V 만성폐쇄성폐질환환자에서흡입스테로이드사용과폐렴위험성 민경훈 고려대학교의과대학고려대학교구로병원호흡기내과 Inhaled corticosteroids (ICS) are commonly prescribed for patients with chronic obstructive airway diseases such as bronchial asthma and severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations in chronic obstructive pulmonary disease, it is associated with increased risk of pneumonia. The risk of pneumonia is associated with types of ICS, duration of use of ICS, and doses of ICS. However, all current studies find either no difference or a reduction in pulmonary-related mortality associated with the use of ICS. Clinicians should be evaluated as a balance between the benefits and the risks of ICS use for an individual patient with chronic obstructive pulmonary disease. Key Words: Chronic obstructive lung disease, Inhaled corticosteroids, Pneumonia, Pneumonia related mortality Corresponding author: Kyung Hoon Min, M.D., Ph.D. Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University Medical School, 148, Gurodong-ro, Guro-gu, Seoul 08308, Korea Tel: +82-2-2626-3308, Fax: +82-2-2626-1166, E-mail: minkyunghoon@korea.ac.kr 1. 서론 흡입스테로이드 (inhaled corticosteroid, ICS) 는항염증효과를가지는효과적인약제로대표적인폐쇄성폐질환인기관지천식과만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 에서기도염증을조절하기위하여사용되는약물이다. 기관지천식에서흡입스테로이드의사용은천식증상의감소, 삶의질호전, 폐기능개선, 기도과민성감소, 기도염증조절, 악화의빈도와중증도감소, 천식으로인한사망을감소시킨다 1,2. COPD 에서흡입스테로이드의사용은논란의여지가있지만폐기능이정상예측치의 60% 미만에서지속기관지확장제의병합요법으로사용했을때 COPD 증상을감소시키고, 건강상태를향상시키며, 급성악화의빈도를감소시킨다 3,4. 흡입스테로이드를사용하였을때구인두캔디다증, 목소리변형등과같은국소부작용과함께고용량흡입스테로이드를장기간사용하였을때부신기능의억제, 골밀도감소등의전신적부작용이발생할수있다. 또한고용량흡입스테로이드를장기간사용하였을때폐결핵의발생의위험성이증가한다는보고도있다 1-4. 현재까지연구결과에따르면기관지천식환자에서는흡입스테로이드의사용이폐렴발생을증가시키지않는것으로보고하고있다. 하지만 COPD 환자에서는흡입스테로이드사용이폐렴의발생을증가시킨다는최근연구결과와함께이를다른관점에서반박하는연구결과들이발표되면서논란이지속되고있다. 이에현재까지의연구결과를바탕으로 COPD 환자에서흡입스테로이드사용과폐렴위험성에대해서정리해보고자한다. 18
2. 본론 1) COPD 환자에서흡입스테로이드사용과폐렴발생 2007년 6,000명이상의환자를대상으로진행된대규모무작위대조군연구인 Toward a Revolution in COPD Health (TORCH) 연구에서최초로흡입스테로이드를사용한환자에서폐렴발생이증가된다고발표한이후 (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.33 2.02) 5, Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) 연구를포함한대부분의무작위대조군연구에서유사한연구결과를발표하였다 (HR, 1.90 [95% CI, 1.04 3.49] to 3.09 [95% CI, 1.34 7.12]) 6-10. 또한 6,235 명을대상으로한코크란메타분석에서역시흡입스테로이드사용이폐렴발생증가와관련되어있음을보고하였다 (odd ratio [OR]: 1.56, 95% CI: 1.30 1.86) 11. 언급된무작위대조군연구결과는폐렴의진단에있어체계적인진단과영상의학적확인이결여되어있는무보정이상반응보고에의존하였다는제한점을갖고있었다. 하지만이를보정한여러대규모관찰연구에서도흡입스테로이드의사용이폐렴발생을증가시킨다는기존의연구와같은결과를보여주었다 (HR, 1.10 [95% CI, 1.08 1.13] to 2.65 [95% CI, 1.25 5.61]) 12-16. 현재까지의연구결과를종합하면 COPD 환자에서흡입스테로이드사용은폐렴발생을증가시키는것으로판단된다. 특히흡입스테로이드를사용하고있는 COPD 환자중 55세이상의연령, FEV 1 50% 미만, 최근 1년동안 COPD 악화경험, 호흡곤란악화, 신체비만지수가 25 kg/m 2 미만의임상적특징이있는경우가위험요소로판단된다 17,18. 2) COPD 환자에서흡입스테로이드종류따른폐렴발생 COPD 환자에서흡입스테로이드사용에의한폐렴발생을보고한대부분의앞서언급된기존연구들은흡입스테로이드단독제제혹은병합제제로서 fluticasone 를사용하였고 fluticasone 사용이폐렴을잘발생하는것으로보고하고있다. 흡입스테로이드로 budesonide 를사용한무작위대조군연구중 Vestbo 등 19 과 Rennard 등 20 의연구는위약군에비해폐렴발생의상대위험도가각각 0.67 (95% CI, 0.37 1.20) 과 0.74 (95% CI, 0.47 1.18) 로 budesonide 사용이폐렴발생의위험도를높이지않는것으로보고하였다. COPD 환자에서 fluticasone/salmeterol과 budesonide/formoterol 의폐렴과폐렴관련사망률을비교한대규모후향적관찰연구 (PATHOS 연구 ) 결과폐렴발생률과폐렴관련입원율이 fluticasone/salmeterol 군에서 budesonide/formoterol 군보다높았다 ( 각각 rate ratio, 1.73; 95% CI, 1.57 1.90; p<0.001과 rate ratio, 1.74; 95% CI, 1.56 1.94; p<0.001) 21. 또한폐렴관련사망률역시 fluticasone/salmeterol 군에서 budesonide/formoterol 군보다높았다 (HR, 1.76; 95% CI, 1.22 2.53; p=0.003). 흡입스테로이드의종류에따른이러한차이는명확히규명되지는않았지만, fluticasone 과 budesonide 의효능혹은기도에서의제거율의차이와관련되어있는것으로보인다 22,23. 즉 fluticasone 의강한지용성이기도의상피세포표면에서천천히분해하여장시간기도표면에머무르면서국소적면역체계에영향을줌으로써폐렴발생의빈도에영향을줄수있을것이다. 3) COPD 환자에서흡입스테로이드용량에따른폐렴발생흡입스테로이드용량관련하여 Ernst 등 14 은 COPD 환자에서 fluticasone 용량을기준으로하여저용량군 (fluticasone <500 μg/day), 중간용량군 (fluticasone 500 999 μg/day), 고용량군 ( 1,000 μg/day) 으로나누어, 각군에서폐렴발생의위험도를분석하였을때, 저용량군보다는중간용량군에서, 중간용량군보다는고용량군에서폐렴이더많이발생되었다고발표하였다 ( 각각 adjusted rate ratio, 1.50 [95% CI, 1.38 1.62]; 1.63 [95% CI, 1.55 1.71]; 2.25 [95% CI, 2.07 2.44]). 따라서사용하는흡입스테로이드용량에비례하여폐렴이잘발생되는것으로생각된다. 19
4) COPD 환자에서흡입스테로이드사용기간에따른폐렴발생흡입스테로이드사용기간과관련하여 COPD 환자를대상으로한관찰연구에서흡입스테로이드사용후첫 3년동안폐렴발생이별로증가하지않았으나, 4년정도지나면서흡입스테로이드를사용하지않는환자에비해서 2배정도폐렴발생이증가하였다 24. 다른관찰연구에서는흡입스테로이드사용한지 18 24 개월째에폐렴발생이 1.8배정도증가되었다 24. 반대로흡입스테로이드를중단하면점차적으로폐렴발생위험성이서서히감소하지만, 1년정도가지나도폐렴발생의위험성은 1.2배정도로남아있었다 14. 5) COPD 환자에서흡입스테로이드사용과폐렴관련사망률 TORCH 연구를포함한다섯개의무작위대조군연구들에서 COPD 환자를대상으로흡입스테로이드사용군과비사용군사이의폐렴관련사망률은차이가없음을보고하였으나, TORCH 연구를제외한연구들은신뢰구간이너무커서폐렴관련사망률을평가하기어렵다거나사망의원인을폐렴과연관시키기에는기준이모호하다는등의제한점이있었다 7,9,17,18,25. 흡입스테로이드를사용중인 COPD 환자중폐렴으로인해입원한환자에대한폐렴관련사망률을분석한 7개의관찰연구를체계적으로분석한결과, 연구대상 75% 를포함한국가관리데이터베이스를분석한 3개의관찰연구에서폐렴관련 30일째사망률이감소함을보여주었다 ( 관찰연구 1 16 : covariate-adjusted relative risk [RR], 0.50 [95% CI 0.41 0.60]; 관찰연구 2 15 : OR, 0.74 [95% CI: 0.66 0.83]; 관찰연구 3 12 : RR, 0.75 [95% CI: 0.69 0.82]) 12,15,16. 연구대상 25% 를포함한 4개의관찰연구에서는폐렴관련 30일때사망률을높이지않는것으로나타났다 26-29. 언급된다섯개의무작위대조군연구와일곱개의관찰연구결과는 Ernst 등 14 의 COPD 환자를대상으로흡입스테로이드사용에대한연구결과의소집단분석에서흡입스테로이드사용한환자가폐렴관련 30일째사망률이증가한다는보고와상반된다. 하지만 Ernst 등 14 의연구에서소집단분류에있어지나치게중증폐질환을갖고있거나 COPD 악화로인한입원빈도가높은환자가많아그로인해전신스테로이드혹은항생제등을포함한다양한호흡기계약물이투여되었던점이소집단분석에영향을주었을가능성을감안하여결과를수용해야할필요가있다. 3. 결론 COPD 환자에서흡입스테이드의치료는일부환자군에서 COPD 증상을감소시키고, 건강상태를향상시키며, 급성악화의빈도를감소시키는이점이있기는하나, 흡입스테로이드의종류에따라정도의차이가있기는하지만용량과사용기간에비례하여폐렴발생을증가시키는단점이있는것은분명해보인다. 하지만현재까지연구결과에따르면이로인한폐렴관련사망률은높이지는않는것으로나타났다. 따라서 COPD 환자에서흡입스테로이드를사용을선택하려고할때는이러한장단점을비교하여필요한경우최소한의용량으로흡입스테로이드를사용하는것이좋을것으로생각된다. 4. 감사의글 This study was supported by a grant from Korea University, Seoul, Korea (K1326181). References 1. GINA. USA: Global strategy for asthma management and prevention [Internet]. 2015 [cited 2015 Novermber 15]. Available from: http://www.ginasthma.org/local/uploads/files/gina_report_2015_aug11.pdf. 2. The Korean Academy of Tuberculosis and Respiratory Diseases. The Korean guideline for management of asthma 20
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