pissn: 2288-0402 eissn: 2288-0410 6(1):47-53, January 2018 https://doi.org/10.4168/aard.2018.6.1.47 ORIGINAL ARTICLE 급성모세기관지염의원인바이러스에따른중증도차이 이수진, 박상규, 김지현, 조성민 동국대학교일산병원소아청소년과 Bronchiolitis severity according to the infected viruses Su Jin Lee, Sang Kyu Park, Ji Hyun Kim, Sung Min Cho Department of Pediatrics, Dongguk University Ilsan Hospital, Goyang, Korea Purpose: The aim of this study was to evaluate the severity of disease in children with acute bronchiolitis according to the type of infected virus. Methods: From November 2007 to May 2015, 768 patients under 2 years of age who underwent real time-polymerase chain reaction of nasopharyngeal aspirates admitted to the Department of Pediatrics of Dongguk University Ilsan Hospital for acute bronchiolitis were enrolled. Severe bronchiolitis was defined as presence of one or more kinds among tachypnea, chest retraction, needs of O2 inhalation or ventilator care. Results: The severity of bronchiolitis was increased with shorter fever duration (P < 0.001) and previous wheezing episodes (P = 0.005). In the case of single infection, respiratory syncytial virus (RSV) A only increased the severity of acute bronchiolitis (P = 0.012). However, the severity of illness decreased when RSV A coinfected with adenovirus (P = 0.034), human rhinovirus (P = 0.038), or human coronavirus NL63 (P = 0.042). On the other hand, when human rhinovirus was coinfected with enterovirus (P= 0.013) or parainfluenza 3 (P= 0.019), the severity was increased. When human metapneumovirus coinfected with human bocavirus, the severity was increased (P= 0.038). Conclusion: Acute bronchiolitis was associated with increased severity only when RSV A infected solely, but several viruses increased or decreased the severity when coinfection occurred. Therefore, it may be helpful in predicting the course of the acute bronchiolitis according to the affected virus. ( 2018;6:47-53) Keywords: Bronchiolitis, Infant, Respiratory syncytial virus, Severity 서론 세기관지염은세기관지와같은하부호흡기의감염질환으로영 아와어린소아가입원하게되는흔한원인중하나이다. 1 세기관지 염은주로생후 2 세이전의영아에서주로발생하며, 콧물, 기침등 의상기도감염증상과함께천명음이나나음등의하부기도감염 징후를나타내는데, 2,3 가벼운증상이나징후를보이는경우부터식 욕저하, 기면, 빈호흡, 비익확장, 심한흉골함몰, 저산소혈증 (SpO 2 <95%) 을보이는경우까지다양한정도의차이를보인다. 4-7 주로바이러스에의해서감염이되는데, 바이러스가직접말단기 관지의상피세포를손상시키거나염증반응으로인한상피세포의 부종, 과도한점액등이작은직경의기도에폐색을유발하고급기 Correspondence to: Ji Hyun Kim https://orcid.org/0000-0001-8493-2881 Department of Pediatrics, Dongguk University Ilsan Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang 10326, Korea Tel: +82-31-961-7190, Fax: +82-31-961-7188, E-mail: eogurdl@gmail.com Received: March 10, 2017 Revised: October 24, 2017 Accepted: October 24, 2017 야는무기폐를일으키게된다. 6-8 중증세기관지염은빈호흡, 비익확장, 흉골함몰등의호흡노력이 증가하는경우, 저산소혈증, 무호흡, 급성호흡부전이보일경우로 정의한다. 9,10 이러한중증세기관지염의경우호흡부전으로인공환기를시행 하게되거나심하면사망하는경우도발생할수있다. 6 그러므로중 증세기관지염의경우집중치료실에입원하거나 ( 전신 ) 스테로이 드투여, 산소흡인, 가온가습고유량비강캐뉼라 (heated humidified high-flow nasal cannula) 요법, 지속적양압환기법 (continuous positive airway pressure), 기도삽관등과같은치료와집중적인감 시와대비가요구된다. 2,4,6 세기관지염의원인바이러스로는 respiratory syncytial virus 2018 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/). 47 http://www.aard.or.kr
Lee SJ, et al. Severe bronchiolitis due to the causative viruses (RSV), human rhinovirus (hrv), parainfluenza virus (PIV), human metapneumovirus (hmpv), enterovirus (ETV), influenza virus (Flu), adenovirus (ADV), human coronavirus (hcov), human bocavirus (hbov) 등이있다. 2,3,6,11 감염된바이러스의종류에따라하부호흡기감염의중증도가달라지는가에대한연구들이있어왔는데, 증상이없는대조군과비교하였을때호흡기증상이있는질환군에서 hmpv, RSV의감염빈도가높으며, hbov는다른바이러스와중복감염 (coinfection) 되었을때중증도가증가한다고하였다. 12 다른연구에서는바이러스종류나중복감염여부는중증도와관련이없으나 RSV의유전체의양 (genomic load) 이많을때입원기간과산소또는인공환기기의사용빈도가증가한다고보고하였다. 4 이연구는위의연구를토대로중증세기관지염의발생과관련된일반적인인자와함께이환된바이러스종류에따라세기관지염의중등도차이가있는지를확인하고자하였다. 6,8,10 하여채취하였고, 바로검사가시행되지못한경우검체들은 72시간까지냉장보관 (2 8 C) 하였다. 2) 바이러스의진단검체에 RV (respiratory virus) 16 IC (internal control) 10 μl를넣은후 Ribo_spin vrd (Viral RNA/DNA Extraction Kit, GeneAll, Seoul, Korea) 를이용하여핵산추출을한후, SEEPREP12 Viral NA Kit (NorDiag ASA, Oslo, Norway) 를이용하여시료를정제하였다. Reverse transcription은 cdna Synthesis Automix (Seegene, Seoul, Korea) 를이용하여검사하였다. 마지막으로 CFX96 Realtime PCR System (Bio-Rad Laboratories, Hercules, CA, USA) 을이용한데이터분석으로바이러스를동정하였다. 13-16 RSV (A/B), hrv, Flu (A/B), ADV, hmpv, PIV (1/2/3/4), hcov (229E/NL63/ OC43), ETV, hbov 등총 16가지바이러스에대한정성검사및정량검사로진행되었다. 대상및방법 1. 대상 2007년 11월부터 2015년 5월까지급성세기관지염으로동국대학교일산병원소아청소년과에입원한환자중비인두흡인물을채취하여중합효소연쇄반응 (real time-polymerase chain reaction, RT-PCR) 검사를실시한 2세미만의소아 768명을대상으로하였다. 세기관지염은상기도감염증상과천명음등하부기도감염징후가동반된임상적증후군으로정의하였다. 급성세기관지염과관련된일반적사항에대해서는병력청취를통해형제유무, 알레르기비염과같은알레르기질환의가족력여부, 이전에천명음을동반한호흡기감염병력 (wheezing episode) 여부를확인하였다. 이때, 알레르기질환의가족력은부모중에한명이라도있는경우로정하였다. 중증세기관지염은환자가빈호흡, 흉골함몰, 산소흡인치료, 기계적환기를시행했는지확인하여이중한가지라도해당이되는경우로정의하였다. 빈호흡은 0 6개월소아의경우 70회 / 분이상일때, 6개월이상의소아의경우 40회 / 분이상일때로정의하였다. 산소흡인치료는산소포화도 (O 2 saturation) 가 95% 미만이거나호흡곤란, 빈호흡, 청색증을보이는환아를대상으로, 비강캐뉼라, 단순마스크, 벤투리마스크등을통해서저유량 (low flow) 뿐아니라고유량 (high flow) 산소공급을받은경우로정의하였다. 2. 바이러스검사방법 1) 검체의채취와보관모든검체는표준프로토콜에따라서의사가대상소아들의비인두에 universal transport medium 에동봉된비인두면봉을이용 3. 통계분석통계분석은 SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 비연속변수에대한비교분석은 chi-square test, Fisher exact test를이용하였고, 연속변수에대한비교분석중일반사항비교는 Student t-test를이용하였다. 연속변수는평균 ± 표준편차, 비연속변수는빈도 (%) 로기술하였다. 유의수준 P<0.05 미만인경우통계학적으로유의한것으로판단하였다. 결과 1. 대상소아의특징연구에포함된대상자는총 768명으로남아가 481명 (62.6%), 여아가 287명 (37.4%) 이었다. 연령은 12개월미만이 583명 (75.9%) 으로가장많았고 1세이상 2세미만은 185명 (24.1%) 으로나타났고, 형제가있는경우가 440명 (57.3%), 형제가없는경우는 328명 (42.7%) 으로나타났다. 평균입원기간은 5.74일로 4일간입원한환아가 188명 (24.5%) 으로가장높은비율을보였고, 5일 169명 (22.0%), 6일 132명 (17.2%), 8 일이상입원한경우는 125명 (16.3%) 이었다. 기계적환기치료가필요했던환아는 62명 (8.1%) 이었다. 발열기간은입원하기전부터, 또는입원기간동안발열징후가동반된경우로정의하였는데, 발열징후가없었던환아가 343명 (44.7%) 으로가장높은비율이었고, 1 일 94명 (12.2%), 2일간의발열이있었던환아는 86명 (11.2%) 순서를보였다 (Table 1). 48 https://doi.org/10.4168/aard.2018.6.1.47
이수진외 원인바이러스에따른중증모세기관지염 2. 중증도에영향을미치는일반적인요인급성세기관지염을중증도에따라중증군 (n= 499명 ) 과경증및중증도 (nonsevere) 군 (n= 269명 ) 으로나누었을때중증군에서남아 (64.3%) 의빈도가높았으나통계적으로유의하지않았다 (P = 0.185). 중증군의평균나이는 2.62개월로경증및중증도군 ( 평균 3.39개월 ) 에비해어렸으나통계적으로유의하지않았다 (P = Table 1. Clinical characteristics of hospitalized children with acute bronchiolitis Characteristic Number (%) Sex Female 287 (37.4) Male 481 (62.6) Age (yr) 1 583 (75.9) > 1, < 2 185 (24.1) Hospitalization period (day) < 3 96 (12.5) 4 188 (24.5) 5 169 (22) 6 132 (17.2) 7 58 (7.6) 8 125 (16.3) Fever (day) None 343 (44.7) 1 94 (12.2) 2 86 (11.2) 3 245 (31.8) Ventilator care, yes 62 (8.1) Siblings, yes 440 (57.3) 0.054). 중증군의평균입원기간은 6.35 일로더길었고 (P<0.001), 발열기간은평균 1.6 일로더짧게나타났다 (P<0.001). 중증군에 서형제가있는경우가많았으나 (57.9%) 통계적으로유의하지않았 다 (P = 0.634). 이전천명음을동반한호흡기감염을보였던환자에 서 (16.6%) 유의하게중증세기관지염의빈도가높았다 (P = 0.005) (Table 2). 3. 감염된바이러스의빈도 중복감염을포함하여세기관지염으로입원한환자들의원인바 Table 2. Clinical characteristics of hospitalized children with acute bronchiolitis analyzed according to disease severity Characteristic Nonsevere (n= 269) Severe (n= 499) P-value Age (mo)* 3.39 2.62 0.054 Hospitalization period (day)* 4.2 6.35 < 0.001 Fever (day)* 2.20 1.60 < 0.001 ICU hospitalization (day)* 0 0.05 0.001 CRP (mg/dl)* 1.05 1.20 0.261 Lymphocyte (%)* 55.99 52.94 0.006 Male sex 160 (59.5) 321 (64.3) 0.185 Siblings, yes 151 (56.1) 289 (57.9) 0.634 Previous wheezing episode 25 (9.3) 83 (16.6) 0.005 Allergic disease family history 2 (0.7) 8 (1.6) 0.316 Previous admission history 53 (19.7) 145 (29.1) 0.005 Values are presented as mean or number (%). CRP: normal range, 0 0.5 mg/dl; lymphocyte: normal range, 20% 50%. ICU, intensive care unit; CRP, C-reactive protein. *Student t-test. Chi-square test. 25 20 % 15 10 5 0 Adenovirus Influenza A virus Influenza B virus Metapneumovirus Respiratory syncytial virus A Parainfluenza virus 1 Respiratory syncytial virus B Parainfluenza virus 2 Parainfluenza virus 3 Parainfluenza virus 4 Rhinovirus A/B/C Coronavirus 229E Coronavirus NL63 Coronavirus OC43 Enterovirus Bocavirus 1/2/3/4 2015 2014 2013 2012 2011 2010 2009 2008 2007 Fig. 1. Year-round change of acute bronchiolitis with 16 respiratory viruses isolated for 768 hospitalized children. https://doi.org/10.4168/aard.2018.6.1.47 49
Lee SJ, et al. Severe bronchiolitis due to the causative viruses 이러스로 RSV (A & B, n=380) 와 hrv (n= 257) 의빈도가월등하게높았고다음으로 ADV (n=139), hbov (n= 99) 순이었다 (Fig. 1). 4. 단독감염과중복감염의빈도단독감염 (n = 291명 ) 인경우 RSV A (n= 95, 37.7%), RSV B (n= 57, 40.7%), hrv (n=53, 20.6%) 의순서로빈도가높았다. 16가 지바이러스가모두단독감염보다중복감염이많았다 (Table 3). 나이를구분하여단독감염과중복감염의차이를있는지보았을때, 1세미만영아에서 hcov 3가지유형중 hcov 229E 에의한단일감염으로세기관지염을일으키지않았고, 1세이상 2세미만의소아에서도 hcov (229E, NL63, OC43의 3가지형태 ) 는단일감염에의한세기관지염을일으키지않았다 (data not shown). Table 3. The ratio of single infection to coinfection of respiratory viruses isolated for 768 hospitalized children with acute bronchiolitis Variable Total (n) Single infection, n (%) Coinfection, n (%) Adenovirus 139 16 (10.5) 123 (88.5) Influenza A virus 16 6 (37.5) 10 (62.5) Influenza B virus 9 3 (33.3) 6 (66.7) Metapneumovirus 40 13 (32.5) 27 (67.5) Respiratory syncytial virus A 252 95 (37.7) 157 (62.3) Respiratory syncytial virus B 140 57 (40.7) 83 (59.3) Parainfluenza 1 35 10 (28.6) 25 (71.4) Parainfluenza 2 10 3 (30.4) 7 (70.0) Parainfluenza 3 33 7 (21.2) 26 (78.8) Parainfluenza 4 27 9 (33.3) 18 (66.7) Human rhinovirus 257 53 (20.6) 204 (79.4) Corona 229E virus 8 0 (0) 8 (100) Corona NL63 virus 11 3 (27.3) 8 (72.3) Corona OC43 virus 22 2 (9.1) 20 (90.9) Enterovirus 60 2 (3.3) 58 (96.7) Human bocavirus 96 12 (12.5) 84 (87.5) 5. 원인바이러스에따른중증도의차이이환된바이러스의종류에따른세기관지염의중증도차이를단독감염과중복감염으로나눠서확인하였다. 단독감염중에서는 RSV A 감염만이심한세기관지염과관련이있었다 (P = 0.012). 각각의바이러스가중복감염되었을때세기관지염의중증도와의관련성을본분석결과를보면, RSV A의경우에는 ADV (P = 0.034), hrv (P = 0.038), hcov NL63 (P = 0.042) 과중복감염되었을때오히려중증도가감소하였다. 또한, hrv는 ETV (P = 0.013), PIV3 (P = 0.019) 와중복감염되었을때중증도가증가하였다. hmpv는 hbov와중복감염되었을때중증도가증가한다 (P = 0.038) (Table 4). 고찰세기관지염은 2세이전의영아에서주로발생하며, 영아입원의가장흔한원인이다. 1,2 사회경제의발전이두드러지면서환자수가 Table 4. Correlation of severity with coinfected viruses for 768 hospitalized children with acute bronchiolitis* Infection Coinfected viruses ADV (n= 139) hmpv (n= 96) RSV A (n= 252) RSV B (n= 140) hrv (n= 257) ETV (n= 60) hbov (n= 96) ADV - 0.239 (0.137) 0.133 (0.034) 0.046 (0.589) 0.002 (0.975) 0.092 (0.484) 0.012 (0.907) Flu A 0.103 (0.226) - 0.106 (0.094) 0.053 (0.532) 0.117 (0.061) 0.066 (0.614) 0.134 (0.195) Flu B 0.100 (0.239) - 0.074 (0.245) - 0.085 (0.175) - 0.106 (0.306) hmpv 0.004 (0.960) - 0.005 (0.940) - 0.081 (0.194) 0.053 (0.688) 0.092 (0.373) RSV A 0.051 (0.550) 0.106 (0.516) 0.057 (0.500) 0.042 (0.503) 0.073 (0.577) 0.027 (0.794) RSV B 0.115 (0.176) - 0.050 (0.432) - 0.077 (0.216) 0.066 (0.615) 0.069 (0.507) hrv 0.015 (0.863) 0.189 (0.242) 0.131 (0.038) 0.011 (0.897) 0.195 (0.135) 0.190 (0.064) PIV 1 0.098 (0.252) - 0.082 (0.197) - 0.055 (0.378) 0.099 (0.452) 0.085 (0.411) PIV 2 0.127 (0.136) - 0.023 (0.718) - 0.093 (0.136) 0.172 (0.189) 0.160 (0.118) PIV 3 0.070 (0.415) 0.280 (0.080) 0.023 (0.718) - 0.146 (0.019) 0.152 (0.246) 0.053 (0.609) PIV 4 0.057 (0.512) - 0.015 (0.840) 0.068 (0.481) 0.016 (0.809) 0.029 (0.826) 0.114 (0.268) ETV 0.132 (0.124) 0.271 (0.115) 0.121 (0.106) 0.010 (0.920) 0.164 (0.013) - 0.170 (0.097) hcov 229E - - 0.031 (0.627) - 0.031 (0.624) 0.149 (0.257) - hcov NL63 0.144 (0.093) 0.136 (0.437) 0.152 (0.042) - 0.002 (0.981) - - hcov OC43 0.047 (0.587) - 0.024 (0.700) 0.039 (0.651) 0.062 (0.322) - 0.106 (0.306) hbov 0.073 (0.397) 0.351 (0.038) 0.034 (0.651) 0.078 (0.418) 0.063 (0.344) 0.035 (0.792) - ADV, adenovirus; hmpv, human metapneumovirus; RSV, respiratory syncytial virus; hrv, human rhinovirus; ETV, enterovirus; hbov, human bocavirus; Flu, influenza virus; PIV, parainfluenza virus; hcov, human coronavirus. *Spearman correlation analysis and then chi-square test. Negative correlation (reduced severity). Positive correlation (elevated severity). 50 https://doi.org/10.4168/aard.2018.6.1.47
이수진외 원인바이러스에따른중증모세기관지염 많이증가하는데이는놀이방등의집단시설을이용하는경우가많아지고, 미숙아의생존율이높아진데에기인한다. 2,3 세기관지염은콧물, 기침등의상기도감염증상과천명음이나나음등의하부기도감염징후를나타내며, 2,3 가벼운증상이나징후를보이는경우부터식욕저하, 기면, 빈호흡, 비익확장, 심한흉골함몰, 저산소혈증을보이는경우까지다양한정도의차이를보인다. 5,7,8,10 중증세기관지염환아는악화시호흡부전에이를수있고, 7,8,11,17 질환이호전된후에도삶의질이감소한다. 18 세기관지염의원인바이러스중에서 2,3,6 RSV가세기관지염의중등도를증가시키는것은이미알려져있는바이다. 6,11 그러나위의결과들은 RSV 단독감염일때의결과이다. 이전의연구를살펴보면호흡기감염환아에서단독감염보다는중복감염이증가하고있고, 4,6 원인이되는바이러스들의단독감염보다중복감염이급성세기관지염의중등도를증가시킨다고보고하여일관성이없었다. 19 이연구는실시간 RT-PCR 방법을시행하여, 검출된바이러스가세기관지염의중증도에어떤영향을주는지와중복감염시세기관지염의중증도에어떤영향을미치는지를확인하였다. 이를통하여원인바이러스의종류에따라세기관지염의경과를예측할수있으면중환자실입원기간의단축과질병의호전후삶의질향상에도움이될수있을것으로생각하였다. 중증세기관지염의발생과관련이있는일반적인인자를살펴보면발열기간이짧을수록세기관지염의중증도가증가하였다 (P<0.001). 세기관지염의경우폐렴처럼폐실질까지염증이있는경우외에는대체로발열을동반하지않는것으로알려져있는데 2 이번연구결과를통해발열이동반된폐실질의염증이세기관지염의중증도와관계가있는것은아니라고추정해볼수있다. 중증군의평균나이는 2.62개월로경증및중증도군의 3.39개월보다조금더어렸지만통계적으로유의하지않았다. 이는세기관지염이주로 1세미만의영아에서발생하며, 1,2 두군모두 1세미만으로수치상큰차이가없기때문으로생각한다. 이연구의결과중이전에천명음을동반한호흡기감염병력이있는전체환자군에서세기관지염의중증도가유의하게증가하였는데 (P = 0.005), 이는세기관지염이천식과소인적관계일수있다는이전의연구들을뒷받침하는결과였다. 2,20 국내의연구에서 hrv 감염의경우천식의악화와관련이있음을보고하였는데, 20 이번연구에서는이전에천명음을동반한호흡기감염병력이있거나천식, 알레르기비염을진단받은적이있는환자가 hrv에감염된경우세기관지염의중증도가증가하지않았다 (P = 0.817). 이는천명음병력을보호자로부터병력청취를통해확인한내용이라제한점이있는것으로생각한다. 그리고이전천명음병력이있었던환아가 116명, 알레르기비염가족력 10명, 천식과거력이있는환자 1명으로확인되어각각의인자들이세기관지염의중증도에영향을미치는지를확인하기에는개별환자군의수가적어서좀더많은환 자군을대상으로확인이필요하겠다. 이연구에서는 RT-PCR을통해세기관지염의원인바이러스를검사했는데, 이연구에서시행된 RT-PCR은반정량검사 (+-+++ 으로표현 ) 로정확한바이러스양을확인할수는없었다. 검출된바이러스의양 (viral load) 에따라중증도가증가한다고했던이전연구와 4,19 다르게본원에서시행한바이러스정량검사결과로는세기관지염의중증도가유의하게증가하지않는것으로나타났다 (P = 0.089). 따라서향후에는바이러스양을측정하는정량검사를이용하여중복감염시세기관지염의중증도에어떤영향을미치는지에대한연구가필요하겠다. 세기관지염을일으키는원인바이러스로는 RSV (50.1%) 가가장흔하고이는이전의연구결과와일치하였다. 6,13,21,22 특히 RSV 중 RSV A (32.8%) 가 RSV B (18.2%) 보다빈도가높았는데이는국내연구와일치하는결과였다. 5 급성호흡기감염에서단일감염과중복감염의빈도에대한이전연구들은통일된결과를보이고있진않았는데, 12,23 이연구에서는단일감염보다중복감염된경우가많았다 (Table 3). 이러한동시감염은 4세이하의어린소아와입원한경우많이나타나는것으로알려져있는데, 24 어린소아는면역학적으로미숙하여잦은빈도의호흡기감염을앓고, 바이러스흘림 (sheeding) 이오래지속되는경우가흔하여잔여바이러스가지속되어검출될수있을것으로생각한다. 단독감염된경우만분리하여분석했을때 RSV A, RSV B, hrv의순서를보였다. hbov는 2세미만의소아에서는세기관지염의단독감염을일으켰다는연구와 13 달리이연구에서는 hbov가단독감염 (12.5%) 보다중복감염의빈도 (87.5%) 가높았다 (Table 3). 나이에따라단독감염과중복감염되는바이러스에차이가있는지보았던분석에서는 1세미만의영아에서는 hcov 229E 는단일감염으로세기관지염을일으키지않았고, 1세이상 2세미만의소아에서는 hcov (229E, NL63, OC43의 3가지형태 ), ETV가단일감염으로세기관지염을일으키지않았다. Flu B는 1세이상 2세미만의소아에서세기관지염을일으키지않는것으로나타났으나, 이러한결과들은 hcov, Flu B에감염된 n 수가적어임상적의미는분명치않다. 세기관지염의중증도가원인바이러스와관계가있는가에대한연구는아직통일된결과를보이고있지는않은듯하다. 증상이없는대조군과비교하였을때질환군에서 hmpv, RSV의단일감염빈도가높으나 hbov는중복감염이되었을때중증도가증가한다고하였다. 12,23 RSV의경우소아급성호흡기감염에서다른바이러스들과중복감염이되었을때질환의중등도를증가시키고, 25,26 호흡기바이러스의중복감염이급성하부호흡기감염의중등도를증가시킨다고하는연구도있다. 27 반면소아의호흡기질환에서단독감염이중복감염보다산소치료를요구하는경우가많았고, 입원기간, 중환자실입원치료기간이길어지는것을보아중복감염여 https://doi.org/10.4168/aard.2018.6.1.47 51
Lee SJ, et al. Severe bronchiolitis due to the causative viruses 부는질환의중증도와상관관계가없다거나, 23,28 RSV는중복감염되는경우가많지만질환의중증도에는영향을미치지않는다고하였다. 29 이번연구에서각각의바이러스가세기관지염의중증도에어떻게영향을미치는지를분석했을때단독감염에서는 RSV A만이세기관지염의중증도와관계가있는것으로나타났다 (P<0.001). RSV가 interferon-γ 등과같은염증성사이토카인생성과세포성면역을자극하고, 이렇게 RSV에의해생성된염증매개세포의부적절한생성이결국 RSV 관련천식과과민반응 ( 천명음병력, 아토피성피부염등 ) 을유발할수있다. 30,31 특히 RSV A의경우 B에비해우점종으로알려져있어이러한 RSV의특성이단독감염만으로도세기관지염의중증도를증가시키는것이아닌가생각한다. 31 한편 RSV A는 ADV (P = 0.034), hrv (P = 0.038), hcov NL63 (P = 0.042) 과중복감염되었을때통계적으로유의하게중증도가감소하였다 (Table 4). 이를통해같은 RSV A지만중복감염된바이러스의종류에따라중증도가달라질수있음을알수있다. 높은바이러스밀도에서경쟁을하는바이러스가있을경우어느바이러스는집락 (colony) 의약화를초래할수있다고보고가있는데, 32 RSV A 역시특정바이러스와이러한상관관계를가지는것이아닐까생각해볼수있겠다. 또한 RSV의경우체내에서완전히제거될때까지많은시간이소요되는것으로알려져있어중증도가감소한경우 RSV가검출된것이현감염이아닐가능성도배제할수없다. 30 RSV A 외의다른바이러스단독감염이세기관지염의중증도를증가시키지는않는것으로나타났지만몇몇바이러스는중복감염이되었을때중증도를증가시키는것으로확인되었다. hbov가 hmpv와중복감염되었을때세기관지염의중증도가증가하였는데 (P = 0.038) 이는이전연구와일치하는결과이다. 12 또한 hrv가 ETV (P = 0.013), PIV3 (P = 0.019) 과중복감염되었을때중증도가증가시키는것으로나타났는데, 이는다른연구에서는확인되지않은내용이었다. 이처럼단독감염시에는세기관지염의중증도를증가시키지않는바이러스들도중복감염된바이러스의종류에따라중증도가변화하는것을확인할수있었다 (Table 4). hmpv가 RSV와중복감염되었을때중증도가증가한다는연구가있지만, 33 이번연구결과에서는 hmpv가 hbov와중복감염되었을때중증도가증가하고다른바이러스와의중복감염시에는중증도에유의하게영향을미치지않았다는점이이전연구와다르다. 이는이연구에서는 hmpv가 768명중 40명으로다른연구에비해상대적으로 n 수가적은것이한가지이유일수있겠다. 이처럼특정바이러스가중복감염되었을때일관적으로중증도를증가시키는것이아니기때문에이러한결과의해석은주의가필요하며향후바이러스사이의역학관계에대한연구가필요할것으로생각한다. 마지막으로이번연구에서중증환자군의정의를빈호흡, 흉골 함몰, 산소흡인치료, 기계적환기시행여부의 4 가지항목중한가 지라도해당되는경우로하였는데중증도정도의기준에해당하는 가지수를달리하여비교하였을때에도결과가달라지지않았다. 중증도를각항목별로점수체계화 (scoring system) 해서 9 분석하면 더좋은결과를얻을수있을것으로생각하나, 이연구는후향적 연구라는제한점이있었다. 그럼에도불구하고이연구는급성세기관지염을일으키는바이 러스의상관관계에대해서자료를제시함으로써, 질환의경과를 예측하고대비함에있어의미있는연구로생각한다. REFERENCES 1. Roh EJ, Won YK, Lee MH, Chung EH. Clinical characteristics of patients with acute bronchiolitis who visited 146 Emergency Department in Korea in 2012. 2015;3:334-40. 2. Coastes BM. Wheezing in infants:bronchiolitis. In: Kliegman RM, Stanton BF, St. Geme JW Ш, Schor NF, Behrman RE, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia (PA): Elsevier, 2016:2044-8. 3. Bordley WC, Viswanathan M, King VJ, Sutton SF, Jackman AM, Sterling L, et al. Diagnosis and testing in bronchiolitis: a systematic review. Arch Pediatr Adolesc Med 2004;158:119-26. 4. Skjerven HO, Megremis S, Papadopoulos NG, Mowinckel P, Carlsen KH, Lødrup Carlsen KC, et al. Virus type and genomic load in acute bronchiolitis: severity and treatment response with inhaled adrenaline. J Infect Dis 2016;213:915-21. 5. Kang SY, Hong CR, Kang HM, Cho EY, Lee HJ, Choi EH, et al. Clinical and epidemiological characteristics of human metapneumovirus infections, in comparison with respiratory syncytial virus A and B. Pediatr Infect Vaccine 2013;20:168-77. 6. Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics 2014;134:e1474-502. 7. Park HJ, Kim JH, Chun YH, Lee SY, Kim SY, Kang JH. Clinical manifestations, management, and natural course of infants with recurrent bronchiolitis or reactive airways disease. Pediatr Infect Vaccine 2014;21:37-42. 8. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998;109:101-9. 9. Jeong Y, Hwang JH, Kwon JY, Shin J, Kwon JH, Han K, et al. Prediction of the severity and length of hospital stay in infants with acute bronchiolitis using the severity score. 2016;4:429-35. 10. Walsh EE, McConnochie KM, Long CE, Hall CB. Severity of respiratory syncytial virus infection is related to virus strain. J Infect Dis 1997;175: 814-20. 11. Mansbach JM, Piedra PA, Teach SJ, Sullivan AF, Forgey T, Clark S, et al. Prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis. Arch Pediatr Adolesc Med 2012; 166:700-6. 12. Rhedin S, Lindstrand A, Rotzén-Östlund M, Tolfvenstam T, Ohrmalm L, Rinder MR, et al. Clinical utility of PCR for common viruses in acute respiratory illness. Pediatrics 2014;133:e538-45. 13. Lim JS, Woo SI, Kwon HI, Baek YH, Choi YK, Hahn YS. Clinical characteristics of acute lower respiratory tract infections due to 13 respiratory viruses detected by multiplex PCR in children. Korean J Pediatr 2010;53: 373-9. 14. Kim KH, Lee JH, Sun DS, Kim YB, Choi YJ, Park JS, et al. Detection and 52 https://doi.org/10.4168/aard.2018.6.1.47
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