원저 Lab Med Online Vol. 6, No. 2: 88-92, April 2016 임상미생물학 A 군연쇄구균인두염의임상양상과두가지신속항원검사의유용성비교 Clinical Manifestations of Group A Streptococcal Pharyngitis and Comparison of Usefulness of Two Rapid Streptococcal Antigen Tests 김인욱 1 양무열 1 정혜령 1 강은경 1 허희진 2 In Uk Kim, M.D. 1, Mu Yul Yang, M.D. 1, Hye Ryung Jung, M.D. 1, Eun Kyeong Kang, M.D. 1, Hee Jin Huh, M.D. 2 동국대학교일산병원소아청소년과 1 진단검사의학과 2 Departments of Pediatrics 1 and Laboratory Medicine 2, Dongguk University Ilsan Hospital, Goyang, Korea Background: Throat culture is the golden standard for diagnosis of group A streptococcal (GAS) pharyngitis. However, because it is a time-consuming procedure, antibiotics are often empirically administrated. Rapid antigen tests (RATs) can detect bacterial infections within 15 minutes, thus helping to reduce unnecessary administration of antibiotics. Methods: In total, 108 patients, between 3 and 17 yr of age, who visited our hospital from August 2011 to July 2012, were tested for suspected acute pharyngitis with two RATs SD Bioline Strep A (SD, Korea) and BinaxNOW Strep A (Binax, Inc., USA) as well as throat culture. We compared the sensitivity, specificity, and consistency of the two RATs and assessed the clinical manifestations of GAS pharyngitis. Results: Of the 108 patients, 15 were confirmed to have GAS pharyngitis by throat culture. The SD test showed a sensitivity of 93.3% and a specificity of 97.8%; the positive and negative predictive values were 87.5% and 98.9%, respectively. The Binax test showed a sensitivity of 86.7% and a specificity of 100%; the positive and negative predictive values were 100% and 97.9%, respectively. The Kappa values for conformity degree were high, 0.887 and 0.918 in the SD and the Binax tests, respectively (P =0.00). Clinical manifestation assessment of GAS pharyngitis indicated that scarlatiniform rash and strawberry tongue were significantly associated signs (P <0.05). Conclusions: GAS pharyngitis diagnosis based on clinical manifestations alone has practical limitations. The two RATs are useful as substitutes for throat culture and their frequent use in clinical settings is advisable. Key Words: Streptococcus group A, Pharyngitis, Rapid antigen test 서론 급성인두염은소아가의료기관을방문하게되는가장흔한질 병중하나이다. 급성인두염의원인은대부분바이러스감염이지 Corresponding author: Eun Kyeong Kang Department of Pediatrics, Dongguk University Ilsan Hospital, 27 Dongguk-ro, Ilsandong-gu, Goyang 10326, Korea Tel: +82-31-961-7183, Fax: +82-31-961-7188, E-mail: silbear@hanmail.net Received: May 29, 2015 Revision received: August 13, 2015 Accepted: August 14, 2015 This article is available from http://www.labmedonline.org 2016, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 만전체의 30% 는세균성감염이고세균성감염중 A군연쇄구균감염이가장흔한원인이다 [1]. A군연쇄구균에의한급성인두염은급성류마티스열및급성사구체신염의합병증을초래할수있고, 감수성이있는사람에게전염될수있기때문에빠른진단과적절한항생제치료가중요하다 [2-4]. 하지만증상과진찰소견만으로세균감염과바이러스감염을구별하는것은매우어렵다. 증상과진찰소견만으로세균성감염을진단하는경우부정확할수있으며, 다수의경험이있는의사라도증상과진찰소견만으로세균성감염을정확하게진단할수있는가능성은 80% 미만이라는보고가있다 [5, 6]. A군연쇄구균인두염을진단하는가장좋은방법은인두배양검사이지만시간이오래소요되는단점이있어실제배양검사결과없이경험적항생제를투여하는경우가많다. 최근에는신속항원검사법이개발됨에따라총 15분만에세균감염여부를판단하는 88 www.labmedonline.org eissn 2093-6338
데많은도움이되고있다. 미국소아과학회 (American Academy of Pediatrics) 에서는세균성인두염진단시신속항원검사를먼저시행하여음성인경우에인두배양검사를시행하도록권장하고있다 [7]. 국내외연구에의하면, 급성인두염이있는경우신속항원검사를먼저시행후검사결과가양성이면항생제를투여하고음성이면배양검사를시행해야하며배양검사결과가나올때까지항생제투여를보류하는것을권하고있다 [5, 8]. 우리나라에서는개인의원에서세균배양검사나신속항원검사를일상적으로시행하지않고있고이에따라항생제오남용이발생하고있으며특히우리나라의항생제남용은심각한수준으로이로인해항생제내성률이매우높은수준으로보고되고있다 [9]. 이에저자들은 A군연쇄구균인두염의임상양상을조사하고, 임상양상과인두배양검사상 A군연쇄구균인두염으로진단된환자를기준으로현재임상에서사용하고있는두가지의신속항원검사법의민감도, 특이도와일치도를평가하기위해본연구를시행하였다. 대상및방법 2011년 8월부터 2012년 7월까지동국대학교일산병원소아청소년과에방문한환자중발열과인두발적또는편도비대가있어급성인두염이의심되는환자를대상으로하였다. 외래및입원환자중만 3세이상, 17세이하를실험군으로정하였고 108명이포함되었으며, 현재검사중인신속항원검사법단독으로만검사된환자들은본연구에서제외하였다. 검사를시행하기전에, 두가지신속항원검사법과인두배양검사를비교하는연구로서 3개의면봉을이용하나총 2회로검사하는것에동의를받았다. 멸균된 3개의면봉으로편도와인두를정확하게문지르고 2개는신속항원검사법에사용하고 1개는인두배양검사에사용하였다. 신속항원검사법은상품화된 SD Bioline Strep A (SD, Yongin, Korea) 와 BinaxNOW Strep A (Binax, Inc., Portland, USA) 를이용하였다. 인두배양검사결과와임상양상과의연관성을평가하고, 인두배양검사를통해진단된 A군연쇄구균인두염환자를기준으로민감도, 특이도와일치도를구하였다. 인두배양검사는 A군연쇄구균만을시행하였고다른세균에대한배양은시행하지않았으며, 한천배지에백금이를이용하여도말하고반정량법으로측정하였다. 1차분획이하인경우 no growth or rare, 2차분획인경우 moderate, 3차분획이상인경우 many로구분하고 moderate 이상일때를 A군연쇄구균배양양성기준으로설정하였다 [10]. SD Bioline Strep A 검사방법은시약을넣은용기에채취한면봉을넣고 5-10회회전시킨후 1분간유지하고면봉을빼낸후 strip 을넣고 5-10 분후결과를판독하며, 검체를채취하고준비하는시 간을포함하여총 15 분안에결과를확인할수있다. BinaxNOW Strep A 검사방법은검사봉투를열어채취한면봉을넣고시약을 떨어뜨린다. 면봉을 3 회회전시킨후 1 분간유지하고봉투를닫은 후 5 분후결과를판독하며총 10 분안에결과를확인할수있다. 통계처리는 SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA) 프로그램을이용하였다. 두신속항원검사와인두배양검사결 과간의비교에서 Pearson 카이제곱검정을이용하였고, 기대빈도 가 5 미만인경우는 Fisher s exact test 를이용하였으며, P 값이 0.05 미만을통계적으로유의한것으로정의하였다. 일치도평가에는 Kappa 값을이용하였고그값은 κ<0.20 : poor; 0.20 κ <0.40 : fair; 0.40 κ <0.60 : moderate; 0.60 κ <0.80 : good; κ 0.80 : very good 으로해석하였다. 각각의증상및징후들과인두배양검 사결과간의비교에서는 Pearson 카이제곱검정을이용하였고, 기 대빈도가 5 미만인경우는 Fisher s exact test 를이용하였다. 결과 A 군연쇄구균인두염으로진단된환자는연령별로 3-6 세가 11 예 (73.3%), 7-10 세가 4 예 (26.7%), 10 세이상은없었다. 임상증상및 징후는발열 15 예 (100%), 성홍열양피부발진 12 예 (80.0%), 인후통 11 예 (73.3%), 딸기모양의혀 8 예 (53.3%), 인두의삼출및연구개의 점상출혈 8 예 (53.3%), 경부림프절종대 7 예 (46.7%), 구토 3 예 (20.0%), 복통 2 예 (13.3%), 두통 0 예로나타났으며이중특징적인 성홍열양피부발진과발열이동반되고인두배양검사에서 A 군연 쇄구균양성으로확인되어성홍열로진단된환자는 12 예 (80.0%) 였다. A 군연쇄구균인두염의진단유무사이에발열, 경부림프절 종대, 구토, 두통, 복통, 인두의삼출및연구개의점상출혈이있는 환자수는통계학적으로유의한차이가없었고 (P >0.05), 성홍열양 Table 1. Symptoms and signs of acute pharyngitis Symptoms and signs Throat culture for group A streptococcus Positive group No. (%) Negative group No. (%) P value Fever* 15 (100) 91 (97.8) 0.740 Scarlatiniform rash 12 (80) 14 (14.6) 0.000 Sore throat 11 (73.3) 35 (37.6) 0.010 Strawberry tongue 8 (53.3) 11 (11.8) 0.001 Palatine petechiae or pharyngotonsillar exudate 8 (53.3) 26 (28.0) 0.051 Cervical lymph node enlargement 7 (46.7) 23 (24.7) 0.077 Vomiting 3 (20) 16 (17.2) 0.516 Abdominal pain 2 (13.3) 18 (19.4) 0.444 Headache 0 (0) 6 (6.5) 0.398 *Body temperature 38.0 C. www.labmedonline.org 89
Table 2. Comparison of rapid antigen detection test results based on the number of colonies of group A streptococcus in throat culture Number of colonies Number of children Positive cases of SD Bioline Strep A Positive cases of BinaxNOW Strep A No growth or rare 93 2 0 Moderate 11 10 9 Many 4 4 4 Total 108 16 13 Table 3. Statistical results of two rapid streptococcal antigen tests SD Bioline Strep A BinaxNOW Strep A Sensitivity 93.3% 86.7% Specificity 97.8% 100% Positive predictive values 87.5% 100% Negative predictive values 98.9% 97.9% P value 0.00 0.00 Kappa 0.887 0.918 피부발진, 인후통, 딸기모양의혀를나타낸환자수는통계학적으로유의한차이가있었다 (P <0.05) (Table 1). 108예의검체중 15예 (13.9%) 에서인두배양검사상 A군연쇄구균이배양되었다. 집락수 moderate는 11예 (73.3%), many는 4예 (26.7%) 로배양되었다 (Table 2). SD Bioline Strep A 검사는민감도 93.3%, 특이도 97.8% 를보였으며양성예측률과음성예측률은 87.5% 와 98.9% 로나타났다. BinaxNOW Strep A 검사는민감도 86.7%, 특이도 100% 를보였으며양성예측률과음성예측률은 100% 와 97.9% 로나타났다. SD Bioline Strep A와 BinaxNOW Strep A의 Kappa값은각각 0.887과 0.918로일치도가높으며, Fisher s exact test로검정한 P값은 P <0.05에서통계적으로유의한데모두 0.00으로확인되었다 (Table 3). 고찰 급성인두염의주원인은바이러스이지만, 임상의가증상과진찰소견만으로세균감염과구분하는것은어려우므로항생제를과잉처방하게되는경우가많다. 급성인두염으로일으키는바이러스로는 adenovirus가가장흔하고, 세균성원인으로는 A군연쇄구균이가장흔하다. A군연쇄구균인두염의가장이상적인검사는인두배양검사이나결과가나오기까지 1-3일의시간이소요되고, 검사실이없는개인의원에서는실행하지못하고있는실정이다. 따라서급성인두염의치료로경험적항생제를투여하는경우가많은데, 이에는찬반론이있다. 반대하는이론적근거는 A군연쇄구균이증명되기까지 2-3일을기다렸다가항생제를투여하더라도사구체신염이나급성류마티스열등의비화농성합병증이증가하지않고 [11, 12], 부비동염, 중이염, 유양돌기염, 경부임파선염, 편도주위및후인두농양, 폐렴등의화농성합병증의발생위험역시더증가하지않으므로 [13, 14], 검사없이항생제를투여함으로항생제남용이나내성균출현을조장할우려가크다는점이다. 반면에찬성하는이론적근거는개인의원에서인두배양검사를시행하기는현실적으로쉽지않고, 항생제를초기에투여함으로써균의전파위험을줄이고임상증상을빨리호전시켜삶의질을높일수있다는것을 들수있다 [15, 16]. 현재국내에서는미국과는달리, 급성인두염에서신속항원검사나배양검사결과가없어도항생제를처방할수있고, A군연쇄구균인두염을치료하지않았을때따르는위험을줄이기위해거의모든급성인두염환자에서항생제를처방하는경향이있다. 그래서신속항원검사법의유용성을증명하고보편화할수있다면급성인두염에서의항생제사용을줄이는데도움이될수있겠다. 본연구에서조사한두종류의신속항원검사모두인두배양검사와의비교에서민감도, 특이도와일치도가높았다. 다른종류의신속항원검사의유용성에대한국내외여러연구도보고되었는데, BD LINK2 (Becton, Dickinson & Company, New Jersey, USA) [17], QuickVue In-Line (Quidel Corporation, San Diago, USA) [17, 18], Testpack+plus strep A Kit (Abbott Laboratories, Illinois, USA) [8], Diaquick Strep. A Test (Dialab GmbH, Vienna, Austria) [19] 등상용화된어느방법이나유용한것으로나타났다. 현재 A군연쇄구균신속항원검사의국내보험급여는급성인두염의증상과진찰소견을만족하는 3-13세의소아에서인정되므로적극적으로사용할수있겠다. 급성인두염의원인균중 A군연쇄구균감염이차지하는비율이 15-30% 범위에서보고되고있는데본연구에서는 13.9% 로약간낮았다. 그이유로는타병원에서이미항생제를처방받아복용중인환자들이배제되지않아실제감염이있었으나인두배양검사에서확인되지않았을가능성이있다. A군연쇄구균인두염은바이러스감염에의한것보다증상이빠르게시작되고, 기침이나콧물등의감기증상은없는경우가많다. 흔히알려진 A군연쇄구균인두염의증상중구토, 복통과두통은본연구에서배양양성인군과배양음성인군사이에유의한차이가없었다. 이는 A군연쇄구균배양양성인환자의연령이 3-6 세 (73.3%) 인비율이커큰소아에비해상대적으로증상표현이불확실한것을그이유로추정해볼수있다. A군연쇄구균인두염의진찰소견으로인두발적외에편도삼출물과연구개점상출혈이동반되는경우가많다고알려져있다 [5, 20]. 그래서편도삼출물이동반되면세균성인두염으로진단하는경향이있다. 하지만광범위하게항생제를사용하기시작한이 90 www.labmedonline.org
후로는삼출성인두염의주원인이더이상 A군연쇄구균은아니라는연구가있으며 [21], 다른연구에서도급성삼출성인두염의원인으로 A군연쇄구균감염이단지 12% 였고아데노바이러스를포함한바이러스감염이원인인경우가더많았다 [22]. 본연구에서도 A군연쇄구균인두염군에서편도삼출물이있는비율이배양음성인군에비해더높은경향을보였으나통계적으로유의한차이는없었다. A군연쇄구균인두염과성홍열양피부발진과딸기모양의혀는유의한결과를보였는데이는다른연구결과와도일치한다 [17, 18]. 결론적으로상용화된 A군연쇄구균인두염신속항원검사는배양검사와의일치도가높은유용한검사이고, 임상양상만으로 A군연쇄구균감염여부를구분하는것은어렵다. 또한신속항원검사는급성인두염환자의치료에있어항생제의사용여부를초기에결정하여, 항생제의오남용을감소시키는데도움이되겠다. 이에저자들은급성인두염을자주접하는진료의사들이 A군연쇄구균인두염신속항원검사의효용성을인식하고적극적으로활용하는것이필요하다고생각된다. 요약 배경 : A군연쇄구균에의한인두염을진단하는가장좋은방법은인두배양검사이나많은시간이소요되어, 경험적으로항생제를투여하는경우가상당수이다. 신속항원검사법은총 15분만에세균감염여부를확인할수있어불필요한항생제사용을줄이는데도움이된다. 방법 : 2011년 8월부터 2012년 7월까지급성인두염이의심되는 3 세이상, 17세이하의환자중 108명에서두가지신속항원검사로 SD Bioline Strep A (SD, Korea), BinaxNOW Strep A (Binax, Inc., USA) 와인두배양검사를시행하여그결과를비교하였고, A군연쇄구균인두염의임상양상에대해평가하였다. 결과 : 108명의환자중 15명에서인두배양검사상 A군연쇄구균양성으로확인되었다. SD Bioline Strep A 검사는민감도 93.3%, 특이도 97.8% 를보였으며양성예측도와음성예측도는 87.5% 와 98.9% 였다. BinaxNOW Strep A 검사는민감도 86.7%, 특이도 100% 를보였으며양성예측도와음성예측도는 100% 와 97.9% 였다. 일치도를보는 Kappa값은 SD Bioline Strep A와 BinaxNOW Strep A 검사에서각각 0.887과 0.918 으로높았다 (P = 0.00). A군연쇄구균인두염의임상양상평가에서는성홍열양피부발진과딸기모양의혀만유의하였다 (P <0.05). 결론 : A군연쇄구균인두염의진단에서임상양상만으로는한계가있으며, 두신속항원검사법모두인두배양검사를대체할수있는유용한검사로적극적인활용이권장된다. REFERENCES 1. Dimatteo LA, Lowenstein SR, Brimhall B, Reiquam W, Gonzales R. The relationship between the clinical features of pharyngitis and the sensitivity of a rapid antigen test: evidence of spectrum bias. Ann Emerg Med 2001;38:648-52. 2. Nelson JD. The effect of penicillin therapy on the symptoms and signs of streptococcal pharyngitis. Pediatr Infect Dis 1984;3:10-3. 3. Kelly MT, Smith JA, Jaffer S, Pearce L, Clarke A. Outpatient evaluation of a rapid, direct test for detection of group A streptococci in throat swabs. Am J Clin Pathol 1987;87:522-5. 4. Redd SC, Facklam RR, Collin S, Cohen ML. Rapid group A streptococcal antigen detection kit: effect on antimicrobial therapy for acute pharyngitis. Pediatrics 1988;82:576-81. 5. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis 2002;35:113-25. 6. Breese BB. A simple scorecard for the tentative diagnosis of streptococcal pharyngitis. Am J Dis Child 1977;131:514-7. 7. Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2009:619. 8. Shin YJ, Jang SH, Dong ES, Ahn YM, Ku MS. Clinical manifestations of group A β-hemolytic streptococcal pharyngits and usefulness of rapid antigen test. Korean J Pediatr 2001;44:732-41. 9. Kim JM. National survey on the current status of antibiotic use in Korea and a proposition on the appropriate use of antibiotics. J Korean Soc Chemother 1999;17:259-61. 10. Garcia LS, ed. Clinical microbiology procedures handbook. 3rd ed. ASM press: American Society of Microbiology, 2010:3.11.2.9-11. 11. Swartz B, Marcy M, Phillips WR, Gerber MA, Dowell SF. Pharyngitis principles of judicious use of antimicrobial agents. Pediatrics 1998; 101:171-4. 12. Kaplan EL, Johnson DR, Del Rosario MC, Horn DL. Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: examination of 301 strains isolated in the United States between 1994 and 1997. Pediatr Infect Dis J 1999;18:1069-72. 13. Jersild T. Penicillin therapy in scarlet fever and complicating otitis. Lancet 1948;1:671-3. 14. Gerber MA and Shulman ST. Rapid diagnosis of pharyngitis caused by group A streptococci. Clin Microbiol Rev 2004;17:571-80. www.labmedonline.org 91
15. Mayes T and Pichichero ME. Are follow-up throat cultures necessary when rapid antigen detection tests are negative for group A streptococci? Clin pediatr (Phila) 2001;40:191-5. 16. Bisno AL, Peter GS, Kaplan EL. Diagnosis of strep throat in adults: are clinical criteria really good enough? Clin Infect Dis 2002;35:126-9. 17. Song SK, Hong MA, Oh KC, Ahn SI, Tae MH, Shin HJ, et al. Comparison of two rapid antigen detection tests for diagnosis of group A streptococcal pharyngotonsillitis. J Korean Pediatr Soc 2002;45:973-9. 18. Lim KH, Choi WJ, Kim MJ, Kim YH, Jung JA, Yang S, et al. Utility of streptococcal rapid antigen detection test in children with acute pharyngitis. Pediatr Allergy Respir Dis 2006;16:57-65. 19. Al-Najjar FY and Uduman SA. Clinical utility of a new rapid test for the detection of group A streptococcus and discriminate use of antibiotics for bacterial pharyngitis in an outpatient setting. Int J Infect Dis 2008; 12:308-11. 20. Gerber MA. Diagnosis and treatment of pharyngitis in children. Pediatr Clin North Am 2005;52:729-47. 21. Hsieh TH, Chen PY, Huang FL, Wang JD, Wang LC, Lin HK, et al. Are empiric antibiotics for acute exudative tonsillitis needed in children? J Microbiol Immunol Infect 2011;44:328-32. 22. Putto A. Febrile exudative tonsillitis: viral or streptococcal? Pediatrics 1987;80:6-12. 92 www.labmedonline.org