pissn 2508-4887 eissn 2508-4895 Original article Vol. 29, No. 3, September, 2018 The Effect of Macrolide Therapy on Bronchopulmonary Dysplasia in Ureaplasma- Positive Very Low Birth Weight Infants Soohyun Kim, MD*, Chae Young Kim, MD*, Euiseok Jung, MD, Heeyoung Kim, CHAPN, PhD, Woo Sun Song, MD, Byong Sop Lee, MD, PhD, Ellen Ai-Rhan Kim, MD, PhD, Ki-Soo Kim, MD, PhD Department of Pediatrics, Asan Medical Center Children s Hospital, University of Ulsan College of Medicine, Seoul, Korea *These authors contributed equally to this work. Received: 13 March 2018 Revised: 3 May 2018 Accepted: 19 May 2018 Correspondence to Euiseok Jung, MD Division of Neonatology, Department of Pediatrics, Asan Medical Center Children s Hospital, 88 Olympic-ro 43- gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-3372 Fax: +82-2-3010-7302 E-mail: euisjung@amc.seoul.kr Copyright 2018 by The Korean Society of This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ license/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original work is properly cited. Objective: Ureaplasma has been demonstrated the cause of short and long-term morbidities of preterm infants, especially such as bronchopulmonary dysplasia (BPD). This study aims to evaluate the influence of Ureaplasma on neonatal morbidities and the effect of macrolide treatment in very low birth weight (VLBW) infants. Methods: We performed a retrospective review of clinical records of VLBW infants born between 2015 and 2016. Their endotracheal aspirate and gastric juice were obtained immediately after birth and tested for Ureaplasma. Therapeutic macrolides were administered according to the clinical judgment, not routinely, in Ureaplasma-positive infants. Neonatal morbidities were compared using individual matching analysis between Ureaplasma-positive and negative groups, and with macrolides administration. Results: A total of 144 infants with the mean (±standard deviation) gestational age of 28 +3 (±3 +3 ) weeks and birth weight of 1,051.9 (±290.0) g were included, and 30 (20.8%) were Ureaplasma-positive. Ureaplasma-positive group was associated with higher incidence of respiratory distress syn drome (RDS, P=0.039) and severe neurologic injury (SNI; intraventricular hemorrhage grade 3 or periventricular leukomalacia, P=0.013). However, Ureaplasma-positive group was not associated with the risk of BPD (P=0.706). In the subgroup analysis for Ureaplasma-positive infants, there was no difference in the incidence of morbidities according to the macrolides administration. Conclusion: Although Ureaplasma has no independent role in the development of BPD, Ureaplasmapositive VLBW infants were more likely to have RDS and SNI. The macrolides administered in Ureaplasma-positive was not effective to reduce neonatal morbidities. Key Words: Ureaplasma, Macrolides, Very low birth weight infant, Respiratory distress syndrome, Intraventricular hemorrhage 서론 최근신생아의료기술의발전으로생존가능한미숙아의재태연령은낮아지고, 출생체 중 1,500 g 미만의극소저출생체중아의생존율은급속히증가하였다. 1,2 따라서이들의신경 학적발달과장기적예후의중요성이커지고있다. 하지만산전스테로이드사용과폐표면 활성제투여및새로운기계환기치료등의다각적노력에도불구하고, 미숙아의주요이환 율인기관지폐이형성증 (bronchopulmonary dysplasia, BPD) 의빈도는크게감소하지못하 였다. 3,4 BPD 는기관마다차이는있지만, 재태나이 28 주이하의미숙아에서약 30% 의발생 률을보이며, BPD 에이환된미숙아들은동반된합병증으로중증의폐동맥고혈압과성장 부전과같은장기적인후유증을경험하고, 중증 BPD 에의하여사망까지이르게된다. 4,5 BPD 는자궁내염증등에의한출생전태아폐손상과, 출생후감염과장기간의기계환기요 법적용등여러원인에의한폐손상으로발생한다. 3-5 특히, 출생전자궁내감염은자궁내 염증의중요한위험인자로알려져있으며, 6,7 이를일으키는원인균중, 유레아플라즈마
Kim S, et al. Ureaplasma-positive VLBW infants and macrolide therapy (Ureaplasma) 는약 80% 의산모에서생식기에상재하는, 조산과관련하여양수와태반으로부터가장흔히획득되는균이다. 6,7 유레아플라즈마와연관된미숙아폐손상에대해서는그동안상반되는연구가보고되어왔다. 유레아플라즈마가미성숙한폐의조기섬유화를유발함으로써폐포화를방해하여 BPD를야기하기때문에, 8-10 이에대한출생후마크로라이드 (macrolide) 항생제를이용한제균치료가 BPD의유병률을감소시킨다는연구와 10 유레아플라즈마가 BPD의병인과는관련이없으며, BPD 발생에대한유레아플라즈마제균치료의효과가없다는연구들도존재한다. 11,12 그리고 BPD라는미숙아폐질환과별개로유레아플라즈마가미숙아의다른주요이환율에도영향을줄수있다는연구들이보고되고있다. 유레아플라즈마양성의미숙아들에서괴사성장염 (necrotizing enterocolitis, NEC) 의발병률이 2배증가되며, 13 뇌실내출혈 (intraventricular hemorrhage, IVH) 의위험도는 2.3배증가되었다. 14 따라서저자들은극소저출생체중아에서유레아플라즈마양성이 BPD를포함하여주요이환율에미치는영향및유레아플라즈마양성에대한마크로라이드항생제투약의효과에대해알아보고자하였다. 대상및방법 1. 대상본연구는 2015년 1월부터 2016년 12월까지서울아산병원에서출생하여신생아중환자실에입원한출생체중 1,500 g 미만의출생아중에서, 예방적으로마크로라이드를투여한산모에게서출생한극소저출생체중아를대상으로하였다. 출생후유레아플라즈마에대한배양검사나중합효소연쇄반응 (polymerase chain reaction, PCR) 을시행하지않은경우, 선천성기형및염색체이상이있는경우와 BPD의중증도를진단할수없었던월경후나이 36주이전에사망한경우는연구대상에서제외하였다. 연구는서울아산병원의임상연구윤리위원회의승인하에의무기록을후향적으로분석하여진행하였으며동의서는면제되었다 (S2018-0346-001). 2. 방법연구대상의임상적특성으로는재태나이, 출생체중, 성별, 분만형태, 산모의조기양막파수, 전자간증, 융모양막염, 자궁내성장지연, 출생전스테로이드사용, 출생후유레아플라즈마검출유무를비롯하여, 신생아호흡곤란증후군 (respiratory distress syndrome, RDS), 동맥관개존증 (patent ductus arteriosus, PDA), NEC, BPD, IVH, 뇌실주위백질연화증 (periventricular leukomalacia, PVL), 미숙아망막증 (retinopathy of prematurity, ROP) 과지연성패혈증 (late-onset sepsis, LOS) 을조사하였다. BPD는미국국립보건원에서제시한기준 (National Institute of Child Health and Human Development criteria) 15 을사용하여, 출생후최소 28일이상산소치료를시행한경우로월경후나이 36주이후에도흡입산소분압 (fraction of inspired oxygen, FiO 2 ) 0.3 미만의산소가필요한경우는중등도로, FiO 2 0.3 이상의산소나양압환기요법이필요한경우를중증으로정의하였다. BPD의치료를목적으로하는출생후스테로이드투여시에는덱사메타손 (dexamethasone) 이사용되었다. 출생전스테로이드사용은분만전한번이라도투여된경우로산정하였다. 한편, 치료가필요한 PDA는심초음파로동맥관을통한좌우단락을보이며, 이로인한임상증상으로이부프로펜 (ibuprofen) 투약과같은내과적치료혹은동맥관결찰술과같은수술적치료를받은경우로구분하였다. NEC는 Bell의분류 16 에따라 2도이상의경우로하였다. 심각한신경학적손상 (severe neurologic injury, SNI) 은 Papile의분류 17 에서 3도이상의 IVH이거나 PVL이발생한경우로정의하였다. ROP는안과전문의의판단에따라레이저치료가필요한경우를, LOS는한국신생아네트워크 (Korean Neonatal Network) 기준에따라출생 7일이후혈액배양검사에서균이동정되는경우 18 산정하였다. 극소저출생체중아의유레아플라즈마양성여부를확인하기위하여, 출생직후멸균위관을삽입하여채취한위액과기관내흡인을통하여채취한검체로배양및 PCR를시행하였다. 이때, 유레아플라즈마양성은검체의배양검사혹은 PCR에서양성결과가확인된경우로정의하였다. 마크로라이드항생제는유레아플라즈마양성으로확인된환아들에서일괄적으로사용되지는않았으며, 신생아분과전문의의임상적판단에따라출생후 2-3일이후산소요구량이증가되면서흉부엑스선소견상조기 BPD 소견 19 이관찰되는경우를고려하여마크로라이드투약여부및종류를결정하였다. 마크로라이드항생제는클라리스로마이신 (clarithromycin) 과아지스로마이신 (azithromycin) 의두가지종류가사용되었다. 투여용량은클라리스로마이신의경우는 20 mg/kg/day로 14일, 20 아지스로마이신의경우는 10 mg/kg/day 로 7일, 이어서 5 mg/kg/day로 7일간 21 사용하였다. 유레아플라즈마의양성이이환율에미치는영향을확인하기위하여, 유레아플라즈마양성여부에따라, 유레아플라즈마양성군을재태나이 (±6일) 와출생체중 (±50 g) 에따라음성군과일치시키는개별매칭 (individual matching) 을통하여두군의 RDS, PDA 치료, NEC, BPD 및치료적스테로이드투여, 산소 108 www.e-kjp.org
2018 September;29(3):107-113 공급기간, 인공호흡기사용기간, SNI, ROP 및 LOS 등을비교분석하였다. 또한유레아플라즈마양성군에서마크로라이드항생제의투약효과를확인하기위하여투여군과투여하지않은대조군으로나누어변수들을비교분석하였다. 3. 통계처리본연구에서통계분석은 SPSS version 21.0 (SPSS, Inc., Chicago, IL, USA) 을사용하였다. 연속형변수는평균 (± 표준편차 ) 으로, 범주형변수는빈도 ( 백분율 ) 로표현하였으며, 변수의특성과검정군의분포도에따라카이제곱검정, Fisher의정확검정, 독립 t검정, Mann-Whitney U검정과 McNemar 검정을이용하여두군을비교하였다. 모든분석에서 P<0.05 경우를통계적으로유의한것으로간주하였다. 결과 1. 연구대상의임상적특징연구기간동안본원신생아중환자실에입원한극소저출생체중아는 158명이었다. 이들중에서선천성기형및염색체이상과월경후주수 36주이전에사망한환자를제외한최종연구대상자는총 144명이었다. 이들의평균재태연령은 28 +3 주 (±3 +3 ), 출생체중은 1,051.9 g (±290.0) 이었다 (Table 1). 산모의전자간증은 24명 (16.7%), 조기양막파수는 52명 (36.1%) 에서확인되었으며, 산전스테로이드치료는 110명 (76.3%) 에게시행되었다. 출생직후시행한유레아플라즈마검출에서는 30명 (20.8%) 에서양성결과를보였다. 극소저출생체중아의주요이환율에있어서는, 치료가필요한 PDA, 중등도이상의 BPD, SNI, NEC와 ROP의발생률은각각 53.4%, 29.9%, 10.4%, 9.7% 와 16.7% 를보였다. 월경후주수 36주이후의사망률은 1.4% 로보고되었다. 2. 유레아플라즈마양성군과음성군간의임상적특성비교총 144명의극소저출생체중아중에서유레아플라즈마양성은 30명 (20.8%), 음성은 114명 (79.2%) 에해당하였다. 개별매칭을통하여적합하지않은 3명을제외후유레아플라즈마양성군 (27명) 과음성군 (27명) 의임상적특성을비교하였다 (Table 2). 분석결과에서, 양성군은음성군의 2배의조기양막파수의빈도를나타내었다 (81.5% vs. 40.7%, P=0.007). 또한음성군에비하여양성군은출생직후 RDS에대한치료를더빈번히받았으며 (92.6% vs. 66.7%, P=0.039), SNI의발생이유의하게증가하였다 (18.5% vs. 3.7%, P=0.013). 반면에, 중등도이상혹은 중증의 BPD, 산소공급기간및기계환기요법 ( 침습적, 비침습 적 ) 의적용기간은두군간의유의한차이가없었다. BPD 에대 한치료로사용된스테로이드의투약빈도및투약된축적용량 도군간차이를나타내지않았다. NEC, ROP, LOS 등의기타질 환의이환율에서도유의한차이가없었다. 3. 유레아플라즈마에대하여마크로라이드투약에따른임상 적특성비교 유레아플라즈마양성으로확인된 30 명중, 치료적목적으로 마크로라이드 ( 클라리스로마이신 12 명, 아지스로마이신 2 명 ) 를 Table 1. Demographic Characteristics Value (n=144) Gestational age (weeks) 28.3±3.3 Birth weight (g) 1,051.9±290.0 Male 67 (46.5) Multiple births 51 (35.4) Maternal age (years) 33.3±3.88 PROM 52 (36.1) Histologic chorioamnionitis 52 (36.1) Pre-eclampsia 24 (16.7) Cesarean section 89 (61.8) Antenatal steroid use 110 (76.3) Apgar score at 1 minute 5.4 (2-7) Apgar score at 5 minutes 7.4 (1-8) IUGR 38 (26.3) Ureaplasma-positive 30 (20.8) RDS 86 (59.7) PDA requiring treatment 77 (53.4) Moderate to severe BPD 43 (29.9) Severe BPD 36 (29.8) Postnatal steroid therapy 35 (24.3) Length of oxygen supply (days) 71.2±45.8 Severe neurologic injury 15 (10.4) NEC ( stage 2) 14 (9.7) LOS 39 (27.1) ROP requiring treatment 24 (16.7) Hospital stay (days) 71.4±45.6 Mortality after 36 weeks of PMA 2 (1.4) Values are presented as mean±standard deviation, mean (interquartile range), or number (%). Abbreviations: PROM, premature rupture of membranes; IUGR, intrauterine growth retardation; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; LOS, late-onset sepsis; ROP, retinopathy of prematurity; PMA, postmenstrual age. www.e-kjp.org 109
Kim S, et al. Ureaplasma-positive VLBW infants and macrolide therapy 투약받은군 (14/30, 46.7%) 과투약받지않은군 (16/30, 53.3%) 을대상으로하위그룹분석 (subgroup analysis) 을시행하였다 (Table 3). 이때유레아플라즈마양성을확인후, 마크로라이드 투약은출생후평균 5 일째 (3-7 일 ) 이루어졌다. 중등도이상의 BPD 발생의경우, 마크로라이드를투약군에 서 8 명 (57.1%), 비투약군에서 5 명 (31.3%) 에서각각중등도이 상의 BPD 가발생하였지만, 두군간의유의한차이는없었다. 중증 BPD 의경우에도각각 7 명 (50.0%) 과 5 명 (31.3%) 에서관 Table 2. Clinical Outcomes between Ureaplasma-Positive Infants and Matched Controls Ureaplasmapositive infants (n =27) Controls (n=27) P- value Gestational age (weeks) 27.4±1.9 27.5±2.0 0.321 Birth weight (g) 1,028.5±277 1,030±273 0.667 Male 13 (48.1) 13 (48.1) 0.782 Caesarean section 13 (48.1) 17 (63.0) 0.412 PROM 22 (81.5) 11 (40.7) 0.007* Histologic chorioamnionitis 21 (77.8) 21 (77.8) 0.072 Pre-eclampsia 1 (3.7) 2 (7.4) 0.564 RDS 25 (92.6) 18 (66.7) 0.039* PDA requiring treatment Ibuprofen treatment 11 (40.7) 15 (55.6) 0.206 PDA ligation 4 (14.8) 6 (22.2) 0.800 Moderate to severe BPD 12 (44.4) 10 (37.0) 0.706 Severe BPD 9 (33.3) 7 (25.9) 0.655 Length of oxygen supply (days) 83.9±81.7 68.7±62.7 0.430 Duration of mechanical ventilation (days) 43.8±44.8 42.4±43.6 0.155 Duration of invasive ventilation (days) 22.4±33.5 21.4±40.3 0.518 Duration of noninvasive ventilation (days) 21.4±21.1 21.0±18.9 0.497 Postnatal steroid therapy 8 (29.6) 8 (29.6) 1.000 Cumulative dose of steroid (mg/kg) 2.1±4.5 2.1±3.9 0.402 Severe neurologic injury (IVH grade 3 or PVL) 5 (18.5) 1 (3.7) 0.013* NEC ( stage 2) 3 (11.1) 4 (14.8) 0.706 LOS 8 (29.6) 8 (29.6) 0.763 ROP requiring treatment 6 (22.2) 6 (22.2) 0.317 Hospital stay (days) 96.0±76.5 83.5±57.5 0.550 Mortality after 36 weeks of PMA 1 (3.7) 0 (0) 0.254 Values are presented as mean±standard deviation or number (%). Abbreviations: PROM, premature rupture of membranes; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; LOS, late-onset sepsis; ROP, retinopathy of prematurity; PMA, postmenstrual age. *P<0.05. 찰되었으며두군간의유의한차이는없었다. 산소공급기간 및기계환기요법의기간, 출생후 BPD 에대한스테로이드투약 빈도및축적용량에있어서도유의한차이는보이지않았다. 반 면에, 마크로라이드투약군에서이부프로펜으로치료한동맥관 개존증의비율이비투약군에비하여유의하게높았다 (57.1% vs. 18.8%, P=0.029). 마크로라이드와이부프로펜의투약시기 에있어서는, 동맥관개존증에대한첫번째이부프로펜투약이 마크로라이드투약보다 77.8% (7/9) 에서먼저이루어졌다. 이 중에서 2 번이상의동맥관개존증의약물치료가이루어진경우 는 55.6% (5/9) 에해당하며, 이것도마크로라이드비투약군에 비하여투약군에서유의하게높았다 (P=0.012). 반면에, SNI 는 Table 3. Subgroup Analysis for Ureaplasma-Positive Infants According to Macrolide Treatment (n=30) Macrolide (n=14) No macrolide (n=16) P-value Gestational age (weeks) 27.3±1.6 27.4±1.9 0.227 Birth weight (g) 1,030±261 1,022±267 0.078 Male 6 (42.9) 9 (56.3) 0.464 Caesarean section 8 (57.1) 6 (37.5) 0.706 PROM 10 (71.4) 14 (87.5) 0.383 Histologic chorioamnionitis 7 (50.0) 14 (87.5) 0.032 RDS 13 (92.9) 15 (93.8) 0.724 PDA requiring treatment Ibuprofen treatment 8 (57.1) 3 (18.8) 0.029* Ibuprofen treatment ( 2 times) 5 (35.7) 0 (0) 0.012* PDA ligation 3 (21.4) 3 (18.8) 0.605 Moderate to severe BPD 8 (57.1) 5 (31.3) 0.153 Severe BPD 7 (50.0) 5 (31.3) 0.296 Ventilator (days) 53.5±53.0 33.0±31.1 0.169 Length of oxygen supply (days) 89.2±108 59.6±45.5 0.356 Postnatal steroid therapy 7 (50.0) 4 (25.0) 0.236 Cumulative dose of steroid 3.2±5.7 1.1±3.2 0.255 Severe neurologic injury (IVH grade 3 or PVL) 3 (21.4) 2 (12.5) 0.642 NEC ( stage 2) 3 (21.4) 0 (0) 0.090 LOS 6 (42.9) 4 (25.0) 0.442 ROP requiring treatment 5 (35.7) 2 (12.5) 0.204 Mortality after 36 weeks of PMA 0 (0) 1 (6.3) 0.533 Values are presented as mean±standard deviation or number (%). Abbreviations: PROM, premature rupture of membranes; RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; LOS, late-onset sepsis; ROP, retinopathy of prematurity; PMA, postmenstrual age. *P<0.05. 110 www.e-kjp.org
2018 September;29(3):107-113 마크로라이드투약여부와는차이가없었으며, NEC, ROP, LOS 등에서도군간유의한차이를보이지않았다. 고찰 유레아플라즈마는두개의다른종 (Ureaplasma urealyticum 과 Ureaplasma parvum) 으로분류되는하위박테리아로서, Ureaplasma parvum보다는 Ureaplasma urealyticum에노출된영아에서 BPD의발생위험도가높으며, 9,21,22 조기부터장기간노출될수록폐의손상은악화될수있다. 22 메타분석을통하여서도유레아플라즈마감염이미숙아의 BPD의발병률증가와연관된것으로보고된바있다. 22-24 하지만유레아플라즈마감염과 BPD의발병이서로관련성이없다는상반된연구들도보고되었는데, 이들연구에서는감염을뒷받침할수있는자궁내유레아플라즈마의존재를쉽게확인할수없고, 유레아플라즈마가자발적조기진통이있는산모의가장흔한자궁내감염병원체이지만, 조기진통의경우유레아플라즈마이외의하나이상의박테리아종에의한자궁내감염과도관련이있기때문에유레아플라즈마감염과 BPD 발생의관련성을명확히뒷받침하기어려웠기때문이다. 11,25-27 본연구의결과에서는유레아플라즈마양성군에서중등도 / 중증 BPD 발생의유의한관련성을확인하지못하였다. 한편, BPD 이외에도유레아플라즈마는 IVH, NEC, ROP 및장기적인신경학적발달에영향을준다는보고가있다. 13,14,28-32 본연구에서의유레아플라즈마양성군과음성군의임상적특징을비교하였을때, RDS와 SNI의유의한차이가있었다. 유레아플라즈마의감염과 RDS와의연관성과관련하여, 유레아플라즈마에의하여생성된 phospholipase A2에의한폐계면활성제의저해와수용성세포간부착분자뿐만아니라 interleukin의생성을포함한많은메커니즘을통하여폐손상을일으킬수있다고알려져있다. 31 Viscardi 등 14 의연구에서중추신경계 (central nervous system, CNS) 외부에서시작된염증이 IVH 발병기전에기여할수있다는점에서유레아플라즈마양성인극소저출생체중아에서 3도이상의 IVH가증가함을보였다. 유레아플라즈마 PCR에서양성혈청이양막염및 IL-1β의증가와관련이있으며, 특히 IL-1β의증가가태아염증반응을유발하여전신성및 CNS에영향을미칠수있다. 14 동물실험이지만, 어린원숭이에서 IL-1β의정맥내투여가 CSF에서의 IL-6를유도함을보여주었다. 32,33 유레아플라즈마에대한출생후항생제사용에의한효과에대하여많은연구들이진행되고있다. 유레아플라즈마는신생 아에사용가능한에리스로마이신 (erythromycin), 아지스로마이신및클라리스로마이신과같은마크로라이드계약물에감수성이있다. 20,21,34 이전연구에서아지스로마이신과클라리스로마이신은에리스로마이신보다유레아플라즈마에대한시험관내 (in vitro) 항균활성이우수하다고보고하였다. 34 유레아플라즈마에감염된미숙아의 BPD를치료하기위하여아지스로마이신 20 mg/kg/day의고용량으로 3일동안사용하였을때, 안전성뿐만아니라항염증작용으로 BPD 발병감소에효과가있음을보였다. 21,35 유레아플라즈마의치료로클라리스로마이신을사용한연구에서도유레아플라즈마양성인미숙아를대상으로클라리스로마이신을 10 mg/kg를 10일간사용하여 BPD의위험도를낮출수있음을보여주었다. 20 하지만아지스로마이신혹은클라리스로마이신을이용한본연구에서는유레아플라즈마양성미숙아에게투약하였을때중등도 / 중증의 BPD의발병률을감소시키지못하였으며, BPD 치료를위한스테로이드치료의빈도도줄이지못하였다. Resch 등 31 의연구에서도, 유레아플라즈마양성미숙아들에게마크로라이드항생제를사용하는것이 BPD의예방에효과가없는것을보고하였으며, 이는본연구와같은결과를보여주었다. 이러한결과는마크로라이드에대한유레아플라즈마의내성을고려할수있다. 36,37 임상적으로분리된유레아플라즈마의균주수가증가하면서마크로라이드에내성을보일수있는데, 특히 CT28 균주는에리스로마이신, 록시스로마이신 (roxithromycin) 등에동등하게내성을보이나, 테트라사이클린 (Teracycline) 내성에는관련이없는것으로알려져있다. 36 이것은유레아플라즈마임상균주의특정저항성유전자 (ermb, msra, msrb, msrc 및 msrd) 에의한 23s RNA의돌연변이로유레아플라즈마의마크로라이드의내성을설명할수있다. 37 본연구에서도마크로라이드의이러한내성기전이작용하였을수도있다. 한편, 본연구에서마크로라이드로치료한유레아플라즈마양성군에서치료하지않은군에비하여내과적치료 (ibuprofen) 를필요로하는 PDA의위험도가의미있게높았다. 산모의융모양막염이있는경우양수나기관지흡입세정액 (bronchial aspirate fluid) 에서 IL-6, TNF-α와같은염증성사이토카인 (proinflammatory cytokine) 이증가하는데이러한융모양막염의흔한원인균으로특히유레아플라즈마 (Ureaplasma urealyticum) 로알려져있다. 7,9,20-22,38 마크로라이드는이와같은염증성사이토카인의분비를억제함으로써항염증작용을지닌다. 20,21,38 하지만마크로라이드의항염증작용으로동맥관개존증의치료의효과를기대할수있는것과는달리, 본연구에서는마크로라이드투여군에서 PDA의치료를위한이부프로펜의재투여가유의하게높았음을관찰하였다. 하지만수술적치료에서는군간 www.e-kjp.org 111
Kim S, et al. Ureaplasma-positive VLBW infants and macrolide therapy 의차이를확인하지못하였다. 이것은유레아플라즈마와 BPD 의연관성을임상적으로염두하여 PDA 에대하여보다적극적 인약물치료가시행되었을가능성을추정하게끔한다. 반면에, 본연구에서는유레아플라즈마양성인극소저출생체중아에대 한마크로라이드치료가 RDS 나신경학적손상을포함한, 다른 주요이환율에미치는영향은관찰되지않았다. 한편, 본연구 동안마크로라이드의잘알려진부작용 39,40 인비후성유문협착 증, 부정맥등과같은심각한부작용은나타나지않았다. 본연구는몇가지제한점을가진다. 첫번째, 단일기관연구 이기때문에연구대상군이적고, 선택편의 (selection bias) 가 있을수있다. 두번째, 유레아플라즈마양성으로확인된극소저 출생체중아중에서임상의의판단에따라마크로라이드투약의 여부가결정되었기때문에상대적으로전신상태가더좋지않 은극소저출생체중아에게치료가집중된경향이있을수있다 는점이다. 이러한점에서항생제를비롯한다양하게투약된약 물들이마크로라이드약동학에영향을주었을가능성이있다. 마지막으로, 본연구에두가지종류의마크로라이드항생제가 사용되었기때문에종류의차이가미치는영향이있을수있으 며, 23s RNA 의돌연변이로인한마크로라이드항생제의감수 성이다를수있고마이코플라즈마호미니스 (Mycoplasma hominis) 와의동시감염의존재등으로제균치료에영향을줄수 있다는점이다. 본연구를통하여유레아플라즈마양성인극소저출생체중아 에서 BPD 발생을포함한주요이환율과이에대한마크로라이 드투약의효과를확인할수있었다. 유레아플라즈마양성은증 등도 / 중증 BPD 와연관성이없었고, RDS, SNI 의발생률증가와 연관성을나타내었다. 마크로라이드항생제에의한유레아플라 즈마치료시도는극소저출생체중아의주요이환율을감소시키 지못하였다. 향후유레아플라즈마가 BPD 를포함하여미숙아 의여러질환에미치는영향을확인할수있는대규모연구가필 요할것으로생각된다. References 1) El-Metwally D, Vohr B, Tucker R. Survival and neonatal morbidity at the limits of viability in the mid 1990s: 22 to 25 weeks. J Pediatr 2000;137: 616-22. 2) Callaghan WM, MacDorman MF, Shapiro-Mendoza CK, Barfield WD. Explaining the recent decrease in US infant mortality rate, 2007-2013. Am J Obstet Gynecol 2017;216:73.e1-73.e8. 3) Voynow JA. "New" bronchopulmonary dysplasia and chronic lung disease. Paediatr Respir Rev 2017;24:17-8. 4) Viscardi RM, Muhumuza CK, Rodriguez A, Fairchild KD, Sun CC, Gross GW, et al. Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res 2004;55:1009-17. 5) Choi CW, Kim BI. Epidemiology, clinical characteristics, and pathophysiology of bronchopulmonary dysplasia. Neonatal Med 2013;20:283-91. 6) Jung E, Kim S, Jung YH, Lee J, Shin SH, Choi CW, et al. Effect of prenatal and postnatal prophylaxis with macrolide of Ureaplasma on the development of bronchopulmonary dysplasia in preterm infants. Neonatal Med 2015;22:78-83. 7) Sweeney EL, Dando SJ, Kallapur SG, Knox CL. The human Ureaplasma species as causative agents of chorioamnionitis. Clin Microbiol Rev 2016;30:349-79. 8) Schelonka RL, Waites KB. Ureaplasma infection and neonatal lung disease. Semin Perinatol 2007;31:2-9. 9) Viscardi RM. Ureaplasma species: role in neonatal morbidities and outcomes. Arch Dis Child Fetal Neonatal Ed 2014;99:F87-92. 10) Ballard HO, Anstead MI, Shook LA. Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study. Respir Res 2007;8:41. 11) Aaltonen R, Vahlberg T, Lehtonen L, Alanen A. Ureaplasma urealyticum: no independent role in the pathogenesis of bronchopulmonary dysplasia. Acta Obstet Gynecol Scand 2006;85:1354-9. 12) Mhanna MJ, Delong LJ, Aziz HF. The value of Ureaplasma urealyticum tracheal culture and treatment in premature infants following an acute respiratory deterioration. J Perinatol 2003;23:541-4. 13) Okogbule-Wonodi AC, Gross GW, Sun CC, Agthe AG, Xiao L, Waites KB, et al. Necrotizing enterocolitis is associated with Ureaplasma colonization in preterm infants. Pediatr Res 2011;69(5 Pt 1):442-7. 14) Viscardi RM, Hashmi N, Gross GW, Sun CC, Rodriguez A, Fairchild KD. Incidence of invasive Ureaplasma in VLBW infants: relationship to severe intraventricular hemorrhage. J Perinatol 2008;28:759-65. 15) Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 16) Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1-7. 17) Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529-34. 18) Lee SM, Chang M, Kim KS. Blood culture proven early onset sepsis and late onset sepsis in very-low-birth-weight infants in Korea. J Korean Med Sci 2015;30 Suppl 1:S67-74. 19) Crouse DT, Odrezin GT, Cutter GR, Reese JM, Hamrick WB, Waites KB, et al. Radiographic changes associated with tracheal isolation of Ureaplasma urealyticum from neonates. Clin Infect Dis 1993;17 Suppl 1:S122-30. 20) Ozdemir R, Erdeve O, Dizdar EA, Oguz SS, Uras N, Saygan S, et al. Clarithromycin in preventing bronchopulmonary dysplasia in Ureaplasma urealyticum-positive preterm infants. Pediatrics 2011;128:e1496-501. 112 www.e-kjp.org
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