대한응급의학회지제 23 권제 3 호 Volume 23, Number 3, June, 2012 원 저 응급실에있어서세균성뇌수막염의초기진단적가치로서의혈중프로칼시토닌과 C- 반응단백질의효용성 울산대학교의과대학서울아산병원응급의학과 오민석 최상식 서동우 손창환 오범진 김원영 임경수 신주용 곽명관 Serum Procalcitonin and C-reactive Protein Level as an Early Diagnostic Marker of Bacterial Meningitis in the Emergency Department Min-Seok O, Sang-Sik Choi, Dong-Woo Seo, Chang- Hwan Sohn, Bum-Jin Oh, Won Young Kim, Kyoung- Soo Lim, Ju Yong Shin, Myoung Kwan Kwak Purpose: Immediate identification of bacterial meningitis (BM) is essential in the emergency department. However, diagnosis of BM from analysis of cerebrospinal fluid has low sensitivity. The goal of this study was to determine the ability of serum procalcitonin (PCT) and C-reactive protein (CRP) for differentiation between BM and non-bm in adult patients. Methods: This retrospective cohort study, which was conducted from Jan 1 2008 to Sep 30 2011, included patients with a diagnosis of meningitis based on compatible clinical features and cerebrospinal fluid (CSF) culture findings with a CSF leukocyte count > 5 /μl. Measurement of Serum PCT and CRP level was performed on initial admission to the emergency department. Patients were divided into two groups, according to the type of meningitis: BM or non-bm. Clinical features, laboratory results, including CSF results, serum PCT, and CRP levels were assessed. Results: A total of 63 patients (age, 49±19) with confirmed meningitis were admitted: 43 patients with non-bm and 20 patients with BM. Significantly higher PCT and CRP levels, CSF white blood cell and neutrophil count, CSF glucose, and protein levels were observed in the BM group. The 책임저자 : 김원영서울특별시송파구풍납2동 388-1 울산대학교의과대학서울아산병원응급의학과 Tel: 02) 3010-3350, Fax: 02) 3010-3360 E-mail: wonpia@yahoo.co.kr 접수일 : 2012년 3월 22일, 1차교정일 : 2012년 5월 8일게재승인일 : 2012년 6월 10일 360 most highly discriminative parameters for differential diagnosis of BM proved to be serum PCT, with a sensitivity of 90%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 96% at a diagnostic cut-off level of 1.0 ng/ml (area under the curve 0.98; 95% confidence interval 0.00-1.00) and CRP, with a sensitivity of 85%, a specificity of 88%, a positive predictive value of 77%, a negative predictive value of 93% at a diagnostic cutoff level of 6.0 mg/dl (area under the curve 0.91; 95% confidence interval 0.76-0.97). Conclusion: Serum PCT and CRP levels appear to be the most highly discriminative parameters for differential diagnosis of BM and non-bm. Key Words: Procalcitonin, Meningitis, C-reactive protein. Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 서 뇌수막염은두통및발열을주소로응급실에내원하는환자에서중요한감별질환중의하나로많은의학적발전에도불구하고여전히높은사망률과이환율을보인다 1). 특히세균성뇌수막염은원인균과발생연령에따라사망률이 30% 까지이르는신경계응급질환으로, 빠른진단과신속하고적절한항생제투여가사망률과이환율감소에중요한인자로알려져있다 2). 그러나무균성뇌수막염의경우항생제투약이불필요하며무분별한항생제투약은의료비용과인적자원을소비할뿐만아니라불필요한입원과항생제에의한부작용의위험성에노출될수있기에뇌수막염의치료에있어서세균성과무균성의감별이필요하다. 응급실에서세균성뇌수막염과무균성뇌수막염을감별하기위해서뇌척수액검사, 뇌척수액그람염색및배양검사등이사용되어왔으나이둘의감별은쉽지않다. 그람염색은비록신속하지만매우비특이적이며민감도도낮다고보고되고있고, 뇌척수액배양검사는매우특이도가높 론
오민석외 : 응급실에있어서세균성뇌수막염의초기진단적가치로서의혈중프로칼시토닌과 C- 반응단백질의효용성 / 361 으나 48~72시간뒤에야결과를확인할수있다는단점이있다 3-5). 뇌척수액분석결과상백혈구수치 1000 /μl, 호중구수치 80%, 단백질 100 mg/dl, 그리고포도당 < 40 mg/dl 등이세균성뇌수막염을시사하는소견으로알려져있으나실제임상에서는매우다양한정도의뇌척수액소견을보이는뇌수막염이많아높은민감도와특이도를보여주지못하고있다 6-9). 또한바이러스성원인을조기에확인하기위한중합효소연쇄반응검사 (Polymerase chain reaction) 가높은민감도와특이도를보이나모든의료기관에서쉽게사용하기어려운것이사실이다 10). 몇몇염증성표지자가세균성뇌수막과무균성뇌수막의감별에도움이되는것으로보고된바있다. C-reactive protein (CRP) 는여러감염성질환의진단에유용하게사용되고있으며세균성원인과비세균성원인의감별에유용하다고알려져있으며 11-13), Procalcitonin (PCT) 는갑상선의 C-세포에서합성되어말초혈액의백혈구에서분비되는칼시토닌의전구체로급성기세균성감염에특이적인것으로알려져있다 14,15). 소아에있어서는소규모전향적연구를통해뇌수막염으로진단된환아를대상으로세균성원인과바이러스성원인을감별하는데있어서 PCT 와 CRP의유용성을제시하였으나, 성인을대상으로한연구결과는부족한상태이며국내보고는아직까지없는실정이다. 이에저자들은응급실에내원한 16세이상의성인뇌수막염환자를대상으로뇌척수액검사와함께시행된 CRP 와 PCT가세균성뇌수막염과비세균성뇌수막염의감별진단에유용한지확인하고자하였고세균성뇌수막염감별할수있는 CRP와 PCT의기준치를확인하고자하였다. 포분석, 뇌척수액그람염색과뇌척수액세균배양검사와신경과및감염내과전문의의임상적판단에따른퇴원시진단명으로하였다. 다음중하나의소견이관찰될경우세균성뇌수막염으로진단하였다 16). 1) 뇌척수액배양검사양성 ; 2) 뇌척수액배양검사는음성이나뇌척수액항원검사양성혹은혈액배양검사양성 ; 3) 뇌척수액검사상호중구수가 500 /μl 이상이고항생제에치료에반응하였던경우. 비세균성뇌수막염의진단은뇌척수액세균배양검사및세균항원검사음성, 뇌척수액바이러스배양검사양성및중합효소연쇄반응검사양성, 그리고항생제처치없이완전치료된경우로정의하였다. 최종진단으로결핵성뇌수막염은비세균성뇌수막염으로포함하였으나진균감염및기생충감염으로진단된경우는연구에서배제하였다. 2. 자료수집전자의무기록을조사하여환자의나이, 성별, 증상, 초기활력징후, 실험실결과, 입원및퇴원당시진단명등의기본적인인적정보와연구에필요한임상정보를수집하였다. 연구에포함된모든환자들에게있어서응급실내원후처음시행된일반혈액검사및 PCT, CRP 검사, 그리고뇌척수액내백혈구수, 호중구수, 단백질및포도당수치를포함한기본뇌척수액검사항목을조사하였다. 혈액에서 PCT의측정은 VIDAS BRAHMS enzyme-linked fluorescence assay (measurement range, 0.05 200 ng/ml; biomerieux, Marcy-l Etoile, France) 를이용하였고 CRP의측정은 automated multichannel analyzer (measurement range, 0.1 200 mg/dl; model TBA- 30FR; Toshiba, Saitama, Japan) 를이용하였다. 대상과방법 3. 통계학적방법 1. 대상및방법 2008년 1월 1일부터 2011년 9월 30일까지본원에내원한 16세이상의환자중응급실에서뇌척수액검사상백혈구수가 5 /μl 이상관찰되어뇌수막염이의심되었던환자중혈중 CRP 및 PCT 검사가시행되었고최종적으로뇌수막염으로진단되어입원치료받았던환자를대상으로하였다. 본원에서는 2009년부터응급실에내원한뇌수막염이의심되는환자에서뇌척수액검사시행시일반혈액검사, 혈중 CRP 및 PCT 검사를시행하고있다. 대상환자중퇴원시최종진단명이뇌수막염이아니거나다른동반된감염이확인된경우및타원에서항생제처치후전원된경우등은연구에서제외하였다. 뇌수막염의진단은임상양상과진찰소견, 뇌척수액세 대상환자의변수는평균 ± 표준편차혹은중위값또는빈도수를이용하여표시하였다. 통계분석은윈도우용 SPSS version 12.0(SPSS Inc., Chicago, IL, USA) 를사용하였으며, 서로다른두군간의평균값은독립표본 t 검정으로, 정규분포를따르지않는연속형자료는 Mann-Whitney U test를이용하였으며, 범주형자료는카이제곱검정 (Chisquare test) 이나피셔의정확한검정 (Fisher s exact test) 을사용하여분석하였다. 세균성뇌수막염을예측할수있는진단의효율성을확인하기위하여수신기작동특성곡선 (receiver operating characteristic curve, ROC curve) 과 area under the curve (AUC) 를이용하여뇌척수액검사항목과 PCT 및 CRP의 AUC를비교하였다. 또한세균성뇌수막염을예측할수있는가장적절한 PCT 및 CRP의경계값 (cutoff value) 을선정하기위해 ROC
362 / 대한응급의학회지 : 제 23 권제 3 호 2012 curve 분석을시행하였다. 그리고 p 값이 0.05 미만인경 우통계적으로유의한차이가있다고판정하였다. 79.0 mmhg, p=0.03). 하지만두통, 구역및구토, 경부경직및발열등에있어서는양군간의유의한차이는없었다. 결과 1. 환자의임상적특성연구기간중총63명의환자가뇌수막염으로최종진단되어연구에포함되었으며, 이중비세균성뇌수막염환자는 43명이었고세균성뇌수막염환자는 20명이었다. 이들의평균나이는 49.1±18.7세였으며남자는 35명 (55.6%) 이었다. 내원시의식상태가명료하였던경우는 45명 (71.4%) 이었고불러서반응하는경우가 10명 (15.9%), 통증자극에반응하는경우및반응이없었던경우가각각 4명 (6.3%) 이었다. 2. 임상양상의비교세균성뇌수막염 20명과비세균성뇌수막염 43명간에는나이및성별에있어서는유의한차이가없었다 (Table 1). 그러나증상발현후응급실까지내원하는시간은세균성뇌수막염환자에서평균 1.1일로비세균성뇌수막염환자 3.9일보다유의하게짧았으며내원시의식변화가있었던경우도관찰되었으나통계학적으로유의하지는않았다. 또한내원시측정된수축기및이완기혈압도세균성뇌수막염환자에서비세균성뇌수막염환자보다유의하게높게측정되었다 (138.5 vs. 127.5 mmhg, p=0.03; 85.4 vs. 3. 생체표지자의비교세균성뇌수막염군과비세균성뇌수막염군사이에혈중백혈구수, PCT 및 CRP 농도에서통계적으로유의한차이를보였다 (Table 2). 또한뇌척수액내백혈구수, 호중구및단백질수치도양군에서유의한차이를확인할수있었다. 하지만뇌척수액내포도당수치는세균성뇌수막염군이 38 mg/dl, 비세균성뇌수막염이 56 mg/dl였으나통계적으로유의한차이는없었다 (Table 2). 4. 세균성뇌수막염진단의유용성세균성뇌수막염진단의유용성을확인하기위한 ROC 곡선분석결과혈중백혈구수, PCT, CRP의 AUC값은각각 0.84(95% CI, 0.72-0.96), 0.98(95% CI, 0.00-1.00), 0.91(95% CI, 0.83-0.99) 였으며뇌척수액검사상백혈구수, 호중구및단백질수치도각각 AUC값 0.87 (95% CI, 0.76-0.98), 0.86(95% CI, 0.73-0.98), 0.80(95% CI, 0.67-0.93) 으로세균성뇌수막염진단에유의하였다 (Table 3). 또한뇌척수액검사상일반적으로세균성뇌수막염을진단할수있는기준인백혈구수 > 1000 /μl, 호중구 > 80%, 단백질 > 100 mg/dl 등은세균성뇌수막염을진단하는데통계적으로유의하였으나포도당 < 40 mg/dl 은유용하지못하였다 (Table 3). 세균성뇌수막염진단을위한 PCT와 CRP의가장적절한경계 Table 1. Demographic features and clinical characteristics in patients with bacterial and non-bacterial meningitis Non-BM (n=43) BM (n=20) p-value Demographic features Age, years 46.5±18.4 54.9±18.5 0.10 Male 23 (53.5) 12 (60.0) 0.79 Clinical characteristics Onset, days 3.9±3.2 1.1±1.2 0.03 Headache 23 (53.5) 09 (45.0) 0.43 Nausea/Vomiting 15 (34.9) 08 (40.0) 0.78 Neck stiffness 19 (44.2) 13 (65.0) 0.17 Fever (>38.3 C) 12 (27.9) 05 (25.0) 0.89 Mental change 09 (20.9) 09 (45.0) 0.05 Vital signs Systolic BP (mmhg) 127.5±18.00 138.5±17.90 0.03 Diastolic BP (mmhg) 79.0±11.3 85.4±9.40 0.03 PR (beats/min) 85.0±17.9 94.8±23.1 0.07 RR (breaths/min) 20.1±2.10 20.8±2.30 0.20 Temperature ( C) 37.6±1.00 37.2±1.20 0.69 Data are expressed as mean±standard deviation or n (%). BM: bacterial meningitis, BP: blood pressure, PR: pulse rate, RR: respiratory rate
오민석외 : 응급실에있어서세균성뇌수막염의초기진단적가치로서의혈중프로칼시토닌과 C- 반응단백질의효용성 / 363 값을확인하였다 (Fig. 1). PCT의경우 1.0 ng/ml 이상일경우민감도 90.0%, 특이도 100.0%, 양성예측도 100.0%, 음성예측도 96.0%, 정확도 95.0% 으로세균성뇌수막염을진단할수있었고, CRP는 6.0 mg/dl 이상일경우민감도 85.0%, 특이도 88.0%, 양성예측도 77.0%, 음성예측도 93.0%, 정확도 87.0% 으로세균성뇌수막염을예측할수있었다 (Table 4). Table 2. Biological findings in patients with bacterial and non-bacterial meningitis Non-BM (n=43) BM (n=20) p-value Blood White blood cell, 10 3 /μl 8.2 (6.3-11.5) 16.8 (8.2-23.9) <0.01 Procalcitonin, ng/ml 0.1 (0.1-1.2)0 5.2 (1.8-9.0) <0.01 C-reactive protein, mg/dl 1.4 (0.2-4.7)0 18.6 (8.2-23.9) <0.01 CSF White blood cell, /μl 083.0 (28.0-360.0) 0004515.0 (1132.5-9500.0) <0.01 Neutrophils, % 11.0 (1.0-45.0)0 084.0 (70.5-91.8) <0.01 Protein, mg/dl 074.0 (48.5-113.9) 00351.4 (175.7-567.1) <0.02 Glucose, mg/dl 56.0 (40.0-69.0) 38.0 (2.5-70.2) <0.60 Data are expressed as median and inter-quartile range or n (%). BM: bacterial meningitis, CSF: cerebrospinal fluid Table 3. Diagnostic value of various biological parameters for bacterial meningitis AUC 95% CI p-value Blood White blood cell 0.84 (0.72-0.96) <0.01 White blood cell > 1000/μL 0.74 (0.61-0.87) <0.02 Procalcitonin 0.98 (0.00-1.00) <0.01 Procalcitonin > 1.0 ng/ml 0.95 (0.00-1.00) <0.01 C-reactive protein 0.91 (0.83-0.99) <0.01 C-reactive protein > 6.0 mg/dl 0.87 (0.76-0.97) <0.01 CSF White blood cell 0.87 (0.76-0.98) <0.01 White blood cell > 1000 /μl 0.85 (0.73-0.97) <0.01 Neutrophils 0.86 (0.73-0.98) <0.01 Neutrophils > 80% 0.77 (0.62-0.91) <0.01 Protein 0.80 (0.67-0.93) <0.01 Protein > 100 mg/dl 0.77 (0.65-0.90) <0.01 Glucose 0.68 (0.48-0.84) <0.05 Glucose < 40 mg/dl 0.64 (0.49-0.80) <0.07 AUC: area under the curve, CI: confidence interval Table 4. Diagnostic accuracy of C-reactive protein and procalcitonin for bacterial meninigitis Procalcitonin C-reactive protein Optimal cut-off value > 1.0 ng/ml > 6.0 mg/dl Sensitivity 0.90 0.85 Specificity 1.00 0.88 Positive predictive value 1.00 0.77 Negative predictive value 0.96 0.93 Accuracy 0.95 0.87
364 / 대한응급의학회지 : 제 23 권제 3 호 2012 고 뇌수막염을치료함에있어세균성뇌수막염여부를조기 진단하는것은경과, 치료, 환자의사망에있어중요한요소이다. 본연구에서저자들은응급실에내원한성인뇌수막염환자에서뇌척수액검사와같이시행된 PCT와 CRP 는세균성뇌수막염환자의진단에각각 AUC 0.98(95% CI, 0.00-1.00), 0.91(95% CI, 0.83-0.99) 로매우높은진단정확도가있음을확인할수있었고, 세균성뇌수막염을감별할수있는 PCT와 CRP의기준치는각각 > 1.0 ng/ml, > 6.0 mg/dl 임을확인하였다. 뇌수막염환자의약 2/3는두통, 발열, 경부경직, 의식변화등의주요증상들중 3가지를보인다 17). 하지만세균성뇌수막염의가능성이높다는경부경직과의식변화가있는경우도진단적타당도는매우낮다고알려져있다 18). 본연구에서도세균성뇌수막염군과비세균성뇌수막염군사이에두통, 발열, 경부경직, 의식변화유무에유의한차이를관찰할수없었다. 세균성뇌수막염을진단하기위해서는뇌척수액분석결과상백혈구수치 1000 /μl, 호중구수치 80%, 단백질 100 mg/dl, 그리고포도당 < 40 mg/dl 등이세균성뇌수막염을시사하는소견이라알려져있으나실제임상에서는매우다양한정도의뇌척수액소견을보이는뇌수막염이많고그결정값들에대한논란이있어높은민감도와특이도를보여주지못하고있다 6-8). 422명의세균성 Fig. 1. Receiver-operating characteristics curve for discriminating between bacterial meningitis and non-bacterial meningitis for procalcitonin and C-reactive protein on initial emergency department visit. Area under the curve 0.98(95% confidence interval 0.00-1.00) for procalcitonin, 0.91(0.83-0.99) for C-reactive protein. 찰 뇌수막염환자를대상으로한연구에서는뇌척수액내백혈구수치 2000 /μl, 호중구수치 1180 /μl, 단백질 220 mg/dl, 그리고포도당 < 34 mg/dl일때세균성뇌수막염을진단할수있다고보고하였으나, Durand 등 17) 이 493명의세균성뇌수막염환자를대상으로보고한연구에서는세균성뇌수막염임에도뇌척수액내포도당수치가 40 mg/dl를넘는경우가 50% 에서관찰되었고, 44% 의환자에서는뇌척수액내단백질수치가 200 mg/dl 보다낮았으며뇌척수액내백혈구수치가 1000 /μ L보다낮은경우가 13% 였다고보고하였다 9). 본연구결과에서는뇌척수액내포도당수치는세균성뇌수막염진단에유용한인자가아니었고뇌척수액내백혈구수치, 호중구수치, 단백질수치는각각 AUC 값 0.87 (95% CI, 0.76-0.98), 0.86(95% CI, 0.73-0.98), 0.80(95% CI, 0.67-0.93) 으로세균성뇌수막염진단에유의한인자였다. 그러나세균성뇌수막염환자의 25% 에서뇌척수액내백혈구수치의상승이없었었고, 40% 환자에서호중구수치가기준보다낮았으며, 15% 의환자에서단백질수치가 100 mg/dl 보다낮아뇌척수액분석만으로세균성뇌수막염을진단하는데제한점이있음을확인할수있었다. 세균성감염에있어 CRP와 PCT가여러임상상황에서다양하게이용되고있다. 소아뇌수막염환자를대상으로세균성원인과바이러스성원인을감별하는데있어서 PCT와 CRP의유용성을제시한문헌들이보고되었다 19-21). Schwarz 등 14) 은 30명의성인환자를대상으로 CRP와 PCT 값을통한세균성뇌수막염을감별하고자하였고혈중 CRP 값 > 8 mg/dl 일때민감도 94% 였으며 PCT >0.5 ng/ml일때특이도가 100% 였다고보고하였다. 또한 Ray 등 16) 은 2007년처음으로응급실에내원한성인뇌수막염환자를대상으로연구를진행하였고 CRP와 PCT 의세균성뇌수막염의진단정확도를확인하였다. PCT는 AUC 값 0.98(95% CI, 0.83-1.00) 으로 CRP 0.81(95% CI, 0.58-0.92) 보다세균성뇌수막염진단에더유용하다고보고하였다. 본연구에서도이들과유사한결과를확인할수있었다. PCT는세균성뇌수막염환자의진단에 AUC 0.98(95% CI, 0.00-1.00) 로 CRP 0.91(95% CI, 0.83 0.99) 보다유용하였으며, PCT > 1.0 ng/ml일경우민감도 90%, 특이도 100%, 양성예측도 100%, 음성예측도 96%, 정확도 95% 으로세균성뇌수막염을진단할수있어, CRP > 6.0 mg/dl 일경우의민감도 85%, 특이도 88%, 양성예측도 77%, 음성예측도 93%, 정확도 87% 보다더유용함을확인할수있었다. 본연구의제한점으로는단일기관에서시행된연구로환자의수가한정적이었으며환자수집은전향적으로이루어졌지만연구에필요한검사결과와임상적정보는후향적으로분석한후향적연구라는점이다.
오민석외 : 응급실에있어서세균성뇌수막염의초기진단적가치로서의혈중프로칼시토닌과 C- 반응단백질의효용성 / 365 결 성인뇌수막염환자에서 CRP 와 PCT 는기존에알려진 뇌척수액분석값들보다세균성뇌수막염과비세균성뇌수막염의감별진단에유용한도구였고, 응급실에서진단된뇌수막염환자에서 PCT > 1.0 ng/ml, CRP > 6.0 mg/dl 일때는세균성뇌수막염의가능성을고려하여야한다. 론 참고문헌 01. van de Beek D, de Gans J, Tunkel AR, Wijdicks EFM. Community-acquired bacterial meningitis in adults. N Engl J Med 2006;354:44-53. 02. Schlech WF, Ward JI, Band JD, Hightower A, Fraser DW, Broome CV. Bacterial meningitis in the United States, 1978 through 1981. The National Bacterial Meningitis Surveillance Study. JAMA 1985;253:1749-54. 03. Feigin RD, McCracken GH, Klein JO. Diagnosis and management of meningitis. Pediatr Infect Dis J 1992;11: 785-814. 04. Marton KI, Gean AD. The spinal tap: a new look at an old test. Ann Intern Med 1986;104:840-8. 05. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004;351:1849-59. 06. Andersen J, Backer V, Voldsgaard P, Skinh j P, Wandall JH. Acute meningococcal meningitis: analysis of features of the disease according to the age of 255 patients. Copenhagen Meningitis Study Group. J Infect 1997;34: 227-35. 07. Hoen B, Viel JF, Paquot C, Gérard A, Canton P. Multivariate approach to differential diagnosis of acute meningitis. Eur J Clin Microbiol Infect Dis 1995;14:267-74. 08. Rodewald LE, Woodin KA, Szilâgyi PG, Arvan DA, Raubertas RF, Powell KR. Relevance of common tests of cerebrospinal fluid in screening for bacterial meningitis. J Pediatr 1991;119:363-9. 09. Spanos A, Harrell FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989;262:2700-7. 10. Scheld WM, Whitley RJ, Durack DT. Infections of the Central Nervous System. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1997. p.7-22. 11. Clarke D, Cost K. Use of serum C-reactive protein in differentiating septic from aseptic meningitis in children. J Pediatr 1983;102:718-20. 12. de Beer FC, Kirsten GF, Gie RP, Beyers N, Strachan AF. Value of C reactive protein measurement in tuberculous, bacterial, and viral meningitis. Arch Dis Child 1984; 59:653-6. 13. Peltola HO. C-reactive protein for rapid monitoring of infections of the central nervous system. Lancet 1982;1: 980-2. 14. Schwarz S, Bertram M, Schwab S, Andrassy K, Hacke W. Serum procalcitonin levels in bacterial and abacterial meningitis. Crit Care Med 2000;28:1828-32. 15. Viallon A, Zeni F, Lambert C, Pozzetto B, Tardy B, Venet C, et al. High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis. Clin Infect Dis 1999;28:1313-6. 16. Ray P, Badarou-Acossi G, Viallon A, Boutoille D, Arthaud M, Trystram D, et al. Accuracy of the cerebrospinal fluid results to differentiate bacterial from non bacterial meningitis, in case of negative gram-stained smear. Am J Emerg Med 2007;25:179-84. 17. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328:21-8. 18. Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig s sign, Brudzinski s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis 2002;35:46-52. 19. Gendrel D, Raymond J, Coste J, Moulin F, Lorrot M, Gué rin S, et al. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. Pediatr Infect Dis J 1999;18:875-81. 20. Lindquist L, Linné T, Hansson LO, Kalin M, Axelsson G. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis 1988;7:374-80. 21. 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.