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<article article-type="research-article" dtd-version="1.0" xml:lang="ko" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">KJM</journal-id>
<journal-title-group>
<journal-title>The Korean Journal of Medicine</journal-title><abbrev-journal-title>Korean J Med</abbrev-journal-title></journal-title-group>
<issn pub-type="ppub">1738-9364</issn>
<issn pub-type="epub">2289-0769</issn>
<publisher>
<publisher-name>The Korean Journal of Medicine</publisher-name></publisher></journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3904/kjm.2022.97.1.23</article-id>
<article-id pub-id-type="publisher-id">kjm-97-1-23</article-id>
<article-categories>
<subj-group>
<subject>What's new?</subject></subj-group></article-categories>
<title-group>
<article-title>COVID-19와 장기 후유증</article-title>
<trans-title-group>
<trans-title xml:lang="en">COVID-19 and Long-Term Sequelae</trans-title>
</trans-title-group>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name-alternatives>
<name name-style="western" xml:lang="en"><surname>Kim</surname><given-names>Youn Jeong</given-names></name>
<name name-style="eastern" xml:lang="ko"><surname>김</surname><given-names>윤정</given-names></name>
</name-alternatives>
<xref ref-type="corresp" rid="c1-kjm-97-1-23"/>
<xref ref-type="aff" rid="af1-kjm-97-1-23"><sup>1</sup></xref>
<xref ref-type="aff" rid="af2-kjm-97-1-23"><sup>2</sup></xref>
</contrib>
<aff-alternatives id="af1-kjm-97-1-23">
<aff xml:lang="en"><label>1</label>Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, <country>Korea</country></aff>
<aff xml:lang="ko"><label>1</label>가톨릭대학교 의과대학 내과학교실</aff>
</aff-alternatives>
<aff-alternatives id="af2-kjm-97-1-23">
<aff xml:lang="en"><label>2</label>Division of Infectious Disease, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, <country>Korea</country></aff>
<aff xml:lang="ko"><label>2</label>가톨릭대학교 인천성모병원 감염내과</aff>
</aff-alternatives>
</contrib-group>
<author-notes><!-- Warning: check the email link -->
<corresp id="c1-kjm-97-1-23" xml:lang="en">Correspondence to Youn Jeong Kim, M.D., Ph.D. Division of Infectious Disease, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon 21431, Korea Tel: +82-32-1544-9004, Fax: +82-32-280-5987, E-mail: <email>muze1004@catholic.ac.kr</email></corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>2</month>
<year>2022</year></pub-date>
<pub-date pub-type="epub">
<day>1</day>
<month>2</month>
<year>2022</year></pub-date>
<volume>97</volume>
<issue>1</issue>
<fpage>23</fpage>
<lpage>27</lpage>
<history>
<date date-type="received">
<day>17</day>
<month>1</month>
<year>2022</year></date>
<date date-type="rev-recd">
<day>21</day>
<month>1</month>
<year>2022</year></date>
<date date-type="accepted">
<day>22</day>
<month>1</month>
<year>2022</year></date>
</history>
<permissions>
<copyright-statement xml:lang="en">Copyright &#x000A9; 2022 The Korean Association of Internal Medicine</copyright-statement>
<copyright-year>2022</copyright-year>
<license xml:lang="en">
<license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions>
<trans-abstract xml:lang="en"><p>After acute corona virus disease 2019 (COVID-19), there have been increasing reports of persistent and long-term symptoms similar to the post- viral syndromes described in survivors of severe acute respiratory syndrome (SARS) or middle east respiratory syndrome (MERS). Here, we provide a comprehensive review of the current literature on long-term COVID-19 focusing on organ-specific sequelae. Many of the recovered COVID-19 patients may be affected by long-term health. The future for COVID-19 survivors remains uncertain, and well conducted long term research will be needed.</p></trans-abstract>
<kwd-group xml:lang="ko">
<kwd>코로나바이러스감염증-19</kwd>
<kwd>급성호흡기증후군 코로나바이러스-2</kwd>
<kwd>합병증</kwd>
</kwd-group>
<kwd-group xml:lang="en">
<kwd>COVID-19</kwd>
<kwd>SARS-CoV2</kwd>
<kwd>Complication</kwd>
</kwd-group></article-meta></front>
<body>
<sec sec-type="intro">
<title>서론</title>
<p>2022년 1월 11일 기준으로 국내에서는 670,483명의 환자가 코로나바이러스감염증-19 (corona virus disease 2019, COVID-19)를 진단받았고, 6,114명이 COVID-19로 사망하였다. 약 2년여간의 임상 자료들이 축적되면서 COVID-19의 장기적인 영향에 대해 관심이 높아지고 있다. 바이러스 감염 이후의 장기적 후유증에 대한 연구는 인플루엔자(influenza), 중증급성호흡증후군(severe acute respiratory syndrome, SARS)이나 중동호흡기증후군(middle east respiratory syndrome, MERS) 환자에서도 보고된 바 있다. 한 연구에서는 2003년 대유행한 SARS의 경우 치료 후에도 만성 피로, 통증, 쇠약, 우울, 불면 등이 만성적으로 나타났다고 하였으며, 또 다른 연구에서는 SARS로 회복된 환자의 40%가 진단 후 3.5년까지 만성 피로 증후군을 겪었다고 발표한 바 있다&#x005B;<xref ref-type="bibr" rid="b1-kjm-97-1-23">1</xref>-<xref ref-type="bibr" rid="b3-kjm-97-1-23">3</xref>&#x005D;. 본고에서는 COVID-19 급성기에서 회복된 환자들에서 나타나는 장기별 후유증에 대해 서술하고자 한다.</p>
</sec>
<sec>
<title>본론</title>
<p>COVID-19 감염 후 대부분의 환자는 정상 생활이 가능하지만, 급성기에서 회복 이후 몇 주 혹은 몇 개월까지 어떤 증상이 지속되기도 한다. COVID-19 이후 12주 이상 지속되나 COVID-19 이외 다른 진단명으로 설명되지 않는 증상과 징후를 COVID-19 장기 후유증(post-COVID condition, long-term COVID, Long COVID, chronic COVID)이라 불리고 있으나, 전 세계적으로 통일된 정의가 있지는 않다. 또한 지속되는 증상뿐 아니라 새롭게 나타난 발병 후기 후유증, 증상이나 상태의 변화 등도 COVID-19의 장기 후유증으로 불리고 있다. 이에 대한 이해는 제한적이며 모든 장기에 영향을 줄 수 있다. 따라서 COVID-19 장기 후유증의 진단은 다른 질환에 대한 감별 진단이 우선이다.</p>
<sec>
<title>역학</title>
<p>COVID-19 250,351명 생존자를 포함한 57건을 체계적으로 분석한 연구에서 54%가 1개월 이내, 55%가 2-5개월 사이, 6개월 이상에서 54%가 최소 1번의 합병증을 경험하였다고 하였다. 관련된 가장 흔한 장기는 폐, 신경, 정신 건강장애, 기능성 이동성 장애였다&#x005B;<xref ref-type="bibr" rid="b4-kjm-97-1-23">4</xref>&#x005D;.</p>
</sec>
<sec>
<title>병태생리</title>
<p>병태생리에 기여하는 가능한 기전으로 직접적인 바이러스 병태생리 변화, 혈전, 급성 감염에 대한 면역학적 이상과 염증 손상, 호르몬 변화, 중증 후 후유증 등으로 설명하고 있으나 정확히 밝혀지지는 않았다. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)의 수용체인 안지오텐신 전환 효소(angiotensin-converting enzyme 2, ACE2)는 신체의 다양한 위치에서 표현되는데, 스파이크 단백질의 활성화를 통해 표적 세포로 바이러스가 들어가게 된다&#x005B;<xref ref-type="bibr" rid="b5-kjm-97-1-23">5</xref>&#x005D;. 이 수용체는 상피 세포, 위장 세포, 췌장 세포, 신장 세포들에서 발현되는데, 이는 직접적인 조직 손상이 SARS-CoV-2 감염의 일차 주요 기전이 될 수 있으며 장기 후유증의 원인이 될 수 있음을 시사한다&#x005B;<xref ref-type="bibr" rid="b6-kjm-97-1-23">6</xref>&#x005D;. 초기 연구에서는 내피세포가 ACE2를 과발현시켜 COVID-19 감염이 혈관 장벽에 변화를 가져와 응고 상태에 영향을 미친다는 연구가 있었으며, 장기 후유증 환자에서도 비슷한 기전을 보여주었다&#x005B;<xref ref-type="bibr" rid="b7-kjm-97-1-23">7</xref>,<xref ref-type="bibr" rid="b8-kjm-97-1-23">8</xref>&#x005D;. 사망자의 부검에서 활성화된 T세포가 발견되었고, 이는 자가 면역 질환과 비슷한 기전의 면역 체계 조절 장애가 또한 관련이 있을 수 있음을 시사한다&#x005B;<xref ref-type="bibr" rid="b9-kjm-97-1-23">9</xref>&#x005D;.</p>
</sec>
<sec>
<title>장기별 후유증</title>
<p>장기별 장기적 후유증에 대해 그림 1에 정리하였다.</p>
<sec>
<title>호흡기계 합병증</title>
<p>호흡곤란, 운동 능력 감소, 저산소증이 가장 흔하게 지속되는 호흡기계 증상이다. 영국에서 384명의 COVID-19 환자를 2개월 동안 관찰한 결과 53% 환자에서 지속되는 호흡곤란, 34%에서 기침이 남아 있었고, 단 27%만이 흉부 X-ray에서 호전을 보였다고 하였다&#x005B;<xref ref-type="bibr" rid="b10-kjm-97-1-23">10</xref>&#x005D;. 6개월 후 흉부 전산화단층촬영법 (CT) 검사 결과 349명 중 50%에서 이상 소견을 보였다는 연구 결과도 있다&#x005B;<xref ref-type="bibr" rid="b11-kjm-97-1-23">11</xref>&#x005D;. 생리학적으로는 확산능(diffusion capacity) 감소가 급성 후 가장 흔히 보고되는 COVID-19 장기 후유증으로, 직접적으로 급성기의 중증도와 연관이 있다. 영국흉부학회에서는 중증 폐렴 환자의 퇴원 후 첫 12주 동안의 환자 평가에 대한 알고리즘을 권장한 바 있으며, 권장안에서는 12주째 환자에 대한 임상적 평가와 흉부 X-ray, 폐기능 검사, 폐색전증에 대한 추적, 흉부 CT, 산소 포화도 평가를 위한 운동 검사, 가래 검사, 심장 초음파를 권고하였다&#x005B;<xref ref-type="bibr" rid="b12-kjm-97-1-23">12</xref>&#x005D;. 스테로이드가 도움이 된다는 연구가 있으나 폐기능 향상이나 흉부 사진 호전과는 관련이 없다는 결과도 있으며 섬유화 폐에 대해 폐이식을 하기도 한다&#x005B;<xref ref-type="bibr" rid="b13-kjm-97-1-23">13</xref>,<xref ref-type="bibr" rid="b14-kjm-97-1-23">14</xref>&#x005D;.</p>
</sec>
<sec>
<title>혈액학적 합병증</title>
<p>파종혈관내응고의 소모성 응고증과는 달리 고염증과 과응고 상태로 설명한다. 대규모 연구가 많지는 않지만 163명을 대상으로 한 연구에서는 COVID-19 환자 퇴원 후 30일째에 2.5%에서 혈전, 3.7%에서 출혈이 누적 발생하였다&#x005B;<xref ref-type="bibr" rid="b15-kjm-97-1-23">15</xref>&#x005D;. D-dimer 증가와 암이나 거동 불가 등 환자의 기저 요소가 혈전의 위험인자였다&#x005B;<xref ref-type="bibr" rid="b16-kjm-97-1-23">16</xref>&#x005D;. 명확한 근거는 없지만 위험-효과를 고려하여 고위험군에서 항응고제를 예방요법으로 고려하기도 한다.</p>
</sec>
<sec>
<title>심혈관 합병증</title>
<p>심혈관 장기 합병증으로 심장 대사 요구율 증가, 심근 섬유화, 부정맥, 빈맥, 자율 이상 등이 있다. COVID-19 이후 두근거림, 호흡곤란, 흉통 등을 호소할 수 있으며, 한 연구에서는 COVID-19 환자 60일째 추적에서 약 20%에서 흉통이 확인되었다&#x005B;<xref ref-type="bibr" rid="b17-kjm-97-1-23">17</xref>&#x005D;. 대유행 이전과 비교하여 대유행 기간 동안 스트레스성 심근병증, 심근염이 증가되었다(7.8% 대 1.5-1.8%)는 보고도 있다&#x005B;<xref ref-type="bibr" rid="b18-kjm-97-1-23">18</xref>&#x005D;. 바이러스 침입이 직접적으로 영향을 미칠 뿐 아니라 ACE2의 조절, 염증과 면역학적 반응이 심근과 심낭의 구조와 전도시스템에 영향을 미칠 수 있다. SARS에서 회복된 환자들을 장기적으로 추적한 결과 심장 대사 요구가 증가되었다는 보고가 있으며, 이는 심근 예비율 감소나 스테로이드 사용, 레닌-안지오텐신-알도스테론의 조절 장애와 연관이 있을 수 있다&#x005B;<xref ref-type="bibr" rid="b19-kjm-97-1-23">19</xref>&#x005D;. 급성기 동안 심혈관 합병증이 있거나 지속적인 심장 증상이 있는 환자에서 정기적 임상 평가 및 심전도나 심장 초음파를 4-12주에 고려할 수 있다&#x005B;<xref ref-type="bibr" rid="b20-kjm-97-1-23">20</xref>&#x005D;. 증상과 질환에 따라 기존 가이드라인에 맞는 검사와 약제를 선택한다.</p>
</sec>
<sec>
<title>정신 신경학적 합병증</title>
<p>SARS와 마찬가지로 COVID-19 회복 후에 만성 쇠약, 우울, 불면 등을 호소할 수 있다&#x005B;<xref ref-type="bibr" rid="b21-kjm-97-1-23">21</xref>&#x005D;. 인지 장애로 집중력이나 기억력 감퇴, 언어 문제 등이 나타나기도 한다. 한 연구에서는 COVID-19 입원 후 1개월째에 약 56% 환자에서 외상 후스트레스 장애, 우울, 불안, 불면 등의 정신과적 후유증을 호소했다는 보고가 있다&#x005B;<xref ref-type="bibr" rid="b22-kjm-97-1-23">22</xref>&#x005D;. 또 다른 연구에서는 COVID-19 환자를 급성기 이후 6개월까지 추적 시 25%의 환자에서 정신과적인 합병증이 있었다&#x005B;<xref ref-type="bibr" rid="b11-kjm-97-1-23">11</xref>&#x005D;. 62,354명의 대규모 연구에서는 14일에서 90일 사이에 18.1%에서 정신과적 증상이 새롭게 생기거나 재발한다고 하였다&#x005B;<xref ref-type="bibr" rid="b23-kjm-97-1-23">23</xref>&#x005D;. 병태생리는 직접적인 바이러스 감염, 전신염증, 신경염증, 미세혈관 혈전증 및 신경 퇴화 등 복합적이다. 신경학적 합병증에 대해 영상 평가와 표준 치료를 할 수 있으며 필요 시 전문가에게 의뢰한다.</p>
</sec>
<sec>
<title>내분비계 합병증</title>
<p>COVID-19 환자에서 당뇨성 케토병증, 아급성 갑상선염 등이 보고되기도 하였으며 잠재적으로 있던 자가면역성을 증진시켜 하시모토 갑상선염, 그레이브스병이 새롭게 생기기도 한다&#x005B;<xref ref-type="bibr" rid="b24-kjm-97-1-23">24</xref>,<xref ref-type="bibr" rid="b25-kjm-97-1-23">25</xref>&#x005D;. 바이러스에 의한 직접 영향, 면역, 염증 반응뿐 아니라 약제 사용과 같은 외인성 원인이 복합적으로 작용하여 발생한다. 전형적인 위험인자는 없으나 새롭게 진단된 당뇨, 시상하부-뇌하수체-부신 축 억제, 갑상선 기능 항진증이 의심되는 경우 적절한 검사를 받고 전문가에게 의뢰한다. 진단과 치료는 기존 지침에 따른다.</p>
</sec>
<sec>
<title>신장 합병증</title>
<p>인공호흡기를 필요로 하는 COVID-19 중증 입원 환자의 20-31%, 모든 입원 환자의 5%에서 투석을 필요로 하는 중증 급성 신장 손상이 발생한다&#x005B;<xref ref-type="bibr" rid="b26-kjm-97-1-23">26</xref>,<xref ref-type="bibr" rid="b27-kjm-97-1-23">27</xref>&#x005D;. 한 연구에서는 급성기 이후 6개월째에 환자의 35%에서 사구체 여과율이 감소하였고, 급성기에 정상이었다가 13%에서 새롭게 감소가 발생하였다고 보고하였다&#x005B;<xref ref-type="bibr" rid="b11-kjm-97-1-23">11</xref>&#x005D;. COVID-19 관련 신장병증 (COVID-19-associated nephropathy)은 국소 분할 사구체 경화증의 변형과 급성 튜브 손상, 사구체 퇴화로 설명되며, 이는 인터페론과 사이토카인 활성화에 반응하여 나타난다&#x005B;<xref ref-type="bibr" rid="b28-kjm-97-1-23">28</xref>&#x005D;. 퇴원 후 투석이 필요한 경우는 별로 없으며, 신장 기능이 회복이 되는지 추적이 필요하다.</p>
</sec>
<sec>
<title>소화기계 합병증</title>
<p>중요한 소화기계, 간담도계 합병증은 보고된 바 없으나 인플루엔자나 다른 호흡기 바이러스 감염에서 알려진 바와 같이 COVID-19가 장관 마이크로비옴을 변화시킬 가능성이 있다&#x005B;<xref ref-type="bibr" rid="b29-kjm-97-1-23">29</xref>&#x005D;. COVID-19 감염 후 과민성 대장 증후군과 소화 불량에 대해 연구가 진행되고 있다.</p>
</sec>
<sec>
<title>피부과적 합병증</title>
<p>716명을 대상으로 한 연구에서 COVID-19 이후 피부과적 합병증은 급성기 증상과 동시에 15%, 급성기 이후 64%까지 보고되었다&#x005B;<xref ref-type="bibr" rid="b30-kjm-97-1-23">30</xref>&#x005D;. 상기도 증상 이후 피부 증상까지 7.9일이 걸렸으며, 약 3%의 환자가 6개월까지 피부 발진이 지속되었다&#x005B;<xref ref-type="bibr" rid="b11-kjm-97-1-23">11</xref>&#x005D;. 가장 주된 피부과 질환은 탈모로 약 20%에서 보고되며 바이러스 감염이나 스트레스로 인한 텔로젠 유출(telogen effluvim)로 설명한다&#x005B;<xref ref-type="bibr" rid="b11-kjm-97-1-23">11</xref>&#x005D;.</p>
</sec>
</sec>
</sec>
<sec sec-type="conclusions">
<title>결론</title>
<p>SARS, MERS와 같이 COVID-19에서도 급성기 치료가 끝난 이후에도 장기적인 후유증이 나타날 수 있으며, 현재까지 보고된 빈도는 적지 않다. 장기 후유증은 여러 장기에 장기간에 걸쳐 나타날 수 있으며 COVID-19 대유행 상황에서 회복된 환자들이 점차 증가될 것으로 예상되는 바, COVID-19 장기 후유증을 직접, 간접적으로 진단, 치료할 수 있는 다학제 진료가 필요할 것이다.</p>
</sec></body>
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