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1 대한내과학회지 : 제 84 권제 2 호 특집 (Special Review) - 면역저하환자의감염 조혈모세포이식환자에서흔히보는감염 가톨릭대학교의과대학감염내과, 가톨릭조혈모세포이식센터 이동건 Common Infectious Diseases in Hematopoietic Stem Cell Transplant Recipients Dong-Gun Lee Division of Infectious Diseases, Department of Internal Medicine, The Catholic Blood and Marrow Transplantation Center, The Catholic University of Korea College of Medicine, Seoul, Korea Hematopoietic stem cell transplantation (HSCT) has improved the outcome of numerous malignant and non-malignant diseases. However, infectious diseases (IDs) still contributes the burden of morbidity and mortality significantly after both autologous and allogeneic HSCTs. IDs are usually classified by the time periods after HSCT; pre-engraftment period, immediate and late post-engraftment period. Kinds of IDs and their frequencies and distribution are dependent not only on the stem cell sources, conditioning regimens, presence of graft-versus-host diseases, but also on the region, prophylactic antibiotics, and so on. In this article, the common IDs after HSCT according to the time periods are reviewed. Additionally, it is tried to focus the recent Korean perspectives, for examples, tuberculosis, herpes zoster, respiratory virus infection-especially hope to be of help for the non-transplant specialists and/or primary physicians. (Korean J Med 2013;84: ) Keywords: Hematopoietic stem cell transplantation; Infectious diseases medicine; Opportunistic infections 서론조혈모세포이식은크게두가지범주의질환을치료하는데이용된다. 첫번째범주는골수혹은골수유래세포의기능부전으로재생불량성빈혈, 골수이형성증후군, 각종면역결핍증후군 ( 중증복합면역결핍병혹은만성육아종병등 ), 유전질환 ( 점액다당류증, 당원축적병등 ), 혈색소병증 ( 지중해빈혈, 겸상적혈구빈혈등 ) 등으로결손된조직을대체하기위해이식을시행하는것이다. 두번째는급ㆍ만성백혈병, 다발골수종, 림프종, 골수증식질환등의혈액종양으로아래두가지목적으로이식을시행한다. 세포독성치료 ( 강력한항암치료, 전신방사선조사등 ) 로인한골수억제혹은골수파괴 (myeloablation) 효과를반전시키고, 종양특이혹은종양관련항원들이표현되는암세포를공격하는면역세포를제공하는것이다 [1,2]. 1970년대에시도되기시작한조혈모세포이식은공여자에따라자가혹은동종으로구분하고, 최근동종이식은조혈모세포의종류 ( 골수, 말초, 제대혈, 중간엽세포등 ), 공여자 ( 형 Correspondence to Dong-Gun Lee, M.D., Ph.D. Division of Infectious Diseases, Department of Internal Medicine, The Catholic Blood and Marrow Transplantation Center, The Catholic University of Korea College of Medicine, 222 Banpo-daero, Seocho-gu, Seoul , Korea Tel: , Fax: , symonlee@catholic.ac.kr Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Dong-Gun Lee. Infectious diseases in HSCT recipients - 제, 타인, 홑배수동종 [haploidentical]), 전처치 ( 표준 [ 골수파괴 ], 저강도 ) 등에따라다양해지고있다. 조혈모세포이식의기술뿐만아니라수혈, 집락자극인자, 항생제등지지치료방법역시발달하였고, 다양한조기진단및치료기술이개발되어이식의성적이현격히개선되었으나감염질환은조혈모세포이식후의환자들의예후에여전히많은영향을미치고있다. 특히이식의종류, 이식편대숙주병의정도에따라환자의면역기능회복이다양하여이에따라발생하는감염질환의종류와역학이다를수있다 [3,4]. 국내에서는 1983년처음으로조혈모세포이식이시작되었고, 지난 30여년간이식건수가급격히증가하였고, 다양한질환에서시도되고있다 [5]. 이식을시행한환자들은이식당시의면역기능저하로감염에취약할뿐만아니라생착후장기간에걸쳐면역기능의회복이이식의종류, 면역억제제사용, 이식편대숙주병에따라다양하게나타나고, 감염질환의종류도지역과시대에따라변하고있어, 이에따른최신지견이필요하다. 본고에서는조혈모세포이식후의감염질환을시기에따라분류하고 (Table 1), 흔히발생하는질환, 특히국내자료에서나타난호발하는질환에대해기술하고자한다. 생착전시기 (pre-engraftment period) 생착전시기에발생하는감염질환의위험인자는 1) 점막피부손상, 2) 호중구감소증으로인한포식작용손실, 3) 전처치와관련된기관장애등이다 [2]. 이식, 공여자, 조혈모세포의종류, 전처치의강도에따라회복의정도가달라지고, 이시기에발생하는감염질환은항암치료후호중구감소성발열과거의비슷하다 [1,2]. 세균감염호중구는인체에침투하는미생물에대해일차적으로방어작용에나서는선천면역 (innate immunity) 중에서도매우중요한요소로호중구수가감소한다는것은감염에취약하게됨을의미한다. 또한호중구감소증환자는염증반응을나타내는데필요한백혈구가수적으로부족하기때문에정상백혈구수를가진환자들에서흔히나타나는염증소견이발열이외에는잘나타나지않는경우가많아서진단이어렵고치료시작의적절한시점을놓칠우려가많다 [6]. 호중구감소성발열환자의원인균분포는지역에따라다를수있다. 미국, 유럽의경우그람양성균이미생물학적으 Table 1. Types of infectious diseases and risk factors according to the various time periods after hematopoietic stem cell transplantation Risk factors Bacteria Fungi Pre-engraftment period (1st 2-4 week) Immediate post-engraftment period (2nd and 3rd month) Neutropenia, barrier breakdown Acute GVHD, Immunemodulating (mucositis, central venous catheter), viruses, Impaired cellular and humoral organ dysfunction due to conditioning immunity; NK cells recover 1st, CD8 regimen T cell numbers increasing but restricted T cell repertoire Gram negative bacteria (especially enteric bacteria) Gram positive cocci Clostridium difficile Candida Aspergillus Gram negative bacteria (especially enteric bacteria) Gram positive cocci Aspergillus and other molds Pneumocystis jirovecii Late post-engraftment period (after 2nd and 3rd month) Chronic GVHD, Hyposplenism, decrease in opsonization, impaired cellular and humoral immunity; B cell and CD4 cell numbers recover slowly and repertoire diversifies Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, etc.) Nocardia Aspergillus and other molds Pneumocystis jirovecii Herpesviruses HSV EBV, CMV, HHV6 EBV, CMV, VZV Others Polyoma virus (BK, JC virus) Respiratory virus with seasonal variations Tuberculosis, NTM CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV6, human herpes virus 6; NTM, non-tuberculous mycobacteria; VZV, varicella zoster virus

3 - 대한내과학회지 : 제 84 권제 2 호통권제 630 호 로확인된감염의 60-70% 를차지하고있으나 2000년대초반까지의국내연구에서아직까지그람음성균이더흔하며이는대부분의아시아- 태평양지역의일반적인특징이다 [7]. 그람양성균중에는 Enterococcus, Streptococcus, Staphylcoccus 등이흔하고그람음성균중에는 Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa 등장내세균이흔히보고된다 [8-12]. 과거에비해 P. aeruginosa가동정되는빈도가급감한것은 fluoroquinolone을예방적항생제로사용한것과관련이있고, 반면 E. coli 에대한 fluoroquinolone의내성률은증가했다. 표 2는저자가근무하고있는혈액종양병동에서호중구감소증시기에동정된균들을정리한것이다. 같은호중구감소증시기지만항암치료병동과조혈모세포이식병동간동정된균주의차이가있고, 그람음성균, 양성균의비율도다르다 [13]. 또한호중구감소성발열의원인균에대한항생제내성률도병원마다다양할수있다. S. aureus 중 methicillin 내성 S. aureus (MRSA) 비율은 38-77%, E. coli의 fluoroquinolone 내성은 16-93%, 3세대 cephalosporin 내성은 0-7% 로보고하고있다 [8-11]. 따라서각병원에서흔히검출되는균의종류와그감수성결과를참고하여초기경험적항균제를선택하는것이필요하다. 지금까지많은치료가이드라인이나와있지만지역에따라호발하는세균의종류, 항생제감수성결과가다를수있음을알아야한다 [6,7,14]. 진균감염호중구감소증시기에호발하는진균감염은칸디다증과아스페르길루스증이다. 점막피부손상과호중구감소증, 광범위항생제사용, 기관장애, 고밀도의효모집락형성등이침습성칸디다증의위험인자가된다 [2,4]. 이식중예방적항진균제 ( 특히 fluconazole) 를사용하는기관이많아지면서칸디다증의역학도과거와는많이달라지고있다 [15]. Fluco- Table 2. Microbiologic classification of bloodstream isolates during neutropenia from chemotherapy ward and hematopoietic stem cell transplantation ward (data from Catholic BMT center, Jun/2009-May/2010) adapted from Kwon et al. [13] Microorganisms (n = 243) Chemotherapy ward HSCT ward Total (%) Gram positives (n = 122) (n = 108) (n = 14) Staphylococcus aureus (4.5) Coagulase negative staphylococci (5.8) viridans streptococci (18.1) Streptococcus pneumoniae (0.8) Rothia mucilaginosa (2.1) Enterococcus spp (14.0) Corynebacterium spp (1.6) Bacillus spp (1.2) Others a (2.1) Gram negatives (n = 119) (n = 100) (n = 19) Escherichia coli (29.6) Klebsiella pneumoniae (12.8) Pseudomonas spp (2.1) Enterobacter spp (1.6) Stenotrophomonas maltophilia (1.6) Others b (1.2) Fungus (n = 2) (n = 2) (n = 0) Candida tropicalis (0.4) Trichosporon asahii (0.4) a Includes Streptococcus agalactiae (2), Clostridium spp (2), and Gemella morbillorum (1). b Include Burkholderia cepacia (1), Sphingomonas paucimobilis (1) and Chryseobacterium indologenes (1)

4 - 이동건. 조혈모세포이식후감염질환 - nazole에감수성을보이던 Candida albicans의빈도가감소하고있어, 항진균제를선택할때주의를요한다 [15,16]. 한가지흥미로운것은저자의병원에서경험하듯이항진균제를예방으로사용하고있는호중구감소증시기에는칸디다혈증은비교적많지않다는것이다 [13]. 칸디다혈증이발생한경우카테터제거를고려할수있으나호중구감소증시기에는카테터관련감염, 위장관감염등에의한것인지감별이어렵고, 파종될위험이있어안과등과의협진이필요하다. 음전되는시기와항진균제투여기간을알기위해주기적인혈액배양검사추적이필요하다 [16]. 침습성아스페르길루스증은지난 20여년동안발생률과사망률이급속히증가한질환중하나이다. 모든장기를침범하나폐와부비동에서가장호발한다. 균사가혈관을침범하는특징이있어혈관내혈전과조직경색및응고성괴사가특징적이다. 배양과조직검사가아스페르길루스증을확인하는것이 1차적인진단방법이나호중구감소및혈소판감소등의면역저하환자여서진단에어려움이많다. 칸디다증과마찬가지로예방적항진균제사용, 종류에따라, 시대에따라역학이달라지고있어지속적인감시가필요하다 [10-12,15]. 2008년 EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) 에서암및조혈모세포이식환자의침습성진균감염에대한국제기준을제시한바있고현재가장널리쓰인다 [17]. 전통적인미생물학적진단방법이외에최근보조진단법으로사용되는방법은 CT와 galactomannan이다. 침습성폐아스페르길루스증은조기에흉부단순 X-선검사에서보이지않지만 CT에서 1개이상의결절이관찰될수있다. 달무리징후 (halo sign) 은결절이나침윤주위의흐릿함 (haziness) 으로혈관침습성인미생물에의한감염시나타나는특징적인 CT소견이며장기간지속되는호중구감소증환자에서아스페르길루스증을예측하는데도움이되지만모든환자나타나는것은아니고, 아스페르길루스증에서만나타나는것이아니다. 호중구감소증에서회복되면서초승달징후 (crescent sign) 이나타나기도한다 (Fig. 1). 비 ( 非 )-배양적검사실생물표지자로 galactomannan, 1, 3-β-D-glucan (BDG), PCR, nucleic acid sequence based amplification assay (NASBA) 등이알려져있고진단의보조적방법, 고위험군에서의감시 ( 증상이나타나기전조기진단을위해 ), 항진균제치료후반응을모니터하기위해사용된다. 특히 galactomannan은아스페르길루스세포벽에있는고유성분으로균사가증식활동을시작할때떨어져나와침습성아스페르길루스증을진단하는데유용하게사용되고있다 [18]. 호중구감소증시기의항진균제는주로경험적, 선제적치료로진균감염이확인되기전부터사용되는경우가많다. 조혈모세포이식을시행하는환자는과거항암치료를수차례받았을가능성이많고, 전처치등의강력한항암치료를시행했으며, 면역억제제등으로인해신독성의위험이매우높은환자들이다. 이런환자들에게항진균제의선택은매우중요하고, 그동안의많은가이드라인에서신독성이적은항진균제를선택하도록제시하고있다 [6,19-23]. 또한침습성아스 A B Figure 1. (A) CT halo sign. The ground glass attenuation surrounding the nodule was considered typical halo sign. (B) CT air-crescent sign. Crescent like pattern was appeared in the nodule during the recovery from neutropenia

5 - The Korean Journal of Medicine: Vol. 84, No. 2, 페르길루스증이확인되지않은상태라하더라도, 장기간지속되는호중구감소증, 생물표지자양성, 폐침윤등의소견을종합하여전문의의소견으로사용할수있어야하나, 국내현실은불행히도제한된보험기준에따라사용하는것이현실이다 [24]. 조기진단, 보조치료법의개선등으로 Herbrecht 등 [25] 이보고한 2002년보다사망률은더감소하였고, 특히조혈모세포이식환자의침습성폐아스페르길루스증에서 voriconazole을 1차로사용한시기와사용하지않은시기로나누어분석했을때사망률이통계학적으로의미있게차이가있었다는보고가있었다 [26]. 앞으로환자의생존을높일수있는개선책이마련되어야하는시점이다. 그외의진균감염으로털곰팡이증, 푸사륨, Alternaria, Scedosporium 등이호중구감소증이지속되는시기에발생할수있고, 특히최근사상진균에효과적인항진균제를예방으로사용하기시작하면서점차증가하고있다는보고가있다. Herpes simplex virus (HSV) 조혈모세포이식중호중구감소증시기에발생하는가장흔한바이러스감염으로 HSV가알려져있다. 대부분점막염의형태로나타나지만식도염, 기관기관지염, 폐렴등도발생한다 [2]. 동종조혈모세포이식환자에서 HSV에대한예방적항바이러스제를사용하지않는경우 HSV IgG 혈청검사양성인환자의 62-80% 정도에서 HSV 재활성화가발생하는것으로알려져있다. 자가조혈모세포이식의경우항바이러스제예방을하지않으면 2-6% 정도에서 HSV에의한병변이발생하는것으로알려져있다 [27]. 따라서동종조혈모세포이식환자, 자가조혈모세포이식환자중점막염발생위험이높은환자중에서 HSV에대한혈청검사양성인경우예방적항바이러스제사용이권장된다. 1990년대초국내 HSV type 1에대한항체보유율은 30대이상인구에서 100% 였고 20대의경우 91%, 10대의경우 82% 으로 [28] 국내에서는대부분항바이러스제예방이권장된다 [3,6]. 초기생착후시기 (immediate post-engraftment period) 전처치항암제의종류와골수파괴유무에따라정도는달라지지만세포면역기능저하가있는시기이고, 동종이식의경우급성이식편대숙주병의정도에따라기회감염의확률 이증가한다. 자가이식은동종이식에비해면역기능회복이빠르다. Cytomegalovirus (CMV) CMV는조혈모세포이식후재활성화또는재감염되어발열, 호중구감소, 간염, 폐렴, 식도염, 위염, 장염, 망막염등의 CMV 질환 (disease) 을일으키며, 질병이발행한경우적극적인항바이러스치료에도치명적이다 [29,30]. 지난수십년간적극적인예방과질환의조기진단을위한모니터링방법들이연구되었고, CMV pp65 항원혈증검사, 실시간정량적 PCR 등이현재감시와선제치료를위해사용되고있다 [31,32]. 조혈모세포이식의경우 CMV 부하 (load) 와 CMV 질환과의관계는고형장기이식과는달리중등도의상관 (correlation) 만을모여 CMV 질환이발생해도항원혈증이나 DNA 혈증이선행되지않거나동반되지않기도하여이런표지자들이질환은예측하지못할수있다. 따라서 CMV 질환의조기진단과치료를위해서는위험군을찾고각침범장기별 CMV 질환의임상양상을알고있는것이중요하다. 국내한보고에서동종이식의 2.9%, 자가이식의 0.5% 에서 CMV 질환이발생하였고, 폐렴 (38.6%), 망막염 (36.4%), 장관염 (15.9%), 순이었으며증상발현시기는이식후평균 90일이었으나 일로넓은범위였다 [33]. CMV DNA혈증이있는환자를대상으로한최근연구에서 > 75,000 copies/ml 이면망막염발생위험이높아진다고보고하였다 [34]. 대부분의이식센터에서선제치료를도입하고있지만성인 CMV 항체양성률이 % 인국내는조혈모세포이식이항체양성자에서항체양성자로이루어지는환경이고이식후증상을동반한 CMV 감염의빈도가 10-50% 에이른다 [30]. 최근적극적인 CMV 모니터링과선제치료로이식직후발생하는 CMV 감염빈도는줄었으나이식 3개월이후발생하는후기 CMV 감염이증가하고있는추세이고특히만성이식편대숙주병으로 CMV 특이 T세포면역기능이회복되지않았을때많이발생한다 [2]. Alemtuzumab 등의단클론항체를사용하거나 [35] 이식편대숙주병이있는경우빈도가높아지고, 이식편대숙주병과구별이안되거나공존하고있는경우도있어진단이어렵고, 진단이늦어질경우 ganciclovir, foscarnet, cidofovir 등의항바이러스제에반응이없을수도있어보다적극적인진단과치료, 경험이필요하다

6 - Dong-Gun Lee. Infectious diseases in HSCT recipients - 진균감염이시기에는호중구감소증과점막피부손실이회복되어칸디다감염의위험은감소하나, 아스페르길루스증의위험은여전히존재한다 [1,2]. 호중구감소증시기의아스페르길루스증은면역반응감소로인한혈관침범 (angioinvasiveness) 이주요발생기전이지만호중구감소증에서회복되었고장기간스테로이드, 면역억제제를사용하는시기에발생하는아스페르길루스증은혈관침범에의한것보다는국소염증 ( 예를들어기도를통한전파 [airway invasiveness]) 이주요기전이다 [18]. 자가이식보다는동종이식에서빈도가더높고, 급성이식편대숙주병과스테로이드사용이위험인자이다 [3,19]. 진단은생착전시기와크게다르지않으나최근혈액질환환자중침습성폐아스페르길루스증의 CT 소견은호중구감소증이있는시기와이식후호중구가회복된시기에따라다를수있으므로진단기준을재정립해야한다는의견이제시되고있어 [36], 현재의진단기준을적용하는데주의가필요하겠다. 치료역시생착전시기와다르지않다. 이식편대숙주병이있어면역억제제를장기간사용하는경우진균감염을예방하기위해항진균제를복용하고있을수있고, 특히사상진균에효과적인항진균제를최근처방하면서털곰팡이증등아스페르길루스이외의사상진균이발생할위험이공존한다 [15,20,22,23]. 폐포자충 (Pneumocystis jirovecii) 폐렴폐포자충폐렴의주증상은화농성가래보다는발열, 호흡곤란, 마른기침등이다. 전형적인방사선소견은양측폐문부주위에서시작하는양측미만성침윤이지만초기엔정상이거나상엽에구역경화 (segmental consolidation), 기흉등비전형적소견이있을수있다. 대개이식후 6개월이내에호발하나만성이식편대숙주병등으로장기간면역억제제를복용하고있는환자들에서 6개월이후에도발생한다 [3,4]. CT, 기관지내시경및기관지폐포세척등이조기에적극적으로시도되어야한다. 동반된감염질환특히 CMV, 아스페르길루스등중복감염이있을수있고이경우예후가나쁘다 [37]. 증상이심할경우 steroid를보조적으로사용할수있다. Trimethoprim/sulfamethoxazole 예방으로발생빈도가현격히줄었고, 동종이식의경우이식후적어도 6개월혹은면역억제제중지할때까지예방이필요하다 [3,6]. Epstein-Barr virus (EBV) 를포함한헤르페스바이러스감염 EBV 감염은만성이식편대숙주병이있는환자에서 3-5개월후발생하지만질환으로진행하는일은비교적드물다. 전염단핵구증과비슷한증상으로발열, 호중구감소증이있을수있고, 그외에재생불량성빈혈, 구강모백반증 (oral hairy leukoplakia), 이식후림프세포증식병 (post-transplantation lymphoproliferative disease, PTLD) 등이나타난다 [2]. 조혈모세포이식후 PTLD는다른고형장기이식에비해그빈도가낮으나타인간동종이식, T세포를제거한조혈모세포이식, 만성이식편대숙주병, 이식편대숙주병예방을위해항-림프구항체를사용한경우등에서나타날수있다 [38]. 다른헤르페스바이러스중 human herpes virus 6 (HHV6) 가뇌수막염, 출혈성방광염등의원인이될수있다 [39]. 출혈성방광염조혈모세포이식후발생하는출혈성방광염은시기에따라구분할수있고, 이식후 7일이내에발생하는경우는대개비-감염성원인이다. 비감염성원인으로는 cyclophosphamide, ifosphamide, busulfan, etoposide 등항암제와방사선치료가주이고, 후기출혈성방광염은바이러스에의한감염을감별해야한다. Adenovirus, polyomavirus (BK, JC virus), CMV, HSV, HHV6 등이원인으로보고되고있다 [40,41]. BK virus DNA 정량검사를시행하여소변에서 > copies/ml, 혈액에서 > 10 4 copies/ml 이상이면출혈성방광염으로진행할확률이높다는보고가있었다 [42,43]. 이식편대숙주병이출혈성방광염의위험인자이고, 감염에의한출혈성방광염치료의시작은가능하면초기에면역억제제를최소화하는것이다. 대부분수액공급, 방광세척등의보존적요법으로호전되지만 Adenovirus, CMV, BK virus는 cidofovir가효과적일수있고, 3등급 ( 육안혈뇨 + 혈액응고 ) 이상이고보존적치료에반응이없는경우항바이러스제치료를고려할수있다 [40,44]. 호전되지않으면급성신손상이진행할수있고, 방광내 alum, formalin, prostaglandin 주입, 혈관색전술등을고려한다 [40]. 후기생착후시기 (late post-engraftment period) 자가이식의경우면역계가재구성되어회복되는시기이고, 동종이식후만성이식편대숙주병이있는시기와일치한

7 - 대한내과학회지 : 제 84 권제 2 호통권제 630 호 다. 따라서자가이식환자는이시기가되면기회감염의위험이거의사라지나, 만성이식편대숙주병으로면역억제제를장기가복용하고있는동종이식환자에선여전히감염의위험이있다. 피막세균감염 (Infection due to encapsulated bacteria) 생착전및초기생착후시기에발생하는감염질환이계속발생할수있으나특히만성이식편대숙주병과관련된체액면역결손으로 Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis 등의피막세균에의한중증감염위험이있다 [2,3]. 만성, 중증이식편대숙주병이있는환자에서 IgG2, IgG4 subclass 결손이보고되고있고, 이는폐렴알균에의한중증폐렴, 뇌수막염, 패혈증과관련이된다 [45]. 조기진단및치료가필수적이고, 그외에예방접종이강조된다. 3개균모두백신이있고, 최근예방접종시기가이식후 1년에서 3-6개월, 6-12개월등으로당겨졌으며최근도입된단백결합백신이기존의다당류백신보다면역원성이더높다고알려져있다 [3,46]. 호흡기바이러스감염호중구감소증시기에도발생할수있고, 지역사회에서의유행과계절변화와관련이된다. Respiratory Syncytial Virus (RSV), parainfluenza virus 1, 2, 3, influenza virus A, B, rhinovirus, coronavirus, adenovirus 등이흔하고최근 human metapneumovirus, bocavirus, parvovirus B19, KI and WU polyoma virus 등이새로이보고되고있다 [1-3]. 조혈모세포이식을시행한환자들에서호흡기바이러스감염은상부호흡기감염에국한되지않고폐렴등의하부호흡기감염으로진행될확률이높고, 일부바이러스에대해서만치료약제가있다는문제가있다 [47,48]. 최근호흡기바이러스정량검사에대한연구가진행중이다 [49]. 국내에서조혈모세포이식후호흡기바이러스감염에대한연구는거의없는상태지만 [50], 최근저자의조혈모세포이식센터의 4년간자료에서 RSV, influenza virus, parainfluenza virus, rhinovirus, adenovirus 등의순으로검출되었고, 12월- 2월에호발하였다 (Fig. 2). 림프구감소증, 폐렴이동반되었을때사망률이증가하였다. 호흡기바이러스중인플루엔자는이환된후 2차세균성폐렴이발생할수있어주의해야하고, 백신이가능하다. 최근의가이드라인에서는매년불활화 Figure 2. Seasonal distribution of respiratory viral infection in hematopoietic stem cell transplant recipients (data from Catholic BMT center, Jan/2007-Dec/2010). 인플루엔자백신접종을권장하고있고이식 4-6개월후접종이가능하다. 또한환자의가족, 밀접한접촉자, 환자를돌보는의료인의예방접종을권장한다 [46]. 대상포진 대상포진은수두대상포진바이러스 (Varicella-Zoster virus, VZV) 초감염후후근신경절에잠복되어있던바이러스가재활성화되어발생하는질환이다. 국내에서는성인의경우대부분자연감염을통해 VZV를획득하여향후대상포진이발생할수있는위험군이된다 [51]. 임상특징은피부병변이시작되기 2-3일전에피부분절을통해이상한감각혹은통증이생기고, 홍반성반점구진, 그후빠르게수포가형성된다. 수포는터져서궤양을형성하고가피가생긴후마르게된다. 통증과대상포진후신경통이큰문제이다. 대부분하나의피부분절을편측으로침범하나조혈모세포이식후와같은면역저하상태에서는 2-3개이상의피부분절을침범하거나파종되고, 내장, 중추신경계등을침범할수있다 [2]. 치료는크게항바이러스제투여와급성통증및대상포진후신경통을감소시키기위한보조요법으로나눌수있다. 발진발생 72시간후항바이러스투여가효과적이지는명확하지않으나새로운수포성발진이계속생기고있는경우, 눈, 피부및신경학적합병증이동반된경우, 중증의증상을보이는경우는발진발생 72시간이후라도항바이러스제를투여한다. 저자가근무하고있는센터의최근경험은 년

8 - 이동건. 조혈모세포이식후감염질환 - 동종이식을시행한 230명의환자에서 79명 (34.3%) 에서대상포진이발생했다. 누적발생률은 1년째 22%, 2년째 30.8%, 3년째 38.6%, 4년째 41.2% 였다. 흉부피부분절이가장많았고 (43.8%), 11.4% 가파종성이었다. 내장을침범한경우는없었고, 대상포진으로사망한경우도없었다. 현재사용가능한대상포진백신은생백신으로이들이식환자에게는사용할수없는상황에서최근 acyclovir 예방을생착때까지만이아니고면역억제제를중지할때까지장기간사용할경우대상포진을줄일수있다는보고가있었다 [52]. 결핵조혈모세포이식후결핵은흔하지않는질환이나국내결핵발병률, 유병률은선진국에비해높아주의가필요하다. 만성이식편대숙주병, 과거결핵을앓았던병력, 이식전처치로전신방사선조사시행, T세포제거등이결핵의위험인자로알려져있다 [3]. 이식후결핵보고는많지않으나반정도가아시아에서보고되고있고 [53] 국내는한후향적보고에서 3.1% 발생하였다. 이식후평균 257.2일에발병하나 일로범위가다양하다 [54]. 저자가근무하고있는센터의최근경험은 2004년 1월에서 2011년 3월기간동종조혈모세포이식을시행한 846명중 19명 (2.25%) 에서평균 331일후에결핵이발생하였다. 이는일반인구표준발생률의 11.86배 (95% 신뢰구간 ) 로만성이식편대숙주병이있는군에서없는군에비해약 3배더많이발생하였다. 침범부위는폐가가장흔하지만폐외결핵이 42% 로국내일반인의폐외결핵분포 (15-20%) 보다높았고, 평균 1년치료하였다. 최근튜베르쿨린검사와인터페론감마분비검사등으로잠복결핵을검사하고양성인경우 isoniazid 예방을하는것이도움이된다는보고가있지만조혈모세포이식환자에서의적절한검사방법, 시기, 기간등이정립되어있지않다 [3,55]. 결론조혈모세포이식은다양한악성혈액종양과면역질환을치료하기위한방법으로널리시행되고있고, 의학의발전과함께더많은질환을치료하기위한다양한기법이개발되고있다. 보존치료역시발전하여환자들의생존율이개선되었으나, 감염질환은여전히유병률, 사망률에많은부분을 차지하고있다. 이식후감염질환은이식의종류, 면역억제제, 이식편대숙주병등에따라, 시기에따라다를수있고, 특히지역과계절에따라서도특징을가지게된다. 이식혹은감염전문의뿐만아니라 1차진료를담당하는의사들도이식후감염질환을이해하는것이환자와가족의건강을개선하는지름길이라믿고, 앞으로관련있는많은사람들이관심을가지고더욱발전이있기를기대한다. 중심단어 : 조혈모세포이식 ; 감염질환 ; 기회감염 REFERENCES 1. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010;24: Dropulic LK, Lederman HM. Overview of infections in the immunocompromised host. In: Hayden RT, Carroll KC, Tang YW, Wolk DM, eds. Diagnostic Microbiology of the Immunocompromised Host. 1st ed. Washinton, DC: ASM Press, 2009: Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15: Safdar A, Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects. Clin Infect Dis 2011;53: Lee JW, Kim CC. The activity of hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2008; 42(Suppl 1):S Lee DG, Kim SH, Kim SY, et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea. Korean J Intern Med 2011;26: Jun HX, Zhixiang S, Chun W, et al. Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever. Int J Antimicrob Agents 2005;26(Suppl 2): S Choi SM, Lee DG, Park YH, et al. Infections in patients with acute leukemia: comparison of induction chemotherapy group and reinduction chemotherapy group. Infect Chemother 2003;35: Kim HB, Park SW, Kim US, et al. Infections in Patients with Acute Leukemia ( ). Korean J Hematol 1999;34: Yoo JH, Lee DG, Choi SM, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell trans

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