. CRB-65 predicts death from community-acquired pneumonia. J Intern Med 2006; 260:93-101. 14. Niederman MS. Recent advances in community-acquired pneumonia: inpatient and outpatient. Chest 2007; 131:1205-15. 15. Tateda K, Kusano E, Matsumoto T, Kimura K, Uchida K, Nakata K, et al. Semi-quantitative analysis of Streptococcus pneumoniae urinary antigen: kinetics of antigen titers and severity of diseases. Scand J Infect Dis 2006; 38:166-71. 16. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care 2006;10:R96. 17. Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med 2000;28:977-83. 18. Linscheid P, Seboek D, Schaer DJ, Zulewski H, Keller U, Muller B. Expression and secretion of procalcitonin and calcitonin gene-related peptide by adherent monocytes and by macrophage-activated adipocytes. Crit Care Med 2004;32:1715-21. 19. Reinhart K, Karzai W, Meisner M. Procalcitonin as a 434
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