pissn: 2288-0402 eissn: 2288-0410 4(1):55-60, January 2016 http://dx.doi.org/10.4168/aard.2016.4.1.55 ORIGINAL ARTICLE 소아폐렴환자에서혈중 procalcitonin 을이용한항생제사용결정과임상적결과의비교분석 안세진, 1 배성필, 2 박준수, 2 최영진, 3 임한혁, 1 이재호 1 1 충남대학교병원소아과, 순천향대학교천안병원 2 소아과 3 진단검사의학과 Antibiotic therapy decision and clinical outcome comparison based on serum procalcitonin in children with pneumonia Se Jin An, 1 Sung Phil Bae, 2 Joon Soo Park, 2 Young Jin Choi, 3 Han Hyuk Lim, 1 Jae Ho Lee 1 1 Department of Pediatrics, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon; Departments of 2 Pediatrics and 3 Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea Purpose: It is difficult to differentiate between viral and bacterial pneumonia in children and to decide antibiotic therapy. Study was conducted to investigate the clinical usefulness of antibiotic therapy based on procalcitonin (PCT) in children diagnosed with viral pneumonia. Methods: This study included 108 patients diagnosed with viral pneumonia. Patient s age, fever duration, hospital stay, and treatment progress were noted, and laboratory study including PCT levels were tested. In addition, Polymerase chain reaction was done to test for viruses. Patients were divided into PCT and non-pct groups according to PCT level. And their clinical patterns, treatment outcome, antibiotic use, severity of complications were compared. Results: The number of patients with respiratory syncytial virus (RSV) was 35 and 50, rhinovirus was 5 and 10 in PCT and non-pct groups, respectively. Fever duration was longer by 2.5 days in PCT group than in the non-pct group (P< 0.001), but there was no difference in the duration of hospital stay (P= 0.191). White blood cell and absolute neutrophil count levels were higher in the PCT group (P= 0.013 and P< 0.001, respectively). Use of antibiotic therapy was performed in group was on 22% and 90% of patients in the PCT and non-pct groups, respectively showing a significant reduction in the frequency of antibiotic therapy in PCT group, without a significant difference in treatment outcome, despite more severe clinical signs (P< 0.001). Conclusion: Antibiotic therapy based on serum PCT levels in children admitted for pneumonia can reduce the frequency of antibiotic therapy in viral pneumonia, without causing significantly different treatment outcome or complications. (Allergy Asthma Respir Dis 2016;4:55-60) Keywords: Procalcitonin, Pneumonia, Child, Antibiotics 서론 Procalcitonin (PCT) 은여러세균성감염을시사하는생화학적표지자로부각되면서, 여러성인연구를중심으로중증또는세균성감염환자의항생제치료전략을수립하는데이용되고있다. 1 116개의아미노산으로구성된 PCT은칼슘조절호르몬인칼시토 닌의전구물질로서건강한사람의혈액에는매우낮은농도로존재하며 (< 0.05 ng/ml), 호르몬으로서의기능은거의없다. 2,3 칼시토닌은갑상선의 C 세포에서호르몬자극을받아생성되지만, PCT 은세균성감염에서전-염증성자극에의해갑상선이외의여러세포와기관에서생성되고혈액에유리되는기전으로세균성감염의진단에유용하게이용된다. 4 Correspondence to: Jae Ho Lee http://orcid.org/0000-0003-4269-8411 Department of Pediatrics, Chungnam National University Hospital, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea 2016 The Korean Academy of Pediatric Allergy and Respiratory Disease Tel: +82-42-280-7247, Fax: +82-42-255-3158, E-mail: immlee@cnu.ac.kr The Korean Academy of Asthma, Allergy and Clinical Immunology This study was supported by Basic Science Research Program through the National Research Foundation of This is an Open Access article distributed under the terms of the Creative Korea (NRF) funded by the Ministry of Education, Science and Technology (2014-046686). Commons Attribution Non-Commercial License Received: July 10, 2015 Revised: September 21, 2015 Accepted: October 1, 2015 (http://creativecommons.org/licenses/by-nc/4.0/). 55 http://www.aard.or.kr
An SJ, et al Serum procalcitonin in children wirh pneumonia 세균성감염에대한정확하면서시기가적절한진단방법은없는실정이다. 따라서세균성감염을진단하기위해여러검사나표지자를사용하고있지만그중배양법의경우결과확인까지시간이오래걸리고, 혈액배양법은민감도가낮고, 객담배양검사는특이도가낮으며, 폐조직검사는침습적인방법이고혈액검사중적혈구침강속도 (erythrocyte sedimentation rate, ESR), C-reactive protein (CRP), 백혈구 (white blood cell, WBC) 가염증지표로사용되나특이도가낮은문제점이있다. 5 또한감염에있어서바이러스, 세균, 진균과같은원인병원체를임상증상만으로구별하는것은어렵다. 특히세균성감염이의심되는경우이를확인할정확하고신속한검사방법이없어항생제를남용하는경우가많다. 6 소아의급성기관지염, 폐렴, 급성세기관지염같은하기도질환은바이러스성과세균성감염의감별이힘들기때문에임상의의판단에따라항생제치료를하게되는경우가있고, 이로인한항생제남용은소아하기도감염의치료에서흔히고민되는문제이다. 6 불필요한항생제사용은설사, 오심, 구토, 복부통증, 피부발진같은부작용뿐만아니라, 항생제내성균이발생하는원인중하나이다. 6-8 여러성인의호흡기감염연구에서 PCT에근거한항생제치료선택을하였을때항생제사용의빈도를의미있게줄일수있음이보고되었다. 9-11 그러나, 소아호흡기감염을대상으로한 PCT에관한연구는적으며, PCT를이용한적절한가이드라인도정립되지않은실정이다. 이에저자들은 PCT을활용한항생제치료지침을정하고, 이치료지침을통해소아폐렴환자를치료하였을때, 치료의효과와항생제사용정도에차이가있는지그의의를알아보고자하였다. 대상및방법 1. 연구대상 2012년 10월 1일부터 12월 30일까지충남대학교병원과순천향대학교천안병원소아청소년과에하기도감염으로입원하여치료를받은환자 181명을대상으로하였다. 그중, 연구기간동안바이러스호흡기감염이빈발하였던시기로, 두군간의환자군을최대한동질적으로비교하기위해바이러스성폐렴으로확진된 108명 ( 남자 63명, 여자 45명 ) 을최종대상으로분석하였다 (Fig. 1). 바이러스성폐렴의진단기준은 (1) 발열 (38 C 이상 ) 및호흡기계증상 ( 기침, 가래 ) 의존재 ; (2) 수포음, 나음의확인 ; (3) 흉부 x-ray 검사상폐침윤의확인 ; (4) 바이러스 polymerase chain reaction (PCR) 검사에서동정된바이러스의확인이며, 위 4가지를모두만족하는경우의환자를대상으로하였다. 배제기준은 (1) 1개월미만의신생아나 18세이상인환자 ; (2) 바이러스 PCR 검사에서균주가확인되지않은경우 ; (3) 발열이없는폐렴 ; (4) 입원전항생제를 사용한경우 ; (5) 세균성감염의증거 ( 객담및혈액, 소변, 인후도말 배양검사에서양성 ); (6) 엽성폐렴이나농흉 ; (7) 마이코플라즈마 현성감염확인 (IgM 양성또는연속으로측정한 IgG titer 의 4 배이 상상승 ); (8) 중이염, 부비동염의호발또는병발 ; (9) 기저질환의존 재 ; (10) 스테로이드를포함한면역조절제또는억제제등의약물사 용중, 한가지이상존재하는환자는배제하였다. 이연구는치료방 침과자료수집에대해환자와보호자의동의를구하였으며, 임상 연구심의위원회의승인을받았다. 2. 연구방법 대상환자들은입원당일검사한 PCT 수치에따라항생제치료 여부를결정한군 (PCT 군, 충남대학교병원 ) 과, 입원하였을때 WBC, CRP 를포함한혈액검사와임상증상을통해임상의의판단 에따라항생제치료여부를결정한군 (Non-PCT 군, 순천향대학교 병원 ) 으로구분하였다. 의무기록을토대로혈액검사, 균동정검사, 항생제사용유무, 임상증상, 병의경과와합병증등을조사하였다. 1) 수정된 PCT- 가이드라인항생제치료전략 PCT 를이용한항생제가이드라인은본원의이전연구 12 와여러 저널 13,14 에서보여준치료전략을수정변형하였다. 이전본원에서 시행한연구 12 에서항생제사용을제한하는결정값으로제안한 0.11 ng/dl 를기준으로 0.11 ng/dl 이하에서는항생제치료를시작 하지않았고, 0.11 0.15 ng/dl 에서는항생제치료고려및다른임 상양상과같이고려하여결정하도록하였고 0.5 ng/dl 이상에서는 항생제치료를시작하도록하였다 (Fig. 2). 2) 의무기록분석 181 Patients with pneumonia 47 PCT group 61 Non-PCT group 73 Excluded: Mixed infection: AOM, sinusitis Mycoplasma infection Bacterial: culture (+) History: premature, RDS Mild case: patient wanted admission. Fig. 1. Trial profile. AOM, acute otitis media; RDS, respiratory distress syndrome; PCT, procalcitonin. 입원당일환자의나이, 성별, 임상증상등에대한병력조사와 흉부 x 선검사결과를조사하였고, 입원중발열기간, 입원기간, 산 소치료, 중환자실치료와같은치료경과와결과에대한조사를하 56 http://dx.doi.org/10.4168/aard.2016.4.1.55
안세진외 소아폐렴환자에서혈중 procalcitonin 의유용성 Procalcitonin guided antibiotics therapy algorithm PCT<0.11 μg/l -Antibiotics :Strongly discourage antibiotics :Supportive care PCT, 0.11 0.5 μg/l -Antibiotics :Consider antibiotics therapy :Encourage antibiotics PCT>0.5 μg/l -Antibiotics :Antibiotics therapy :Strongly encourage antibiotics Fig. 2. Modified procalcitonin (PCT) guided antibiotics therapy. 였다. 3) 생화학적지표분석입원초기에환자의정맥에서혈액을채취하여감별백혈구계산을포함한전혈구검사, ESR, CRP, PCT를검사하였다. PCT는전혈을 3,000 rpm에서 20분간원심분리하여혈청을분리하였고, VIDAS (BRAHMS PCT, biomerieux, Marcy L Etoile, France) 를이용한효소면역측정법 (enzyme-linked fluorescent immunoassay) 으로정량측정하였다. 4) 원인균주의동정원인균확인을위해입원초기에혈액배양검사, 객담배양검사, 인후부도말검사, antistreptolysin (ASO) 검사를실시하였다. 비전형폐렴균인마이코플라즈마에의한감염을확인하기위해마이코플라즈마항체검사로 IgM 검사를시행하였고, 바이러스를확인하기위해비인두분비물을흡입하여서 Seeplex RV Detection kit (Seegene, Seoul, Korea) 를이용하여바이러스다중역전사중합효소연쇄반응검사방법으로, 호흡기중합체바이러스 (respiratory syncytial viruses A and B), 인플루엔자바이러스 (influenza viruses A and B), 파라인플루엔자바이러스 (parainfluenza viruses 1, 2, 3), 아데노바이러스 (adenovirus), 리노바이러스 (human rhinovirus), human metapneumovirus 및코로나바이러스 (corona viruses OC43, 229E/NL43) 를확인하였다. 3. 통계분석통계분석은 IBM SPSS Statistics ver. 20.0 (IBM Co., Armonk, NY, USA) 을사용하였고, 환자의나이, 성별, 발열기간, 입원기간및혈액검사는평균과표준편차로표시하였고, PCT군과 Non- PCT군의평균치비교에는 t-test를사용하였으며항생제사용에대한분석및그결과에대한비교에는 chi-square test 및 odds ratio (OR) 를사용하였다. 신뢰구간은 95% 로정하였고, 유의수준은 P 값이 0.05 미만인경우로정의하였다. Table 1. Information of children with pneumonia Variable PCT group (n= 47) Non-PCT group (n= 61) P-value Age (yr), mean (range) 1.4 (0.1 8.1) 0.8 (0.1 13.4) 0.139 Sex Male:female 27:20 36:25 0.870 Pathogen* RSV A 31 43 RSV B 4 7 Rhinovirus 5 10 Adenovirus 2 0 Coronavirus 0 1 Parainfluenza 4 0 Influenza B 1 0 P-values were analyzed by chi-square test. PCT, procalcitonin; RSV, respiratory syncytial virus. *Pathogens included combined isolation of viruses. 결과 1. 연구대상환자의임상적특성 총 181 명의환자중에서 73 명의환자가입원하였을때다른세균 감염의증거가있거나기저질환이있는경우및입원전항생제치 료여부등에따라배제되었고 PCT 군환아는 47 명 Non-PCT 군환 아는 61 명이최종선정되었다. A 군과 B 군의환아평균연령은각각 1.4 세, 0.8 세였고 (P = 0.116), 남녀성비는각각 27:20, 36:25 명으로 유의한차이는없었다 (P = 0.871). 원인이확인된바이러스로는 PCT 군과 Non-PCT 군에서 RSV A 는각각 31 명, 43 명, RSV B 는각각 4 명, 7 명, rhinovirus 는각각 5 명, 10 명, adenovirus 는각각 2 명, 0 명, coronavirus 는각각 0 명, 1 명, parainfluenza virus 각각 4 명, 0 명, influenza B virus 는각각 1 명, 0 명이었다 (Table 1). 2. 두그룹간의임상양상및실험실결괏값의차이 PCT 군과 Non-PCT 군각각에서발열의기간은 3.7±2.5 일과 1.2 ±0.5 일로 PCT 군이 Non-PCT 군보다 2.5 일많아유의한차이가있 http://dx.doi.org/10.4168/aard.2016.4.1.55 57
An SJ, et al Serum procalcitonin in children wirh pneumonia Table 2. Clinical and laboratory differences in children with viral pneumonia according to procalcitonin-guideline antibiotic therapy Variable PCT group (n= 47) Non-PCT group (n= 61) P-value Duration of fever 3.7± 2.5 1.2± 0.5 < 0.001 Length of hospital stay (day) 6.9± 2.1 7.8± 4.5 0.191 White blood cell (/mm 3 ) 10,962± 4,153 9,177± 3,169 0.013 ANC (/mm 3 ) 5,012± 2,974 2,283± 1,860 < 0.001 CRP (mg/dl) 1.43± 1.25 1.28± 1.09 0.508 Values are presented as mean± standard deviation. P-values were analyzed by chisquare test. PCT, procalcitonin; ANC, absolute neutrophil count; CRP, C-reactive protein. Table 3. Clinical outcomes in patients receiving antibiotic therapy based on procalcitonin or standard guidelines Variable Odds ratio 95% CI P-value Antibiotic overuse 0.033 0.011 0.098 < 0.001 Oxygen supply 0.352 0.107 1.151 0.075 ICU care 0.951 0.898 1.007 0.176 P-values were analyzed by chi-square test. CI, confidence interval; ICU, intensive care unit. 었으나 (P<0.001), 입원기간은각각 6.9±2.1 일과 7.8±4.5 일로유 의한차이가없었고 (P = 0.191), WBC (P = 0.013) 및 absolute neutrophil count (P<0.001) 는 PCT 군이높았고유의한차이가있었으 나 CRP 는양군간의유의한차이가없었다 (P = 0.508) (Table 2). 3. 연구두그룹간의항생제사용에따른임상적결과양상 PCT 가이드라인에따른 PCT 군에서는 47 명중 10 명은항생제 치료하였고, PCT 검사를하지않았던 Non-PCT 군에서는환아 61 명중 55 명에서항생제치료를하였다. 따라서 PCT 군과 Non-PCT 군에서의항생제사용의비율을보면 PCT 군에서는 22%, Non- PCT 군에서는 90% 에서항생제를사용하여더중한임상지표에도 불구하고 PCT 군에서항생제사용을의미있게줄일수있었다 (OR, 0.033; 95% confidence interval, 0.011 0.098; P < 0.001) (Fig. 3). PCT 군과 Non-PCT 군간의임상경과나예후와의비교를위해 산소공급유무나중환자실치료가필요했는지에대해평가하였 고, 각군에서산소공급 (P = 0.075) 이나중환자실치료 (P = 0.176) 정도는통계학적차이가없었다 (Table 3). 고찰 1993 년에 Assicot 등 4 이세균감염에서초기염증표지자로혈청 PCT 를제안한이후, PCT 은전신성염증반응및패혈증등의세균 성감염의표지자로이용되고있다. 15-17 PCT 은칼슘조절호르몬인 칼시토닌의전구체로심한세균성감염에서현저히증가하는데, 18 미생물독소 ( 예, 내독소 ) 들을통해서직접적으로염증반응을일으 Antibiotic use (%) 100 90 80 70 60 50 40 30 20 10 키거나간접적으로는체액성면역반응이나세포성면역반응들을 통해 interleukin (IL) 1, tumor necrosis factor-α, IL-6 등을유도하 여증가하는것으로알려져있다. 16 이러한 PCT 의사이토카인양특 징으로 Hormokines 로불리기도한다. 19 고전적인염증매개인자인 CRP 등이세균성감염성질환의진단 에사용되지만, 특이성및질환의중증도와의연관성에한계가있 는문제점이있다. 5 반면 PCT 은감염후초기에상승하는특징이 있으며, 20 중증의바이러스감염에도변화가거의없거나경미한상 승만보이는특징이있어, 세균성감염의조기평가를위해활용될 수있다. 따라서최근 PCT 를이용하여하부호흡기감염과지역사 회획득폐렴에서의항생제치료와그기간을결정하는데이용하 려는시도들이많다. 9,19 0 PCT group Non-PCT group Fig. 3. Antibiotic use according to PCT-guidance strategy in children with viral pneumonia. The PCT group significantly showed lower rate of antibiotic use than non-pct. PCT, procalcitonin. 이전문헌들에서성인을대상으로하부호흡기질환을치료하는 데있어서 PCT 값에따라 4 개의군으로나누어항생제사용을조 절하였을때, 기존의질환치료군에비해서항생제의사용빈도와 사용기간을의미있게줄일수있었고치료결과도기존의치료군 과차이가없었음을보고하였다. 1,9 다른성인호흡기감염연구에서 도항생제치료에대한지표로 PCT 수치가세균감염일때증가하 였다가회복기에는감소하는양상을보여항생제사용에있어지 표로유용하게사용할수있을것이라고주장하였다. 21,22 또한, 호흡 기감염으로입원한환자에서입원부터 4 시간까지 PCT 수치가낮 은경우세균감염에대해뛰어난음성예측도를보였고, 초기항생 제사용의빈도와기간을줄이는효과가있었다고한다. 23 소아에서세균성폐렴의표지자에대한가능성으로 PCT 의값 을측정한여러연구들이있었지만연구결과들이일치하지는않 았다. 세균성호흡기감염에서 CRP 와높은 PCT 값이유의한상관 관계를보이면서항생제치료에도움을주었다고하였으며, 24 또다 른연구에서는 CRP 는다양한감염질환에서좋은지표로사용될 수있으나세균과바이러스감염을구별하는데사용할수는없었 58 http://dx.doi.org/10.4168/aard.2016.4.1.55
안세진외 소아폐렴환자에서혈중 procalcitonin 의유용성 고 PCT 측정이소아폐렴에서원인을진단하는데유용한방법이될수있다고발표하였다. 25,26 앞의 3개의연구에서는 PCT 값이 CRP 값보다더나은표지자로보고하였으나다른 4개의소아대상으로한연구에서는 PCT 값이높을수록민감도나특이도가증가하긴하지만의미있게세균성폐렴과바이러스성폐렴을구별하는데도움이되지않는다고보고하기도하였다. 27-30 본원에서의이전연구에서 12 바이러스와세균감염을구별하는데 receiver operating characteristics 곡선을사용하여 PCT 0.11 ng/ml의혈청값을 cutoff 값으로설정하였었고이기준값으로 PCT 값이높은군에서항생제사용이환자들의입원기간및입원후발열기간을호전시키는데도움을주는것을보여, PCT의사용이앞으로소아하기도호흡기감염에서불필요한항생제사용을감소시키는데기여할것으로보고하면서이번논문에서도참고값으로사용하게되었다. 따라서, 이번연구에서는저자들은비슷한규모의대학병원에서하기도감염으로입원한환아에서바이러스감염과세균감염의감별전 PCT을기준으로항생제치료결정을한곳과그외의고식적인방법으로항생제치료결정을한그룹간의비교를하였고두병원간의환자군들을최대한동질하게하기위해폐렴으로치료한환자중바이러스폐렴으로확진된환자만대상으로하였다. PCT군에서는혈청 PCT 값이 0.11 ng/ml보다낮은군에서는항생제사용을하지않았고 PCT 값이 0.11 0.5 ng/ml에서는다른요소들을고려해세균성감염이의심될때항생제사용을고려하였었고 PCT 값이 0.5 ng/ml 이상에서는항생제치료를하기로하였다. 연구결과를통해혈청 PCT 값을통해바이러스와세균감염을구별하는데활용하여바이러스성의하기도감염에서항생제사용을줄일수있었음을볼수있었고, 입원기간은차이가없었으며, 임상경과도큰차이가없어두군간의치료에따른예후의차이가없음을알수있었다. 두군의비교에서오히려고식적인치료군인 non-pct 군에서임상적지표가더경해보였으나항생제를더적극적으로사용하게되었던것을알수있었다. 그러나, PCT의값이낮은수치가항상세균감염을배제할수는없으며 31 패혈증환자에서 PCT의값이낮은경우도있다는보고도있으며 32 게다가, 바이러스폐렴환자에서치료중이차세균감염이일어날수도있으므로소아의폐렴환자에서치료할때에는다른염증지표뿐만아니라임상적인평가가완전히이루어져야하는것을항상고려해야하겠다. 이번연구의제한점은연구대상의수가적으며, 다기관연구가아니라는점, 두기관의환자의성격이나중등도의직접적비교에한계가있다는점이다. 그리고이연구는이중맹검에의한치료전략을사용하지않은전향적연구이며, 입원해있는동안 PCT를연속적으로확인하여항생제치료종료를결정하지못했고, 그리고, 두병원의환자군을동질하게비교하기위해바이러스폐렴에만한 정해서분석하여세균성폐렴에대해서는비교하지못했다는제한 점이있다. 결론적으로본연구를통해소아에서폐렴으로입원하였을때, 기존의 PCT 을사용하지않은고식적치료방침과비교하여 PCT 를 이용한항생제치료방침이임상경과나예후에대한차이는없으면 서바이러스폐렴에서항생제오남용을줄일수있음을알수있었 다. 추후이러한 PCT 가이드라인치료전략이항생제오남용을막 고내성균의감소에도의미있는역할을할수있는지다기관연구 를통한장기적인연구가지속되어야하겠다. REFERENCES 1. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004;363:600-7. 2. Deis JN, Creech CB, Estrada CM, Abramo TJ. Procalcitonin as a marker of severe bacterial infection in children in the emergency department. Pediatr Emerg Care 2010;26:51-60. 3. Schuetz P, Christ-Crain M, Albrich W, Zimmerli W, Mueller B; ProHOSP Study Group. Guidance of antibiotic therapy with procalcitonin in lower respiratory tract infections: insights into the ProHOSP study. Virulence 2010;1:88-92. 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. Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med 2011; 9:107. 6. Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, Ruuskanen O. Differentiation of bacterial and viral pneumonia in children. Thorax 2002; 57:438-41. 7. Ashworth M, Charlton J, Latinovic R, Gulliford M. Age-related changes in consultations and antibiotic prescribing for acute respiratory infections, 1995-2000. Data from the UK General Practice Research Database. J Clin Pharm Ther 2006;31:461-7. 8. Don M, Valent F, Korppi M, Canciani M. Differentiation of bacterial and viral community-acquired pneumonia in children. Pediatr Int 2009;51: 91-6. 9. Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006;174: 84-93. 10. Muller B, Christ-Crain M, Nylen ES, Snider R, Becker KL. Limits to the use of the procalcitonin level as a diagnostic marker. Clin Infect Dis 2004; 39:1867-8. 11. Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012;55:651-62. 12. Lim HH, Kang HJ, Yang EA, Lee JH. Clinical usefulness of procalcitonin as guideline of antibiotic treatment in children with respiratory tract infection. Pediatr Allergy Respir Dis 2012;22:110-5. 13. Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kuhn F, et http://dx.doi.org/10.4168/aard.2016.4.1.55 59
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