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1 대한내과학회지 : 제 88 권제 4 호 혈액투석환자에서크립토코쿠스혈증을동반한크립토코쿠스연조직염 고려대학교의과대학내과학교실신장내과 정일우 김지은 김상훈 김지형 홍유아 고강지 권영주 Cryptococcus neoformans Cellulitis with Cryptococcemia in a Patient on Maintenance Hemodialysis Il Woo Jeong, Ji Eun Kim, Sang Hun Kim, Ji Hyoung Kim, Yu Ah Hong, Gang Jee Ko, and Young Joo Kwon Division of Nephrology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Cryptococcus neoformans is a fungus that cas opportunistic infections in immunocompromised hosts. Skin lesions are found in 10-20% of systemic cryptococcal infections, usually secondary to cryptococcemia, while primary cutaneous cryptococcosis with cryptococcemia is very rare. We report a case of rapidly spreading cryptococcal cellulitis in a 64-year-old male on maintenance hemodialysis taking steroids for encapsulated peritoneal sclerosis. Bluish bullous cellulitis developed on the left and spread rapidly to the other. We identified C. neoformans in the blood and skin lesions. We treated him successfully with liposomal amphotericin B and fluconazole for 15 months. We also review the literature. (Korean J Med 2015;88: ) Keywords: Cryptococcus neoformans; Cellulitis; Immunocompromised host; Renal dialysis 서론 Cryptococcus neoformans는피막성진균 (encapsulated fungal organism) 으로세계각지에서발견되며부패한조류분비물에오염된토양이나부패한나무, 과일, 야채또는먼지등에서관찰된다. C. neoformans에의한감염은후천성면역결핍증 (acquired immune deficiency syndrome, AIDS) 발생및면역억제제사용에따라증가하는추세로정상면역을가진사 람에서도감염이보고되고있다 [1]. 일차성피부크립토코쿠스증은피부의단독병변으로관찰되며연조직염 (cellulitis) 이나궤양 (ulceration), 표저 (whitlow) 등의양상을보여다른세균성피부감염과감별이어려울수있어광범위항생제에반응이없는경우배양및조직검사가도움을줄수있다 [2]. 국내에서는병변부위의균배양검사를통해 C. neoformans가동정되어피부에국한된피부크립토코쿠스증을진단하고항진균제치료를시행한예가보고되었으나 [3-9] Received: Revised: Accepted: Correspondence to Young Joo Kwon, M.D., Ph.D. Division of Nephrology, Department of Internal Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul , Korea Tel: , Fax: , yjkwon@korea.ac.kr Copyright c 2015 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, distribution, and reproduction in any medium, provided the original work is properly cited.

- The Korean Journal of Medicine: Vol. 88, No. 4, 2015 - cryptococcemia를동반한피부크립토코쿠스증의진단또는치료에대한증례는보고되지않았다.

5 mg 투여중내원 10일전부터발생한고열을주소로입원하였으며특발성세균성복막염 (spontaneous bacterial peritonitis) 으로진단하였다. 이에대해항생제치료및 peritonectomy 시행후증상이호전되던중입원 56일째복부증상은보이지않으나고열과동정맥루가있는좌측상완의부종, 통증및발열감이발생하였다.

5 mg/kg) 을투여하였다. 이후지속감량하여투여 12주후부터 7.5 mg까지감량하여유지중이었다. 사회력 : 음주및흡연은하지않았고직업력상무직으로이전에토양에흔한노출은없었으며조류에대한노출역시없었다. 가족력 : 없음. 신체검사소견 : 고열발생당시혈압은 130/70 mmhg, 맥박수 108회 / 분, 호흡수 20회 / 분, 체온 38.3 였다.

2 - The Korean Journal of Medicine: Vol. 88, No. 4, cryptococcemia를동반한피부크립토코쿠스증의진단또는치료에대한증례는보고되지않았다. 저자들은피막성복막경화증 (encapsulated peritoneal sclerosis) 으로스테로이드를복용중인유지혈액투석환자에서발생한좌측상완에서우측상완으로빠르게퍼지는양상을보인 cryptococcemia를동반한크립토코쿠스연조직염을경험하여문헌고찰과함께보고하는바이다. 증례환자 : 64세남자주소 : 고열, 좌측상완부종현병력 : 피막성복막경화증으로프레드니솔론 7.5 mg 투여중내원 10일전부터발생한고열을주소로입원하였으며특발성세균성복막염 (spontaneous bacterial peritonitis) 으로진단하였다. 이에대해항생제치료및 peritonectomy 시행후증상이호전되던중입원 56일째복부증상은보이지않으나고열과동정맥루가있는좌측상완의부종, 통증및발열감이발생하였다. 과거력 : 만성사구체신염으로내원 20년전부터복막투석을시행하였으며내원 5년전좌측흉수가있어 underdialysis 를의심하여좌측팔에동정맥루를수술하고 continuous cycling peritoneal dialysis로전환하였으며내원 1년전흉수가다시발생하여혈액투석으로전환하였다. 이후복부팽만소견을보여피막성복막경화증진단후에 3주간프레드니솔론 30 mg (0.5 mg/kg) 을투여하였다. 이후지속감량하여투여 12주후부터 7.5 mg까지감량하여유지중이었다. 사회력 : 음주및흡연은하지않았고직업력상무직으로이전에토양에흔한노출은없었으며조류에대한노출역시없었다. 가족력 : 없음. 신체검사소견 : 고열발생당시혈압은 130/70 mmhg, 맥박수 108회 / 분, 호흡수 20회 / 분, 체온 38.3 였다. 급성병색을띠었으나의식은명료했고두경부및흉부진찰에서이상소견은보이지않았으며복부진찰에서장음이감소되어있었다. 좌측상완은수포, 부종, 통증및압통 (Fig. 1A) 이관찰되었다. 검사소견 : 말초혈액검사에서혈색소 9.1 g/dl, 백혈구 18,300/μL ( 호중구 97.6%, 림프구 1.6%, 단핵구 0.7%, 호산구 0.1%), 혈소판 153,000/μL였고, 생화학검사에서 Na/K/Cl 133/4.3/93 mmol/l, BUN 38.9 mg/dl, creatinine 5.31 mg/dl, 총단백 4.8 g/dl, albumin 2.5 g/dl, AST/ALT 21/14 IU/L, total bilirubin 0.58 mg/dl를보였다. C-반응단백은 mg/l 로증가되어있었다. 영상의학소견 : 단순흉부방사선에서양측의흉막삼출이소량관찰되었으며단순복부방사선은이상소견이없었다. 좌측상완에대해구획증후군 (compartment syndrome) 의감별을위해초음파와자기공명영상 (magnetic resonance imaging, MRI) 을시행하였으며초음파에서피하부종및피하층의에코발생도가증가하여연조직염이의심되었으며 MRI 에서농양은보이지않으나피부및피하층의부종및앞구획근육의전반적인부종이관찰되었다 (Fig. 2). 치료및경과 : 혈액배양및좌측상완수포의삼출액에대해배양을시행하였으며연조직염에대해 vancomycin을 A B C Figure 1. Skin lesions. (A) Initially, the left shows swelling, a discharge, and a skin defect. (B) The right is red and felt warm. (C) After treatment for 15 days, the swelling and discharge of the left had improved

- Il Woo Jeong, et al. A case of cellulitis with cryptococcemia - A B Figure 2.

subcutaneous layer swelling with interstitial edema and enhancement (arrowheads) is seen involving the entire left

Microscopically, the skin biopsy showed small round microorganisms.

(B) GMS stain revealed black organisms - numerous yeasts (arrowheads).

3 - Il Woo Jeong, et al. A case of cellulitis with cryptococcemia - A B Figure 2. Initially, magnetic resonance imaging of the left upper extremity shows extensive circumferential cutaneous and subcutaneous layer swelling with interstitial edema and enhancement (arrowheads) is seen involving the entire left distal upper arm down to the hand (A: sagittal plane, B: transverse plane). A B Figure 3. Microscopically, the skin biopsy showed small round microorganisms. (A) PAS stain identifies numerous yeast-form fungi (arrows). (B) GMS stain revealed black organisms - numerous yeasts (arrowheads). PAS, periodic acid-schiff stain; GMS, Grocott s methenamine silver stain. 신기능에따라용량을조절하여투여하기시작했다. 4일간항생제투여후좌측상완의병변호전은보이지않으며오히려우측상완도발적및열감이발생하여 (Fig. 1B) 좌측상완병변부에대해피부생검을시행하였다. 증상발생 5일째 삼출액및혈액배양에서 C. neoformans가동정되었다. 이에대해 liposomal amphotericin B 5 mg/kg/day를정주하기시작했고병변에대해과망간산칼륨용액으로소독하였다. Liposomal amphotericin B 투여후우측상완의병변은빠르게호

4 - 대한내과학회지 : 제 88 권제 4 호통권제 656 호 전을보였고이후확인된조직검사에서 C. neoformans가관찰되었다 (Fig. 3). Liposomal amphotericin B 투여 1주일후시행한혈액배양에서음전되었고 15일간 liposomal amphotericin B 투여후좌측피부병변역시호전추세 (Fig. 1C) 를관찰할수있었다. 관해치료로 liposomal amphotericin B 5 mg/kg/day로 4주간투여후공고치료로 fluconazole 400 mg/day를경구로 8주간투여하고유지치료로 fluconazole 200 mg/day를경구로 8-12 개월간투여하기로했다. 환자는재원중에관해치료를마치고 2주간공고치료를시행후병변이거의호전되어외래에서약을유지하기로하고퇴원했으며현재유지치료종료후에특이증상없이경과관찰중이다. 고찰 C. neoformans는주로호흡기를통해인체로들어오게되며지난 30년간 AIDS, 장기이식이후거부반응의방지를위한스테로이드등면역억제제복용환자의증가등으로인해 C. neoformans 감염의중요성이점차대두되고있으며 [10], 주로폐, 중추신경계등에증상을유발하며그외피부, 간, 신장등을침범한다 [1]. 피부크립토코쿠스증은국소적침범 (local inoculation) 에의한일차성병변으로발생하거나다른크립토코쿠스감염의파급에의한이차성피부병변으로도발생할수있다. Systemic cryptococcsis가있으면서발생하는이차성피부병변은신체의여러부위에다발성으로모든양상의피부병변이가능하지만주로구진양상의피부병변형태가가장많으며 10-20% 에서발생한다. 일차성병변의경우훨씬드물며, 전신침범없이단독병변으로관찰되고주로연조직염 (cellulitis), 궤양 (ulceration), 특히표저 (whitlow) 양상을보인다 [11]. 본환자의경우호흡기와중추신경계등다른신체부위감염의징후가없었고병변이상완의피부만국한되어수포및연조직염양상을보이고발생 4일만에우측상완으로빠르게퍼지며삼출액과혈액에서동정되고조직검사에서 C. neoformans를보여 cryptococcemia를동반한크립토코쿠스연조직염으로진단하였다. 피부크립토코쿠스증은대개의경우폐또는중추신경계등에서감염발생후전신으로퍼지는경우가많으나외국의일부증례에서는일차성피부크립토코쿠스증이원인병 변이되어다른부위로퍼지는증례가있었다. 첫번째증례는신장이식환자로좌측하지의일차성피부크립토코쿠스증에대해치료하던중경련이발생하고 computed tomography (CT) 상처음진단당시관찰되지않았던뇌의파종성병변이관찰되어사망하였다 [12]. 또다른증례에서는류마티스관절염환자로좌측하지의일차성피부크립토코쿠스증에대해치료중에좌측상완으로퍼지는양상을보이고진단당시에관찰되지않았던단순흉부방사선상우측폐하엽의병변이관찰되며패혈증으로사망하였다 [13]. 본증례에서는좌측상완의피부병변이외의임상증상은관찰되지않았고 cryptococcemia가발생하여 cryptococcemia에의한전신증상으로고열이발생한것으로생각되며우측상완으로퍼지는양상이었으나항진균제의신속한투여로더진행하지않고회복된것으로생각된다. C. neoformans의흔한감염병소인호흡기계감염여부에대해서는흉부 X-선에서이상소견이나호흡기증상을보이지않고동맥혈가스분석 (arterial blood gas analysis) 에서 PaO 2 82 mmhg, O 2 saturation 96% 로잘유지되고있어추가검사를시행하지않았고, 중추신경계감염동반여부에대해서는뇌척수액검사를시행해보면정확히알수있겠지만환자는 cryptococcemia가동반되어있어이러한경우뇌척수액검사결과와관계없이중추신경계감염에준하여치료하는것을권고하고있어중추신경계증상이없는상태에서관혈적검사를시행하지는않았다. 본환자에서는시행하지않았지만다른신체부위침범여부에대한평가를시행하는것이환자의제반상태를확인하는데도움이될수있고정확한진단및치료방법및기간결정에도역시필요할것으로사료되며, 호흡기및중추신경계감염뿐아니라피부감염을통해서도파종성병변이발생할수있음을인지하는것이필요하다. 병변부위의균배양을통해진단된 C. neoformans에의한국내의피부감염증례는다음표 1과같다. 국내에서진단된증례중상완에서발생한경우가가장많았고저자들이과거에경험한예 (un-published) 와본증례역시상완에서발생했으며수포병변이푸른색을보이며궤양성병변으로급속히진행하는양상이므로피부병변을자주확인하여변화양상의추적과삼출액배양이진단에도움될것으로생각된다. 여러증례에서보여주는것처럼피부에국한된크립토코쿠스감염증은치료를거부했던 1예를제외한다른증례들에서 fluconazole이나 itraconazole 등항진균제로완치가되므

5 - 정일우외 6 인. 크립토코쿠스혈증을동반한연조직염 - Table 1. Clinical characteristics of cutaneous cryptococcosis reported in the Korean literature Sex/ age Underlying condition Kim et al. [3] F/52 Long-term steroid and methotrexate Ko et al. [4] F/72 Iatrogenic Cushing s syndrome Site Skin finding Treatment Prognosis ear Erythematous papules, vesicles Itraconazole and topical flutrimazole for 12 weeks Ulcer Debridement and fluconazole for 3 months Chung et al. [5] F/18 Not recognized Lower lip Granuloma Itraconazole for 12 weeks Kang et al. [6] F/63 Long-term steroid Kim et al. [7] F/72 Long-term steroid Ulcer Debridement and fluconazole for 2 months Ulcer Fluconazole and itraconazole for 10 weeks Jeong et al. [8] F/52 Not recognized Right wrist Ulcer Itraconazole for 6 weeks Jeong et al. [9] M/70 Chemotherapy for peripheral T-cell lymphoma Our case M/64 Long-term steroid Face Erythematous papules and central crusted nodules Bluish erythematous vesicle and ulcer Fluconazole for 1 week Liposomal amphotericin B for 4 weeks and fluconazole 400 mg/day for 8 weeks and fluconazole 200 mg/day for 12 months Died (treatment refd) 로의심될경우적극적인치료를시행하는것이중요하다. 2010년 Infectious Diseases Society of America (IDSA) 의 cryptococcal disease 에대한치료지침에서는중추신경계감염이배제되고 cryptococcemia가동반되지않고면역저하의위험인자가없는일차성피부크립토코쿠스증의경우 fluconazole 을 6-12개월간사용하기를권고하고있다. 하지만이증례에서처럼 cryptococcemia가동반된경우에는중추신경계감염에준하여치료하도록권고하고있다. 이에따르면관해치료방법으로는 amphotericin B deoxycholate/liposomal amphotericin B/amphotericin B와 flucytocine 병합요법, liposomal amphotericin B/amphotericin B의단독요법을추천하고있으며이후 fluconazole로공고치료및유지치료를추천하고있다 [14]. 투석중인환자에서 liposomal amphotericin B는약물의분포가적게이루어지고혈청에서의약물의농도가높아혈액투석의순환시간동안에도지속적으로좀더높은농도를유지할수있어 [15] 본환자에서는 liposomal amphotericin B 단독요법으로관해치료를시행하였고이후 fluconazole 로공고치료를시행후유지치료를하여완치되었다. Cryptococcemia를동반한크립토코쿠스연조직염은적절 한항진균제사용으로완치될수있으므로특히면역저하자에서연조직염에대한진단과치료시세균뿐만아니라 C. neoformans와같은진균에의해발생할수있음을염두에두고접근해야하며 cryptococcemia 분리시치료방침이다르므로반복적인혈액배양및다른신체부위의전이성감염이동반되었는지확인하는것이필요하다. 요약일반적으로피부에연조직염의증상을보일때많은경우에세균성연조직염을생각하고치료하는경향이있으나스테로이드등의면역억제제를사용하거나면역이저하되어있는환자의경우, 그리고면역저하요인이없지만항생제에치료반응이낮을경우에는진균에의한감염의가능성을고려해야한다. 이때정확한진단을위해피부조직생검등의추가적인검사가필요하고또한혈액배양과 latex agglutination test 역시도움될수있으며, 검사결과에따라서항진균제사용을고려하는것이중요하다

6 - The Korean Journal of Medicine: Vol. 88, No. 4, 중심단어 : 크립토코쿠스네오포르만스 ; 연조직염 ; 면역약화숙주 ; 혈액투석 REFERENCES 1. Sabiiti W, May RC. Mechanisms of infection by the human fungal pathogen cryptococcus neoformans. Future Microbiol 2012;7: Baer S, Baddley JW, Gnann JW, Pappas PG. Cryptococcal disease presenting as necrotizing cellulitis in transplant recipients. Transpl Infect Dis 2009;11: Kim YG, Kim HW, Park HC, Kim JE, Ko JY, Ro YS. Primary cutaneous cryptococcosis mimicking herpes zoster. Korean J Dermatol 2013;51: Ko YJ, Hong MH, Park CM, Moon HW, Hur M, Yun YM. Primary cutaneous cryptococcosis in a patient with iatrogenic Cushing s syndrome: a case report and review of the literature. Korean J Clin Microbiol 2012;15: Chung WG, Park J, Park YK, Lee KH. A case of cutaneous cryptococcosis resembling verrucous granuloma. Korean J Med Mycol 2002;7: Kang HY, Kim NS, Lee ES. Primary cutaneous cryptococcosis treated with fluconazole. Korean J Dermatol 2000; 38: Kim DH, Kim M, Kim SJ, Lee SC, Won YH. A case of primary cutaneous cryptococcosis in a patient with iatrogenic Cushing s syndrome. Korean J Med Mycol 1998;3: Jeong MC, Park SH, Kim KJ, Kang HJ. Primary cutaneous cryptococcosis treated with itraconazole. Korean J Med Mycol 1998;3: Jeong KB, Kim HC, Park JW, Choi JS, Kim KH. A case of cutaneous cryptococcosis clinically mimicking keratoachantoma. Korean J Med Mycol 2001;6: Pukkila-Worley R, Mylonakis E. Epidemiology and management of cryptococcal meningitis: developments and challenges. Expert Opin Pharmacother 2008;9: Neuville S, Dromer F, Morin O, et al. Primary cutaneous cryptococcosis: a distinct clinical entity. Clin Infect Dis 2003; 36: Van Grieken SA, Dupont LJ, Van Raemdonck DE, Van Bleyenbergh P, Verleden GM. Primary cryptococcal cellulitis in a lung transplant recipient. J Heart Lung Transplant 2007;26: Lu HC, Yang YY, Huang YL, et al. Disseminated cryptococcosis initially presenting as cellulitis in a rheumatoid arthritis patient. J Chin Med Assoc 2007;70: Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010;50: Heinemann V, Bosse D, Jehn U, et al. Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients. Antimicrob Agents Chemother 1997;41:

Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical