pissn: 2288-0402 eissn: 2288-0410 Allergy Asthma Respir Dis 3(4):297-301, July 2015 http://dx.doi.org/10.4168/aard.2015.3.4.297 CASE REPORT 이차항결핵제에약물과민반응증후군을보인다제내성결핵환자에서급속탈감작요법에준한항결핵제재투여 1 예 문성도 1,2, 원하경 1,2, 조재영 1, 강민구 1,2, 김주영 1,2,3, 박한기 1,2,3, 김수정 4, 강혜련 1,2,3 1 서울대학교의과대학내과학교실, 2 서울대학교의학연구원알레르기및임상면역학연구소, 3 서울대학교병원지역의약품안전센터, 4 경북대학교의과대학내과학교실 Successful readministration of second-line antituberculous agents in a patient with near-fatal drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome Sung Do Moon 1,2, Ha Kyung Won 1,2, Jae-Young Cho 1, Min-Koo Kang 1,2, Ju-Young Kim 1,2,3, Han-Ki Park 1,2,3, Sujeong Kim 4, Hye-Ryun Kang 1,2,3 1 Department of Internal Medicine, 2 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul; 3 Regional Pharmacovigilance Center, Seoul National University Hospital, Seoul; 4 Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea For the treatment of multidrug-resistant (MDR) tuberculosis, maintenance of appropriate antituberculous agents is essential because of its low cure rate and high dropout rate. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug-induced systemic hypersensitivity response resulting in cessation of causative agents. In cases of second-line antituberculous agent-induced DRESS, it is extremely difficult to find other replacement medications to cure MDR tuberculosis. A 53-year-old male who had taken the second-line antituberculous agents (cycloserine, streptomycin, p-aminosalicylic acid, and prothionamide) as well as pyrazinamide for 5 weeks experienced DRESS syndrome accompanying hepatic coma. His symptoms improved with discontinuation of antituberculous agents and administration of high-dose methylprednisolone for 1 month. To resume the antituberculous medication, second-line antituberculous agents were administered one by one using a rapid desensitization protocol. While kanamycin, levofloxacin, and cycloserine were successfully readministered, p-aminosalicylic acid- and prothionamide-induced cutaneous hypersensitivity symptoms were relatively mild compared to previous reactions. Herein, we report a case of successfully treated MDR tuberculosis having a history of fatal DRESS syndrome to antituberculous agents using the rapid desensitization protocol. (Allergy Asthma Respir Dis 2015;3:297-301) Keywords: Drug hypersensitivity syndrome, Antitubercular agents, Immunologic desensitization 서론결핵은 2002년부터전세계적으로는발생률이감소추세를보이고있으나, 아직까지유병환자수는 2012년기준 1,200만명에달하는보건학적으로중요한질환이다. 1) 우리나라의활동성폐결핵환자의유병률은과거와비교하여많이감소하였지만경제협력개발기구 (Organization for Economic Cooperation and Development) 에속한국가중에서는발생률과유병률이가장높다. 2) Isoniazid (INH), rifampin (RFP) 은결핵치료의근간이되는가장중요한약제로, 이들두가지약제에대해동시에내성을보이는결핵균에의한감염을 다제내성결핵 이라고한다. 다제내성결핵의비율은근래들어새로발생한환자중 3.6%, 재발한환자중 20% 인것으로보고되었으며 1) 우리나라의경우전국실태조사에서다제내성률은새로진단된결핵환자의 1.9% 2.9%, 재발한환자의경우 8% 내외로약 5천명가량의환자가있을것으로추산된다. 다제내성결핵의경우치료가매우어려울뿐아니라치료성공률또한낮 Correspondence to: Hye-Ryun Kang http://orcid.org/0000-0002-2317-4201 Division of Allergy and Clinical Immunology, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea 2015 The Korean Academy of Pediatric Allergy and Respiratory Disease Tel: +82-2-2072-0820, Fax: +82-2-742-3291, E-mail: helenmed@snu.ac.kr The Korean Academy of Asthma, Allergy and Clinical Immunology This study was supported by a grant from Ministry of Food and Drug Safety to operation of the Regional This is an Open Access article distributed under the terms of the Creative Pharmacovigilance Center in 2015. Commons Attribution Non-Commercial License Received: April 9, 2015 Revised: June 8, 2015 Accepted: June 17, 2015 (http://creativecommons.org/licenses/by-nc/3.0/). 297 http://www.aard.or.kr
Allergy Asthma Respir Dis Moon SD, et al. Antituberculous treatment in a patient with DRESS syndrome with desensitization protocol 아지속적인의학적관심과보건관리체계의보완이필요하다. 저자들은다제내성폐결핵환자에서 pyrazinamide (PZA) 와함께이차항결핵제인 cycloserine (CS), streptomycin (SM), p-aminosalicylic acid (PAS), prothionamide (PTH), levofloxacin 투약후 drug reaction with eosinophilia and systemic symptom (DRESS) 증후군이발생했던환자에서탈감작요법에준해항결핵제를재투여하여 cycloserine, kanamycin, levofloxacin을포함한약제로결핵치료를성공적으로마친사례를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 최OO, 남 /53세주소 : 발열을동반한전신반점구진상발진현병력 : 외부병원에서활동성폐결핵으로진단받고 1차항결핵제 (INH, RFP, ethambutol [EMB], pyrazinamide [PZA]) 를 4개월간복용하였다. 감수성검사결과 INH, RFP, EMB에대해내성을보여, 다제내성결핵으로진단하였고, 항결핵제를 PZA, SM, levofloxacin, CS, PAS, PTH로변경하였다 (Table 1). 약제변경 20일째발열이시작되었고, 30일째양측상완과안면에반점구진상발진이나타났다. PZA, SM, levofloxacin을중단하고 CS, PAS, PTH만유지하였더니발열이소실되고발진은더이상진행하지않았다. 5일뒤상용량의 PZA 재투여하였고다음날고열과함께전신성급성신손상 (prerenal acute kidney injury) 이발생하여 PZA를중단하였다. 그러나이후에도전신에반점구진상발진이진행하여나머지항결핵제들도중단하였으나, 피부병변악화와함께의식혼탁을보여전원되었다. 과거력 : 특이사항없음. 알레르기병력 : 특이사항없음. 가족력 : 특이사항없음. 신체검진 : 생체활력징후는혈압 113/73 mmhg, 맥박수 117 beats/min, 호흡수 32 breaths/min, 체온 37.3 C 로측정되었고, 지남력은있었으나경미한수준의의식수준저하를보였고, 힘들어하는급성기병색을보였다. 안면부의피부발진및탈락소견을보이고사지에도홍반과융합형발진이산재한양상이었다. 검사소견 : 말초혈액검사에서백혈구 19,600/mm 3 ( 호산구 19.1%), 혈색소 11.3 g/dl, 혈소판 133,000/mm 3, 아스파르테이트아미노전이효소 1,265 IU/L, 알라닌아미노전이효소 553 IU/L, 프로트롬빈시간 international normalized ratio 1.74, blood urea nitrogen 66 mg/dl, creatinine 2.27 mg/dl 였다. 경과및치료 : 2차항결핵제투여후 7주경발생한전신의반구진성발진, 간효소수치상승, 급성신장손상, 고열, 호산구증가, 경부임파선증대소견에대해 2차항결핵제에의한 DRESS 증후군으로진단하였다. 18일간 methylprednisolone 1 mg/kg 투여하면서의식수준호전과함께피부증상, 간 / 신장기능회복하여, 경구스테로이드로전환후점진적으로감량하면서퇴원하였다. 한달후스테로이드는감량하여중단하였고, 피부병변의재악화소견은관찰되지않아다제내성결핵에치료를재개하기로하였다. 이전경과에서 PZA는단독재투여후급격한악화를보였기때문에원인약제로강력하게의심되어재투여에서배제하였고, PTH부터 250 mg 1일 2회로투여를재개하였으나, 4회복용후고열과함께전신에심한홍조및두드러기발생하여중단하였다. 이에다약제과민반응 (multiple drug hypersensitivity) 가능성을배제할수없어이후항결핵약제들은급속탈감작요법에준해재투 Table 1. Summary of drug administration and related symptoms Day PZA SM CS PAS PTH LVFX KM AC Remarks 0 PZA was already started 4 months ago. 27 Fever on day 27, maculopapular rash on day 37 31 Clinical improvement after discontinuation of PZA, SM, and LVFX 36 Fever on the next day of PZA readministration 37 Maculopapular rash and azotemia despite discontinuation of PZA 42 Generalized maculopapular rash and hepatic encephalopathy despite discontinuation of CS, PAS, PTH 43 71 Administration of systemic steroid 74 Severe generalized erythema and urticaria 79 81 83 Pruritus, erythema, and urticaria 107 119 Erythema urticaria on both arms 134, administration of full dose;, discontinuation;, administration with desensitization protocol;, hypersensitivity reaction despite administration with desensitization protocol; PZA, pyrazinamide; SM, streptomycin; CS, cycloserine; PAS, p-aminosalicylic acid; PTH, prothionamide; LVFX, levofloxacin; KM, kanamycin; AC, amoxicillin clavulanate. 298 http://dx.doi.org/10.4168/aard.2015.3.4.297
문성도외 항결핵제 DRESS 환자에서급속탈감작요법에준한항결핵제재투여 Allergy Asthma Respir Dis 여하기로결정하였다. PTH 재투여로인한과민반응이발생하고 48 시간경과후피부증상이소실됨을확인하였으며, 다음단계로 kanamycin 을세가지농도로만들어순차적으로정맥투여하였으 며별다른과민반응없이목표용량 (1,000 mg/day) 에도달하였고, 이후 2 일간상용량의 kanamycin 투여하여과민반응이없음을확 인하였다 (Table 2). Levofloxacin 도 kanamycin 과마찬가지로세가 지농도의용액을만들어탈감작요법에준한방법으로목표용량인 1 일 750 mg 까지정맥투여하였으며이어 2 일간상용량을투여하면 서과민반응이발생하지않음을확인한후경구로전환하였다. 이 어 PTH 를두가지농도로만들어탈감작요법에준해경구투여하 였으나 (Table 3), 7 단계 (125 mg) 에서홍조와두드러기, 가려움이발 생하였다. 이전에상용량으로투여하였을때보다훨씬경한증상을 보였으나탈감작에실패한것으로보고투여를중단하였다. 4 일후 과민반응증상이모두소실된상태에서 CS 에대해서도동일하게 세농도의용액을만들어탈감작요법에준해과민반응없이투여 하였으며, 이후 2 일간상용량을복용하여과민반응이발생하지않 음을확인하였다 (Table 4). 이틀후 PAS 역시두가지농도 (6.6 mg/ ml, 66 mg/ml) 로탈감작요법에준해 CS 와유사한방법으로순차 적으로투여하였으나 13 단계 (3,300 mg) 에서홍조및열감, 양팔의 두드러기, 손바닥발바닥의이상감각을호소하여중단하였다. 이후두달간 kanamycin, levofloxacin, cycloserine 의 3 제를유지 하면서과민반응이발생하지않아, amoxicillin clavulanate (625 mg, 3 회 /day) 를추가하여, 이후 10 개월간 kanamycin, levofloxacin, Table 2. Intravenous rapid desensitization protocol for kanamycin (target dose: 1,000 mg) Step Concentration (mg/ml) Rate (ml/hr) Time (min) Administrated dose (mg) Cumulative dose (mg) 1 0.0491 5 15 0.0614 0.0614 2 0.0491 10 15 0.1228 0.1841 3 0.0491 20 15 0.2455 0.4297 4 0.0491 40 15 0.4910 0.9207 5 0.0491 80 15 0.9821 1.9027 6 0.0491 160 6.3 0.8225 2.7252 7 0.4955 15 15 2.4775 5.2027 8 0.4955 40 15 4.9550 10.1577 9 0.4955 80 15 9.9099 20.0676 10 0.4955 160 5.6 7.4324 27.5000 11 5.0 20 15 25 52.5 12 5.0 40 15 50 102.5 13 5.0 80 133.4 897.5 1,000 1:100 solution for steps 1 6: 5.5 ml of 1:10 solution was added to normal saline 50 ml (0.0491 mg/ml); 1:10 solution for steps 7 10: 5.5 ml of 1:1 solution was added to normal saline 50 ml (0.4955 mg/ml); 1:1 solution for steps 11 13: Kanamycin 1,000 mg in normal saline 200 ml (5.0 mg/ml). cycloserine, amoxicillin clavulanate 의 4 제를유지하였다. Kanamycin 총 1 년간투여후중단하였으며, 나머지 levofloxacin, cycloserine, amoxicillin clavulanate 를총 1 년 6 개월간별다른과민반응 없이유지후치료를종료하였다. 항결핵제중단후 3 개월후항결핵제 10 종에대한첩포시험을시 행하였고 48 시간경과후 PAS, PTH, SM 에양성반응을확인하였 다 (Fig. 1). 첩포를제거한후 72 시간째관찰하였을때도여전히양 성반응이관찰되었다. Table 3. Oral rapid desensitization protocol for prothionamide (target dose: 250 mg twice a day) Step Time from start (hr) Administered dose (mg) Cumulative dose (mg) 1 0 0.025 0.025 2 1 0.050 0.075 3 2 0.125 0.2 4 3 0.25 0.45 5 4 0.5 0.95 6 5 1.0 1.95 7 6 2.0 3.95 8 7 3.75 7.7 9 8 7.5 15.2 10 9 15 30.2 11 10 30 60.2 12 11 62.5 122.7 13 12 125 247.7 14 13 250 497.7 1:10 solution for steps 1 6: 5.5 ml of 1:1 solution was added to 5% dextrose water 50 ml (0.248 mg/ml); 1:1 solution for steps 7 11 prothionamide 125 mg in 5% dextrose water 50 ml (2.5 mg/ml). Tablets were used for steps 12 14. Table 4. Oral rapid desensitization protocol for cycloserine (target dose: 500 mg twice a day) Step Time from start (hr) Administered dose (mg) Cumulative dose (mg) 1 0 0.05 0.05 2 1 0.10 0.15 3 2 0.25 0.4 4 3 0.5 0.9 5 4 1.0 1.9 6 5 2.0 3.9 7 6 4.0 7.9 8 7 7.5 15.4 9 8 15.0 30.4 10 9 30.0 60.4 11 10 60.0 120.4 12 11 125 245.4 13 12 250 495.4 14 13 500 995.4 1:10 solution for steps 1 6: 2.0 ml of 1:1 solution was added to 5% dextrose water 18 ml (0.5 mg/ml); 1:1 solution for steps 7 12 cycloserine 250 mg in 5% dextrose water 50 ml (5.0 mg/ml). Tablets were used for steps 13 15. http://dx.doi.org/10.4168/aard.2015.3.4.297 299
Allergy Asthma Respir Dis Moon SD, et al. Antituberculous treatment in a patient with DRESS syndrome with desensitization protocol Fig. 1. Skin findings of patch test to antitubercular drugs read at 48 hours. Test drugs are isoniazid (INH), levofloxacin (LV), prothinamide (PTH), p-aminosalicylic acid (PAS), streptomycin (SM), ethambutol (ETM), cycloserine (CS), amoxicillin clavulanate (Am), pyrazinamide (Pyz), rifampicin (RFP) in clockwise direction from the right top. 고찰 다제내성결핵의경우감수성결핵에비해더욱오랜치료기간 과많은비용이들며 2 차항결핵제의독성으로인해치료및관리 에어려움이있다. 3) 결핵약에대한과민반응은치료중단으로이어 지기때문에이에대한적절한평가와대처가중요한데, 특히다제 내성결핵의경우약제선택의폭이제한되어있어다제내성결핵 약에대한과민반응이발생할경우보다신중한접근이필요하다. DRESS 증후군은약물에대한지연형과민반응의일종으로 2 8 주간의지속적인약물투여이후피부발진, 발열, 호산구증가 및다발성내부장기손상이발생하는것이다. DRESS 증후군은일 반적인약진과는달리발열, 피부발진, 림프절종대, 호산구증다증 과함께여러내부장기를침범하는데, 사망률이 10% 에달하는중 증과민반응으로알려져있다. DRESS 증후군으로진단되면, 최대 한빨리원인약물을중단해야하며, 장기침범이있을경우다량의 스테로이드전신투여가필요하다. 내부장기침범은간손상 (94%) 이가장흔하며이는주요사망원인이기도하다. 다른장기의손상 은상대적으로드물지만, 신장 (8%), 폐 (5%), 심장 (2%), 뇌 (2%) 등의 손상을보이는경우가있다. 4,5) Intravenous immunoglobulin (IVIG) 및 cyclosporin은주로 Stevens Johnson syndrome, Toxic epidermal necrolysis 에서시도되고있으며 DERSS에도 IVIG를사용했다는보고들이있으나아직까지연구결과가부족하고고가의약제비때문에임상에서적용하기어려운면이있다. 6) 현재까지 DRESS의 1차치료제는전신스테로이드요법이활용되고있으며, 본증례의환자는스테로이드투여로빠른호전을보여 IVIG나 cyclosporine 투여는고려하지않았다. 6-8) DRESS 증후군에서는드물지않게 다약제과민반응 을보인다. 9) DRESS 증후군에서다약제과민반응은각약제가모두과민반응의원인인지, 아니면면역체계가활성화된상태에서원인약이아닌약제에도반응하는것인지는확실하지않다. 본증례의환자도이전병력에서 PZA 과민반응이의심되었으며, 재투여를하면서 PTH와 PAS에과민반응을보여최소한 3가지이상약제에과민반응을보이는것으로추정되었고, 이후첩포검사에서도 PTH, PAS, SM의 3가지약제에양성을보였다. 일반적으로 DRESS 증후군으로진단되면원인약제의재투여는금기사항이다. 10) 그러나, 본증례의환자처럼활동성다제내성결핵으로진단받은경우다른효과적인대체약제가없기때문에, 원인약제가의심됨에도불구하고항결핵제치료를재개해야했다. 일반적으로항결핵제를재투여할경우에는한가지약제씩용량을점진적으로증량하여과민반응이생기는지확인하는단계적시험투여 (graded challenge) 를하는것이일반적이다. 그러나, DRESS 증후군을포함한전신과민반응환자의경우항결핵제와같이여러가지약제를동시에투여하는경우두가지이상의다양한약제에반응할수있으며, 단계적시험투여를할경우심한전신증상을유발시킬수있다. 따라서항결핵제에의한전신과민반응을보인경우, 일반적인접근법으로는결핵치료가상당기간지연되는결과를초래할수있다. 반면, 탈감작요법은과민반응을일으키는원인항원을극소량을투여한후점차항원의양을늘려궁극적으로상용량의원인항원에대한 면역관용 (immune intolerance) 상태를유도하는것이다. 과거에는 IgE 매개즉시형과민반응에대해주로사용되었으나, 최근 T 세포매개의지연형과민반응에도종종사용되고있다. 10) 전통적으로즉시형과민반응은급속탈감작요법 (rapid desensitization), 지연형과민반응에는완만탈감작요법 (slow desensitization) 을적용하였지만, 최근지연형과민반응에도급속탈감작요법을적용하여성공한사례들이다수보고되었다. 11,12) 본증례의환자는단기간내에과민반응발생을최소화하여항결핵제재치료를하기위해위해급속탈감작요법에준한순차적인항결핵약제재투여를시작하였다. 급속탈감작요법에준해투여한결과 PTH, PAS의경우증상의발생을완전히예방할수는없었으나, 이전에비해상대적으로경한증상만을유발하여이후항결핵약제투여일정에지장을주지않았다. 항결핵제전신과 300 http://dx.doi.org/10.4168/aard.2015.3.4.297
문성도외 항결핵제 DRESS 환자에서급속탈감작요법에준한항결핵제재투여 Allergy Asthma Respir Dis 민반응환자에서이전에투여한적이없는새로운약제를투여하 여전신과민반응이발생하는 multidrug hypersensitivity syndrome 가능성이있는바본증례의환자에서도이러한경과가발 생하는것을우려하여보다안전한약물치료를위해탈감작요법에 준해 kanamycin 을투여하였다. 이처럼재투여가반드시필요한전 신중증과민반응에서재치료를위해원인약제로의심되는약제 를투여할때급속탈감작요법에준해재투여를하는것을하나의 선택사항으로고려해볼수있겠고, 이에대해향후보다많은임상 적경험의축적이필요하리라예상한다. 저자들은항결핵제투여후발생한 DRESS 증후군에서다제내 성결핵에치료재개를위하여 2 차항결핵제를신속탈감작요법에 준해재투여하여결핵치료를성공적으로유지및종결한임상사 례를경험하였기에보고하는바이다. REFERENCES 1. World Health Organization. Global tuberculosis report 2013 [Internet]. Geneva: World Health Organization, 2013 [cited 2014 Apr 1]. Available from: www.who.int/iris/bitstream/10665/91355/1/9789241564656_eng. pdf. 2. Kim HJ. Current status of tuberculosis in Korea. Korean J Med 2012:82: 257-62. 3. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, et al. Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med 2008;178:1075-82. 4. Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking. Clin Exp Dermatol 2011;36:6-11. 5. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med 2011;124:588-97. 6. Galvao VR, Aun MV, Kalil J, Castells M, Giavina-Bianchi P. Clinical and laboratory improvement after intravenous immunoglobulin in drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol Pract 2014;2:107-10. 7. Joly P, Janela B, Tetart F, Rogez S, Picard D, D'Incan M, et al. Poor benefit/ risk balance of intravenous immunoglobulins in DRESS. Arch Dermatol 2012;148:543-4. 8. Santhamoorthy P, Alexander KJ, Alshubaili A. Intravenous immunoglobulin in the treatment of drug rash eosinophilia and systemic symptoms caused by phenytoin. Ann Indian Acad Neurol 2012;15:320-2. 9. Chiriac AM, Demoly P. Multiple drug hypersensitivity syndrome. Curr Opin Allergy Clin Immunol 2013;13:323-9. 10. Scherer K, Brockow K, Aberer W, Gooi JH, Demoly P, Romano A, et al. Desensitization in delayed drug hypersensitivity reactions: an EAACI position paper of the Drug Allergy Interest Group. Allergy 2013;68:844-52. 11. Holland CL, Malasky C, Ogunkoya A, Bielory L. Rapid oral desensitization to isoniazid and rifampin. Chest 1990;98:1518-9. 12. Matz J, Borish LC, Routes JM, Rosenwasser LJ. Oral desensitization to rifampin and ethambutol in mycobacterial disease. Am J Respir Crit Care Med 1994;149(3 Pt 1):815-7. http://dx.doi.org/10.4168/aard.2015.3.4.297 301