02-기동훈

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1 대한응급의학회지제 28 권제 5 호 Volume 28, Number 5, October, 2017 원 저 Medical 응급실에내원한급성신우신염환자에서장기입원기간예측에있어서델타뉴트로필의유용성 기동훈 1 유제성 1 이종욱 2 이혜선 3 이진애 1 정성필 1 공태영 1 주영선 1 고동률 1 연세대학교의과대학응급의학교실 1, 진천성모병원진단검사의학과 2, 연세대학교의과대학연구부통계지원팀 3 Delta Neutrophil Index as a Predictive Factor of Prolonged Hospitalization in Emergency Department Patients with Acute Pyelonephritis Dong Hune Key, M.D. 1, Je Sung You, M.D. 1, Jong Wook Lee, M.D., Ph.D. 2, Hye Sun Lee 3, Jinae Lee, M.D., Ph.D. 1, Sung Phil Chung, M.D. 1, Tae Young Kong, M.D. 1, Young Seon Joo, M.D., Ph.D. 1, Dong Ryul Ko, M.D. 1 * Department of Emergency Medicine, Yonsei University College of Medicine, Seoul 1, Department of Laboratory Medicine, Jincheon Sungmo Hospital, Jincheon 2, Department of Research Affairs, Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul 3, Korea Purpose: The delta neutrophil index (DNI) corresponds to evaluated immature granulocyte counts and severity of sepsis. The aim of this study was to investigate the diagnostic value of DNI as a predictable laboratory marker for prolonged hospitalization in patients with acute pyelonephritis in the emergency department (ED). Methods: We retrospectively analyzed medical records in two EDs and screened eligible adult patients who were admitted to the ED with acute pyelonephritis from July 2012 to July The DNI was calculated for all patients as a part of routine complete blood analysis, and diagnostic performance of DNI for predicting prolonged hospitalization (over 14 days) in patients with acute pyelonephritis (APN) was evaluated. Results: A total of 308 patients with APN were enrolled in the study. Among them, 89 patients (29.9%) were hospitalized for more than 14 days. The initial DNI value was significantly higher in patients with more than 14 days of hospitalization than in those with less than 14 days of hospitalization (6% vs. 2%, p<0.001). The peak value of DNI was also significantly higher in patients discharged after 14 days of hospitalization than in those discharged before 14 days (8% vs. 2%, p<0.001). Multivariate Cox proportional hazard models showed that a DNI of more than 6.3 on ED admission day (hazard ratio [HR], 0.314; 95% confidence interval [CI], , p<0.001) and on peak day (HR, 0.37; 95% CI, , p=0.028) was an independent risk factor for hospitalization over 14 days. Conclusion: DNI is potentially useful as an independent factor for predicting hospitalization for more than 14 days. Key Words: Pyelonephritis, Neutrophils, Hospitalization 서론급성신우신염은응급실또는외래에서흔히볼수있는감염성질환중하나로적절한치료가이루어지지않을경 우사망까지이를수있는질환이다. 미국에서는매년약 25만명의환자가보고되고있으며, 남자보다는여자에서높은유병률을보이고 10만명이상이입원치료를하고있다 1). 한국에서는매년 10만명당 36명의유병률을보인다. 또한, 응급실을방문하는신우신염환자의약 10% 에서입 책임저자 : 고동률서울특별시강남구언주로 211 연세대학교의과대학응급의학교실 Tel: , Fax: , kkdry@yuhs.ac 접수일 : 2017년 6월 1일, 1차교정일 : 2017년 6월 1일, 게재승인일 : 2017년 8월 22일 413

2 414 / 기동훈외 Article Summary What is already known in the previous study The delta neutrophil index (DNI) corresponds to evaluated immature granulocyte counts and severity of sepsis. What is new in the current study DNI is potentially useful as an independent factor for predicting hospitalization for more than 14 days. 원치료가필요한상태이며특히소아, 고령환자및임산부에서는패혈증으로진행되는경향이높으므로입원치료가추천된다 2). 급성신우신염환자에서약 20%-30% 가량이세균혈증이동반되며, 패혈증이동반되는경우사망률은 30% 이상이기때문에빠르고적절하게항생제를사용하는것이환자의예후향상및다발성장기부전으로의진행을막는데중요하다 3,4). 또한감염환자의경우재원기간이길어질수록이환율및의료비용의급증을초래한다는보고가있었다 5). 급성신우신염의경우최근치료지침상경증으로분류되는경우통원치료를권장하고있다. 따라서신우신염환자에서생화학적지표로서재원기간및예후를예측하는것에대한연구가많이이루어졌다. 그중 C- 반응단백질 (C-reactive protein, CRP) 은재원기간및재발의예측에인자로서유용성이있다는보고가있었다 6). 또한젖산염 (lactate) 은관류저하와조직의저산소혈증을반영하는생화학적지표로알려져있으며, 패혈증진단의주요표지자이다. 하지만급성신우신염환자에관련한연구에서단독으로사용시낮은패혈증예측력을보여주었다 4). 프로칼시토닌 (procalcitonin) 은 CRP, 젖산염보다패혈증발생예측에있어서유용한생화학적표시자로알려져있다 7). 하지만연속적으로검사하기어렵고검사하는데있어서비용적인부분이부담될수있다. 델타뉴트로필인덱스 (delta neutrophil index, DNI) 는자동혈액분석기의일종인 ADVIA 2120 (Siemens, Forchheim, Germany) 을이용하여측정할수있는데측정된호중구와호산구를합한값에서측정된다형핵호중구의값을뺀차이이다 8,9). DNI는미성숙과립구를반영하는지표로과립구의좌측이동을반영하는미성숙과립구의비율이감염및균혈증과연관이있고, 감염이나전신염증반응에서미성숙과립구 (immature granulocyte) 의존재는골수세포 (myeloid cell) 생산을증가시키기때문에패혈증이의심되는환자들의중증도를판별하는데유용하다고보고되었다 10,11). 또한 DNI는특정혈액검사장비에서전체혈구계산 (complete blood count, CBC) 를시행하면서자동으로계산된값을얻을수있으므로프로칼시토닌, CRP, 젖산염과 비교하면추가비용없이응급진료센터에서연속적으로결과를비교하면서빠른결과를얻을수있다는장점이있다. 따라서우리는응급실에내원한신우신염환자에서 DNI와재원기간연장의상관관계를알아보고자한다. 대상과방법 1. 대상환자및의무기록조사이연구는 2012년 7월 1일부터 2014년 6월 30일까지연세대학교응급의료센터세브란스병원에내원하여입원한환자중최종진단명이급성신우신염 (International Classification of Diseases, 10th revision; N10) 으로진단된 19세이상의성인환자를대상으로의무기록을조사하였으며 IRB 승인을받았다 ( ). 급성신우신염의정의는 (1) 응급실내원 24시간전부터체온이 38 이상혹은열과오한이있거나, (2) 적어도하나이상의요로감염의징후혹은증상 ( 배뇨통, 급박뇨, 빈뇨, 옆구리통증, 치골위통증또는신체검진상늑골척추각의압통 ) 이갑자기생긴경우, (3) 중간뇨, 청결채취도뇨, 도뇨관을이용한소변검사에서백혈구가 milliliter 당 10개이상검출되면서아질산염혹은백혈구에스테르분해효소양성인경우진단하였다. 응급실에입원하지않고외래에서치료한환자들은제외하였다. 또한델타뉴트로필을상승시킬수있는골수섬유증, 장기이식후급성거부반응, 골수증식증, 골수이형성증후군, 뼈전이암및최근의수술력질병, 임상적혹은영상의학적으로급성신우신염을제외한다른감염이의심되는환자들은제외하였다. 나이, 성별, 내원당시수축기 / 이완기혈압, 내원당시와입원중최고치의백혈구수 (white blood cell count, WBC), 분엽핵호중구 (segmented neutrophil), 적혈구침강속도 (erythrocyte sedimentation rate, ESR), CRP, 젖산염, 알부민, Acute Physiology and Chronic Health Evaluation (APACHE) II 점수, 재원기간등을조사하였다. 2. DNI 및기타검사내원당시전체혈구계산, ESR, CRP, 알부민등의혈액검사를조사하였다. CBC에서는총백혈구, 백혈구분율, 다형백혈구, 델타뉴트로필등을조사하였다. CBC는자동혈액분석기를이용하여시행하였다. 자동혈액분석기는유체역학을바탕으로 2개의독립적인백혈구분석방법을가지고있는데 peroxidase 채널은텅스텐할로겐을기반으로빛을조사하여굴절되거나흡수되는정도를측정하여백혈구를크기와염색정도에따라구분하고 lobularity/ nuclear density 채널은레이저다이오드를기반으로빛

3 Delta Neutrophil Index in Acute Pyelonephritis / 415 을조사하여백혈구를구분한다. Peroxidase 채널에서는호중구와호산구를구분해내고, lobularity/nuclear density 채널에서는다형핵호중구를구분해내며두채널의차이가 DNI이다 7,12,13). 이것은 CBC 결과중백혈구분율을이용하여 DNI=(cytochemical reaction을이용한 myeloperoxidase 채널에서분석된백혈구분율 )- (reflected light beam을이용하여 nuclear lobularity channel에서분석된백혈구분율 ) 의공식으로계산된다. 3. 분석방법인구통계학적자료및임상데이터는중앙값 ( 범위 ) 과표준편차를각각에맞게구하여표기하였다. 범주형변수의경우 chi-squared test or Fisher exact test를이용 하여비교하였다. 연속변수는 independent 2-sample t test를이용하여비교하였다. Univariate Cox proportional analyses를이용하여인구통계특성, 임상데이터및 14일이상재원기간의관계를분석하였다. 결과에서 p<0.05 가되는항목은 14일이상재원기간에영향을미치는독립적인예후인자를확인하기위하여 multivariate Cox proportional hazard regression analysis를수행하였으며, 결과는 hazard ratio (HR) 와 95% 신뢰구간 (confidence interval, CI) 으로표현하였다. 젖산염은 DNI 1 day( 응급실내원시 DNI 값 ) 및 DNI peak( 입원중가장높은 DNI 값 ) 와피어슨상관계수 (Pearson correlation coefficient) 가각각 R=0.528; p<0.001와 R=0.485; p<0.001로중등도의상관관계를보여결과에영향을줄수있어, multivariate Cox proportional- Table 1. Baseline characteristics Variables Total Discharge within Discharge after (N=308) 14 days (N=222) 14 days (N=86) p-value Sex <0.038 Male (14.29) (11.71) (20.93) Female (85.71) (88.29) (79.07) Age (yr) ± ± ±15.07 <0.001 Hypertension (43.18) (36.04) (61.63) <0.001 Diabetes mellitus (28.57) (24.77) (38.37) <0.018 Hepatitis (2.27) (1.35) (4.65) <0.098 Malignancy (18.18) (15.77) (24.42) <0.077 Renal diseases (13.11) (11.36) (17.65) <0.145 Shock on admission (11.69) (9.46) (16.28) <0.091 Heart rate (beats/min) ± ± ±21.70 <0.230 Body temperature ( C) 38.25± ± ±1.23 <0.071 Respiratory rate (breaths/min) 16.59± ± ±2.90 <0.009 White blood cell ( 10 3 /μl) 13.08± ± ±8.42 <0.013 Neutrophil segment (%) ± ± ±8.73 <0.001 Hemoglobin (g/dl) 12.10± ± ±1.80 <0.024 Hematocrit (%) 35.65± ± ±5.41 <0.100 Platelets ( 10 3 /μl) ± ± ± <0.384 RDW (%) 13.73± ± ±2.27 <0.001 Blood urea nitrogen (mg/dl) ± ± ±22.87 <0.001 Creatinine (mg/dl) 01.26± ± ±1.68 <0.001 Albumin (g/dl) 03.48± ± ±0.65 <0.001 ESR (mm/hr) ± ± ±31.43 <0.811 CRP (mg/l) ± ± ± <0.093 DNI 1 day (%) 03.71± ± ±7.31 <0.001 DNI peak (%) 04.71± ± ±9.01 <0.001 DNI peak day (%) 01.96± ± ±3.039 <0.013 APACHE II score 10.20± ± ±7.23 <0.001 Values are presented as number (%) or median±standard deviation. DNI 1 day, DNI value at time of arrival; DNI peak, the highest DNI during hospitalization; DNI peak day, the day when DNI value was highest. RDW: red cell distribution width, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, DNI: delta neutrophil index, APACHE: Acute Physiology and Chronic Health Evaluation

4 416 / 기동훈외 hazard regression analysis에서제외하였다. 14일퇴원에대해 14일내퇴원한그룹과 14일이후퇴원한그룹으로나누어비교하였다. 14일이전퇴원을기초로해서사건 (event) 과시간 (time) 을고려하여, Contal and O Quigley technique를이용하여분석하였다. 시간을기반으로하여최적의결정점 (cut-off point) 을구하기위해 14일이내에퇴원하는것을사건으로하여통계분석하였다. 14일이내퇴원가능함을 DNI 값으로예측하기위해가장최적값을찾으려면 HR이가장작은점을찾아야하므로, DNI 값이최소의 HR를보이는포인트를선택하였다 14,15). 통계분석은 IBM SPSS Statistics ver (IBM Corp., Armonk, NY, USA) 를이용하였으며 p-value가 0.05 이하이면통계학적으로유의한것으로해석하였다. 결과본연구기간동안급성신우신염으로입원한환자는총 714명이었으며, 선정기준및제외기준에따라본연구에포함된환자는총 308명이었다. 본연구에서제외된환자는 18세미만의소아환자가 371명, 다른감염이동반된환자가총 12명, 임산부가 4명, 만성적으로면역저하상태인환자가 14명, 혈액종양환자 2명, 소화기출혈환자가 1명, 최근수술환자가 2명이었다. 대상환자들의평균나이는 57.7±18.3세였고, 남자는 44명 (14.3%), 여자는 264명 (85.7%) 이었으며남자가여자보다 14일이상재원기간에서차이를보였다 (p=0.038). 14일이상재원한환자의평균연령이 64.0± 15.0세였고 14일미만으로재원한환자나이의평균이 55.3±19.0세로의미있는결과를보였다. 과거력에서고혈압, 당뇨를앓고있는환자군에서유의한차이를보였으며 (p<0.001 and p=0.018), 신장질환이있는환자에서는유의한차이를보이지않았다 (p=0.145). 생체징후중에서는최근개정된 quick Sequential Organ Failure Assessment score의기준에들어가있는호흡수에서양군간의유의한차이를확인하였다 (p=0.009). 검사결과상백혈구수, 적혈구크기분포폭, DNI, APACHE II 점수, 혈액요소질소, 크레아티닌, 알부민, 헤모글로빈에서유의한차이를관찰할수있었다. 다른연구에서의미있었던 ESR, CRP은통계적으로유의한차이를보이지않는결과를보였다 (Table 1). 항생제사용빈도는 14일내퇴원군의경우총 219명중퀴놀론 (quinolone) 사용이 78명 (36%), 3세대세팔로스포린 (cephalosporin) 100명 (45%), 카바페넴 (carbapenem) 등의베타락탐계 (beta-lactam) 항생제내성균에쓰이는항생제를사용한경우가 41명 (19%) 이었다. 14일이상재원환자의경우총 89명중퀴놀론사용이 19 명 (21%), 3세대세팔로스포린사용이 26명 (29%), 카바페넴등의베타락탐계항생제내성균에쓰이는항생제를사용 Table 2. Baseline characteristics by septic shock Variables Total Non-shock Septic shock (N=308) (N=273) (N=35) p-value Sex, male (14.29) (13.92) (17.14) Age (yr) ± ± ± Heart rate (beats/min) ± ± ± Body temperature ( C) 38.25± ± ± Respiratory rate (breaths/min) 16.59± ± ± WBC ( 10 3 /μl) 13.08± ± ± Hemoglobin (g/dl) 12.10± ± ± Hematocrit (%) 35.65± ± ± Platelet ( 10 3 /μl) ± ± ± RDW (%) 13.73± ± ± Blood urea nitrogen (mg/dl) ± ± ± Creatinine (mg/dl) 01.26± ± ± Albumin (g/dl) 03.48± ± ± ESR (mm/hr) ± ± ± CRP (mg/l) ± ± ± DNI 1 day (%) 03.71± ± ± DNI peak (%) 04.71± ± ± Discharge after 14 days (27.92) (26.37) 0.14 (40) Values are presented as number (%) or median±standard deviation. DNI 1 day, DNI value at time of arrival; DNI peak, the highest DNI during hospitalization. RDW: red cell distribution width, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, DNI: delta neutrophil index

5 Delta Neutrophil Index in Acute Pyelonephritis / 417 한경우가 44명 (50%) 이었다. 또한, DNI 값이가장높게측정되는시점은전체환자군대상으로중앙값 1일로나타났으며, 14일이전퇴원환자군에서중앙값은 1일, 14일이후퇴원환자의중앙값은 2일로나타났다 (Table 1). Septic shock 여부에따라환자를분류하였을때, WBC 혈소판, 크레아티닌, 혈액요소질소, ESR 등이 p<0.05를나타내어통계학적으로유의한차이를보였으나, CRP, DNI, 14일이상재원여부는통계학적차이를보이지않았다 (Table 2). 14 일내의퇴원이가능한경우, 어떤인자들이영향을주는지알아보기위하여, 위에차이를보였던데이터를이용하여 univariate Cox regression 분석을진행하였다. 성별이여성이었을경우에 14일내퇴원가능성이높은경향을보였으나통계적으로유의한차이는보이지않았다 (p=0.06). 최근감염질환의예후와관련성이높은알부민의경우도수치가높을수록 14일내에퇴원할가능성이높은것으로나타났다 (p<0.001). 반면에혈액요소질소, 크레아티닌, DNI 1 day( 응급실내원시 DNI 값 ) 및 DNI peak( 입원중가장높은 DNI 값 ), 젖산염, APACHE II 점수의수치가높거나, 처음시작한항생제의종류가카바페넴인경우 14일이상재원기간을보일가능성이높음을확인하였다 (p<0.001) (Table 3). 이결과를기반으로하여각변수의영향을보정하기위하여 multivariable Cox regression을시행하였 다. 초기결과와달리연령, 당뇨, 고혈압, 혈액요소질소, WBC 등은통계적으로유의한차이를보이지않았으며, 알부민의경우수치가높을수록 14일내퇴원이가능함을예측할수있음을확인하였다 (p=0.019). 그외에 DNI 1 day( 응급실내원시 DNI 값 ) 및 DNI peak( 입원중가장높은 DNI 값 ) 의경우수치가클수록 14일이상재원기간을가질것으로예측할수있음을확인하였다 (p=0.010 and p=0.001) (Table 4). Contal and O Quigley technique 을이용하여 DNI 값에대한최적의결정점을구하였으며, DNI 1 day 값이 6.3 미만일경우 (HR, 0.314; 95% CI, ; p<0.001), DNI peak 값이 6.3 미만일경우 (HR, 0.266; 95% CI, ; p<0.001) 로가장낮은값을보이는것으로타났다. 그러므로 DNI 1 Day 값이 6.3 이상일경우사건즉, 14일내에퇴원할가능성이떨어진다는것을알수있다. DNI peak 값역시 6.3 이상이면재원기간이 14일이상될가능성이커진다고볼수있다 (Fig. 1). 본연구에서는재원시최대델타뉴트로필값이측정되는시점은전체평균 1.96±1.96 일로나타났다. Receiver operating characteristic curve를이용하여 Area under the ROC curve (AUC) (95% CI) 를구하였으며, 이를통해델타뉴트로필단일인자로서예측력및 Null 모델에 DNI 1 day, DNI peak와함께이용하였을때예측력 Table 3. Univariable cox regression HR (95% CI) p-value Sex ( ) <0.065 Hypertension ( ) <0.001 Diabetes mellitus ( ) <0.013 Renal diseases ( ) <0.175 Shock on admission ( ) <0.127 Age ( ) <0.001 Body temperature ( ) <0.058 Respiratory rate ( ) <0.027 White blood cell ( ) <0.005 Albumin ( ) <0.001 Blood urea nitrogen ( ) <0.001 Creatinine ( ) <0.001 DNI 1 day ( ) <0.001 DNI peak ( ) <0.001 ESR ( ) <0.773 CRP ( )000. <0.017 Lactate ( ) <0.001 APACHE II score ( ) <0.001 Antibiotics type Quinolone Reference (1) Third generation cephalosporin ( ) <0.486 Carbapenem ( ) <0.001 DNI 1 day, DNI value at time of arrival; DNI peak, the highest DNI during hospitalization. HR: hazard ratio, CI: confidence interval, RDW: red cell distribution width, ESR: erythrocyte sedimentation rate, CRP: C- reactive protein

6 418 / 기동훈외 을계산하였다. DNI 1 day 는 ( ), DNI peak는 ( ) 로나타났다 (all p<0.001). Multivariable Cox regression model을이용한경우 AUC 가 Null model의경우 ( ) 을보였으며 (p<0.001), Model 1, Model 2가각각 ( ), ( ) 을보였다 (all p<0.001) (Fig. 2). DNI 단일로서의예측력은각각 0.5보다유의하게나타났으며, Null 모델에 DNI 1 day, DNI peak을각각더한 Model 1, Model 2의경우예측력이더욱높아지는것을확인할수있었다. AUC (95% CI) 에계산된세가지값을서로 비교하여통계학적으로유의한차이가있는지를확인하였으며, Model 1, 2를비교하였을때는 p=0.217로통계학적인차이를보이지않았으나 Null model과 Model 2를비교하였을때는p=0.048로통계학적으로유의한차이를보였으며, 예측력역시최대치를보이는것을확인할수있었다. 따라서 Null model에내원기간에가장높은델타뉴트로필수치를더할경우예측력이최대가됨을확인하였다. 반면에 WBC, ESR, CRP를이용하여 AUC를구하여예측력을각각계산하였을때, 각각 CRP ( ), ESR ( ), 95% CI), WBC ( ) 으 Table 4. Multivariable Cox regression Model 1 Model 2 Variables HR (95% CI) p-value HR (95% CI) p-value Age ( ) < ( ) Respiratory rate ( )0 < ( ) Carbapenem ( ) < ( ) Hypertension ( ) < ( ) DM ( ) < ( ) BUN ( ) < ( ) Creatinine ( ) < ( ) WBC ( ) < ( ) Albumin ( ) < ( ) DNI 1 day ( ) <0.010 DNI peak ( ) DNI 1 day, DNI value at time of arrival; DNI peak, the highest DNI during hospitalization. HR: hazard ratio, CI: confidence interval, DM: diabetes mellitus, BUN: blood urea nitrogen, WBC: white blood cell Univariate Cox regression <0.05 variables (age, respiratory rate, carbapenem) + DNI 1 day Univariate Cox regression <0.05 variables (age, respiratory rate, carbapenem) + DNI peak A Fig. 1. Delta neutrophil index (DNI) as a predictor of hospitalization over 14 days. Our study demonstrated that increased hospitalization over 14 days with DNI 1 day, DNI peak >6.3 (A) hazard ratio, 0.314; 95% confidence interval, ; p<0.001), and (B) hazard ratio, 0.266; 95% confidence interval, ; p<0.001). B

7 Delta Neutrophil Index in Acute Pyelonephritis / 419 A Fig. 2. Receiver operating characteristic curve. (A) Predictive ability of DNI 1 day and DNI peak. (B) Predictive ability of Null model, Null+DNI 1 day (Model 1), and Null+DNI peak (Model 2). B Fig. 3. Receiver operating characteristic curve. Predictive ability of DNI 1 day, DNI peak, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC). 로나타났으며 (p=0.022, p=0.006, and p=0.133), 모두 95% CI의하한이 0.5를포함하고있으므로결과예측의가치가떨어진다고볼수있다. 따라서, 14일이상재원기간예측력이 DNI보다떨어짐을확인하였다 (Fig. 3). 고 요로감염은흔한감염질환중하나이며, 특히고연령군에서는패혈증으로진행하는흔한원인중하나이다. 비록 찰 요로감염에의한사망률은폐렴과같은질환과비교할때높은편은아니지만, 저연령층과비교할때는상대적으로높은사망률을보인다 16,17). 급성신우신염은요로감염의하나로응급실에서자주볼수있는질환중하나이다. 특히여성의경우입원이필요한감염증중흔한원인중하나로대개항생제복용으로완치할수있지만여러가지임상양상에따라패혈증으로이행하여사망까지가능한질환으로환자가패혈증으로진행하는지, 입원이필요한지를정확하게판단하는것이매우중요하다 18-20). 요로감염환자중패혈증으로이행하는경우는연구에따라차이가있으나대략 10%-30% 내외로보이며, 패혈증으로이행한환자에서기타합병증이동반될경우사망률이 40% 가까이된다고알려져있다 21-23). 그러므로많은연구자자가쉽고빠르게급성신우신염에서패혈증으로이행하는것을예측할수있는검사들을찾기위해노력하고있으며, 프로칼시토닌은신우신염에서패혈증으로진행하는것을예측하는검사로서유용성이확인되었다 24). 젖산염에대한연구역시진행되었는데, 패혈증예측인자로서는그다지좋은결과를얻지못하였다 4). CRP 역시패혈증으로진행하는것을예측하는인자로서는부족하지만, 14일이상재원기간이늘어나는경우와재발할경우를예측하는데있어서유용성이있다는연구가있었다 25). 중증도예측을위해 DNI 분석이임상적으로유용한점은백혈구감별계산 (leukocyte differential count) 과동시에진행되므로추가적인채혈이나검사시간, 비용추가가없이도정보를얻을수있다는점이며, 전골수구 (promyelocyte) 등의미성숙과립구들을반영하므로주로감염시에증가하게된다. 이를바탕으로최근에는다양한감염증에서 DNI과사망률의관련성이연구되었으며, 유용성이확인되었다 10,26,27). 특히패혈증환자에서 DNI과좋지않은예후와의연관성이있다

8 420 / 기동훈외 는연구가있었으며, 이때 CRP, 젖산염보다델타뉴트로필이더예측력이좋은표지자로보고하였으며, 이연구에서제시한델타뉴트로필의최적결정점은 6.5였다 10). 급성담관염환자군에서 DNI과사망률의관련성을연구한것에서는델타뉴트로필의최적결정점이 4.9로나타났다 27). 본연구에서는 DNI 1 day 값이 6.3 미만일경우 (HR, 0.314; 95% CI, ; p<0.001), DNI peak 값이 6.3 미만일경우 (HR, 0.266; 95% CI, ; p<0.001) 로가장낮은값을보이는것으로나타났다. HR에따라 DNI 값이높을수록 14일이내에퇴원하지못하는확률이증가하는것으로해석할수있으므로 6.3 이상일경우 14 일이상재원가능성이높음을알수있었다. 재원일수가증가함에따라감염환자의이환율이증가한다는보고가있었으며, 이에따르는합병증역시증가하는것으로나타난보고가있었다 5). 따라서 14일이상재원가능성을예측하는것을통해중증도를간접적으로예측할수있을것이다. DNI의경우일반혈액검사로자동으로시행되는검사이며검사시간도짧은장점이있다. 본연구결과에따르면내원시 DNI 보다가장높은값일때더좋은예측력을보였으며, 이는반복적인일반혈액검사에의해얻어진결과로환자의상태변화를 DNI 수치가반영하고있음을알수있다. 본연구에서는재원시최대 DNI 값이측정되는시점은전체평균 1.96±1.96 일로나타났다. 타연구에서최대 DNI 값이측정되는시점은 2.5±2.0으로나타났다 14). 충분히많은수의연구자료는아니지만, DNI 값이대략 2 일에서 4일사이에최대치를나타내므로재원시연속적인검사를통해. 최대치를예측하는데도움을줄수있을것이다. DNI 재검시간에참조할수있을것으로보인다. 응급실과같은환경에서는빠르고편리한것이중요한요소이며, 장기재원을예측할수있는독립적인인자이므로임상적으로의미가있다. 또한, 입원후에도 DNI 값을 CBC를통해얻을수있으며, 이를통해환자의재원기간이늘어날지를예측할수있으므로환자의입퇴원의사결정에도움이될것으로보인다. 예를들어화학검사가쉽지않은환경이나, 경한증세의환자에서 DNI이높게측정된다면입원기간이길어질수있는환자임을인식하고추가검사및의사결정에있어도움이될수있을것이다. 이번연구는후향적연구로시행되어몇가지제한점들이있다. 첫째, 후향적연구로선택바이어스 (selection bias) 의가능성이존재한다. 모든검사를프로토콜에따라진행하지는못하였으므로이것이결과에영향을주었을가능성이있다. 둘째, 결과에영향을줄수있는요인들을모두통제하지못하였을가능성이존재한다. 항생제사용이나타병원에서의자료등본원응급실전단계치료에대한정보가부족하므로이런요소들이결과에영향을주었을가능성을배 제할수없다. 셋째, 내원시 DNI 값은내원시간기준으로보았을때모든환자가동일하나재원시최고 DNI 값은정확하게언제가될지예측하기어려우며반복적인검사를통해야만알수있는값이므로한계가있다. 다만위에서언급한대로 2일에서 4일사이에최고값이나타날가능성이높으므로이에유의하여검사를반복적으로진행되어야하나본연구는후향적연구이므로검사시점이환자마다일정하지않은한계를가지고있다. 특히, 환자의상태가양호할수록검사의반복이적으므로최대값의시점이달라질가능성이더욱높다고볼수있다. 넷째, 우리연구에서 14일이상재원기간의연장과 DNI 과의연관성을확인하였으나, 해당질병을가진환자의장기간의임상경과를확인할수없었으며, 예후를예측하는것은사망률을기준으로하는것이본연구에서는사망률이 1% 미만으로나타나대상군의수가적어사망률에대한비교를할수없었다. 또한사망률및이환율에직접적으로영향을줄수있는폐혈성쇼크여부에따라환자를분류하여통계적유의성을확인하려하였으나폐혈성쇼크로진행한환자수가그렇지않은환자에비해적어 (35명) 회귀분석등을진행하기어려운점이있었다. 따라서 DNI 이급성신우신염환자에서사망률및폐혈성쇼크로진행하는것과어떤연관성이있는지알기위해서는추가적으로전향적다기관연구가진행되어야할것으로보인다. 결 DNI은쉽고빠르게측정이가능한검사로서급성신우신염환자에서 14일이상재원여부를예측을통한중증도예측의독립인자로서의미가있다. 따라서초기 DNI이높게평가된환자는추가적인검사나입원의고려가필요할것이며, 재원후에도반복적인검사를통해재원기간의예측에도움이될수있을것이다. 론 References 01. Foxman B, Klemstine KL, Brown PD. Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality. Ann Epidemiol. 2003;13: Ki M, Park T, Choi B, Foxman B. The epidemiology of acute pyelonephritis in South Korea, Am J Epidemiol. 2004;160: Peschanski N, Chenevier-Gobeaux C, Mzabi L, Lucas R, Ouahabi S, Aquilina V, et al. Prognostic value of PCT in septic emergency patients. Ann Intensive Care. 2016;6: Seo DY, Jo S, Lee JB, Jin YH, Jeong T, Yoon J, et al.

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon