DOI: 10.4046/trd.2010.68.3.162 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2010;68:162-167 CopyrightC2010. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 신종플루폐렴으로입원한환자들에서주요합병증발생과관련된인자 울산대학교의과대학서울아산병원 1 응급의학교실, 2 감염내과학교실, 3 호흡기내과학교실최상식 1, 김원영 1, 김성한 2, 홍상범 3, 임채만 3, 고윤석 3, 김원 1, 임경수 1 Original Article Associated Factor Related to Major Complications of Patients with Hospitalized for 2009 H1N1 Influenza Pneumonia Sang-Sik Choi, M.D. 1, Won Young Kim, M.D. 1, Sung-Han Kim, M.D. 2, Sang-Bum Hong, M.D. 3, Chae-Man Lim, M.D. 3, Youn-suck Koh, M.D. 3, Won Kim, M.D. 1, Kyung-Su Lim, M.D. 1 Departments of 1 Emergency Medicine, 2 Infectious Diseases, 3 Respiratory and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Background: To date, there are few data on the risk factors for severe cases and deaths associated with the 2009 pandemic H1N1 influenza A. Here, we describe the clinical and epidemiologic characteristics of patients hospitalized for pneumonia and identify those factors associated with the development of major complications (MC). Methods: We reviewed the medical records of 41 cases of pneumonia admitted to a university-affiliated tertiary hospital between Aug 26 and Dec 10, 2009, and who had confirmed H1N1 influenza A based on real-time reverse transcriptase-polymerase-chain-reaction assay. There were 7,962 patients that fit these criteria. We compared the clinical features and demographic characteristics of patients who developed MC to with those who did not develop MC. Results: During the study period, 10 patients developed MC (required admission to the intensive care unit, n=10; required ventilator therapy, n=6; death, n=4). Patients with MC were significantly older than those without MC and more frequently had underlying medical conditions (90.0% vs 41.9%, p-value <0.01). In the patients with developed MC, the median PaO 2 /FiO 2 ratio of 230.0 (145.0 347.3) at admission and pneumonia severity index (PSI) score of 141.5 (88.3 158.5) were higher than patients without MC. However, no differences were observed in laboratory findings or in viral shedding between the 2 groups. Conclusion: In hospitalized pneumonia patients of 2009 H1N1 influenza, old age, a history of malignancy, initial hypoxemia, PaO 2/FiO 2 ratio, and PSI score appear to be risk factor significantly related to developing MC. These findings might be the basis to influence strategies for admitting patients to an intensive or intermediate care unit and for pre-emptive antiviral therapy. Key Words: Influenza A Virus, H1N1 Subtype; Pneumonia; Critical Illness; Risk Factors 서 인플루엔자항원변이에의해발생하는대유행성은 Address for correspondence: Won Young Kim, M.D. Department of Emergency Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea Phone: 82-2-3010-3350, Fax: 82-2-3010-3360 E-mail: wonpia@yahoo.co.kr Received: Jan. 26, 2010 Accepted: Mar. 10, 2010 론 1888 년에첫발병하여 1918 년약 2천만명의사망자를발생하게한스페인인플루엔자 (Spanish influenza), 1977 1978년대유행등총 5차례의발병이있었으나, 이후 30년간대유행은보고되지않았다 1. 2009년 4월멕시코, 미국에서인체감염사례가첫발생된이후돼지유래신종플루 ( 이하신종플루, Swine influenza, 2009 H1N1) 는급속히전세계로확산되었다 2. 세계보건기구 (World Health Organizatin, WHO) 는신종플루가세계적으로확산되면서 28,744 명의감염자와 144명의사망자를초래하자 21세기최초의인플루엔자대유행을선언하고각국의신속한대 162
Tuberculosis and Respiratory Diseases Vol. 68. No. 3, Mar. 2010 응을촉구하였다. 그럼에도불구하고, 2009년 12월까지신종플루로인한사망자수는세계적으로 11,516명에이른다 3. 국내질병관리본부의보도자료에의하면 2009년 5월국내최초로신종플루감염환자가보고된이후, 8월 15일경남지역에서첫사망환자가발생하였고국가적인감염방지노력에도불구하고감염속도는급속히확산되어, 12 월초하루감염자수가만명에이르고사망자수는 117 명으로매우증가하였다 4. 계절인플루엔자를대상으로한이전연구에서 65세이상과당뇨, 심폐질환의기저질환이있는경우 20% 에서폐렴등의합병증으로이환된다고보고하였고, 인플루엔자의사망률에관계되는위험인자로고령, 만성심폐질환, 만성대사성질환, 신장질환, 면역억제상태등이제시되었다 1,5. 그러나신종플루에대해서는호발연령대가학령기이며고위험군이아닌경우에도사망이많았다는점등계절인플루엔자와는상이한결과가외국에서보고되고있으나아직까지국내자료는없는실정이다 6,7. 특히외국에서사망원인이대부분폐렴합병에의한급성호흡곤란증후군과패혈증으로보고되고있기에, 신종플루로인한폐렴환자에서중증환자와관련된인자들을확인하는것은매우중요할것이다 8. 이에저자들은신종플루에의한폐렴으로입원한환자들을대상으로내원시일반적인특성, 활력징후, 검사실소견과방사선소견을분석하여병원내사망, 중환자실입원처치혹은기계환기치료같은주요합병증 (major complications, MC) 발생과관련된위험요인과예후인자가무엇인지확인하고자하였다. 로판단되거나타원에서폐렴으로진단받은경우는본연구에서제외하였다 10. 환자들의전자의무기록지와검사소견을토대로내원당시연령, 성별, 동반질환 ( 고혈압, 당뇨, 호흡기질환, 악성종양등 ), 증상, 활력징후, 검사실소견, 흉부방사선소견및흉부전산화단층촬영소견등을양식화된조사지에근거하여후향적조사를하였다. 또한입원첫날가장좋지않았던활력징후, 동맥혈가스분석및검사실소견을조사하였고지역사회획득폐렴환자에서예후를판단하는지표인 pneumonia severity index (PSI) 값을계산하였다 11,12. 주요합병증은병원내사망, 심폐소생술시행, 중환자실입원처치혹은기계환기치료가필요로하였던경우들중한가지이상의사건이입원중에발생된경우로정의하였다. 주요합병증이발생한군 (MC group, 이하 MC군 ) 과발생하지않은군 (non-mc group, 이하 non-mc 군 ) 으로나누어각변수들을비교분석하였다. 통계검정은 SPSS 12.0 프로그램 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 연속형변수의경우평균 (± 표준편차 ) 이나중앙값 (Inter-quartile range [IQR]) 을구하였고, 범주형변수의경우빈도를구하였다. 주요합병증이발생한군과발생하지않는군을대상으로연속형변수의비교는정규분포를따르는경우 Student's t-test를시행하였고정규분포를따르지않는경우 Mann-Whitney U test 를시행하였다. 범주형변수의비교는카이제곱검증 (chi-square test) 이나 Fisher의정확한검정 (Fisher's exact test) 을시행하였다. p-value 0.05 미만인경우통계적으로유의한차이가있다고판정하였다. 대상및방법 결 과 본연구는 2009년 8월 26일부터 12월 10일까지약 4개월간서울소재일개병원응급의료센터에내원하여신종플루로확진받은 7,962명의환자중폐렴으로입원한 16 세이상의성인환자 41명을대상으로하였다. 신종플루의확진은인후도말 (nasopharyngeal swab) 검체를이용한 real-time reverse transciptase-polymerase chain reaction assay (RT-PCR) 검사를통하여이루어졌다 9. 폐렴의진단은흉부단순촬영이나흉부전산화단층촬영에서영상의학과판독과 Infectious diseases Society of America/American Thoracic Society consensus guideline 의병원외폐렴정의에합당한경우로하였고, 병원내감염으 연구기간동안본원에서신종플루 RT-PCR 검사양성환자로병원외감염에의한폐렴이확진되어입원치료받은성인환자는총 41명이었고, 10명에서주요합병증이발생하였고 4명이사망 (9.8%) 하였다. 증상발생후병원내원까지걸린시간의중앙값은 2.0 (IQR, 1.0 4.0) 일이었고주증상으로는기침 (38/41, 92.7%) 이가장흔하였고발열 (34/41, 82.9%) 과호흡곤란 (27/41, 65.9%) 순이었다. 중환자실처치를받지않았던 31명의평균입원기간은 6.0 (IQR, 4.0 7.0) 일이었고중환자실처치를받은 10명의환자중 4명의환자가사망하였고이중한명은인공호흡기치료를거부한상태였다. 10명중 6명이인공호흡 163
SS Choi et al: Associated factor related to complications of H1N1 influenza pneumonia 기치료를받았고이중 50% 인 3명의환자는발관을하지못한채사망하였다. MC군나이의중앙값은 64.0 세 (IQR, 48.5 67.5) 로 non-mc군 39.0세 (IQR, 19.0 61.0) 보다 고령이었고 (p<0.01), 4명의사망환자들의평균연령은 64.5세였다 (Table 1). 동반질환중악성종양의유무만이두군에서유의한차이가있었으나 (50.0% vs. 3.2%, Table 1. Baseline clinical characteristics of major complications (MC) group and non-mc group Variables MC group (n=10) non-mc group (n=31) p-value Demographic factor Age, yr 64.0 (48.5 67.5) 39.0 (19.0 61.0) 0.03 Sex, Male/Female 7 (70)/3 (30) 19 (61.3)/12 (38.7) 0.62 BMI, kg/m 2 22.7 (19.7 24.7) 23.1 (18.4 24.9) 0.79 Comorbidity 9 (90.0) 13 (41.9) 0.01 Asthma 0 (0.0) 3 (9.7) 0.31 Chronic lung disease 2 (20.0) 4 (12.9) 0.58 Cardiovascular 2 (20.0) 3 (9.7) 0.39 Neoplasm 5 (50.0) 1 (3.2) 0.01 Liver 2 (20.0) 1 (3.2) 0.07 DM 1 (10.0) 3 (9.7) 0.98 Renal 1 (10.0) 3 (9.7) 0.98 Immunosuppressant 3 (30.0) 4 (12.9) 0.21 Corticosteroid 2 (20.0) 4 (12.9) 0.58 Initial vital sign SBP, mm Hg 115.5 (101.0 115.5) 121.0 (112.0 129.0) 0.52 DBP, mm Hg 65.0 (61.8 75.5) 76.0 (67.0 85.0) 0.10 PaO 2/FiO 2 ratio 230.0 (145.0 347.3) 350.0 (315.0 410.0) 0.02 PSI score 141.5 (88.3 158.5) 33.0 (19.0 70.0) <0.01 Values are expressed as median (inter-quartile range) or n (%). MC: major complications; DM: diabetes mellitus; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; PaO 2: partial oxygen tension in arterial blood; FiO 2: fraction of inspired oxygen; PSI: pneumonia severity index. Table 2. Baseline laboratory findings and outcomes of the study population Variables MC group (n=10) Non-MC group (n=31) p-value Laboratory findings WBC, 10 3 /mm 3 11.1 (5.8 15.2) 9.3 (6.9 12.7) 0.73 Hemoglobin, g/dl 12.0 (9.5 15.0) 13.2 (12.0 14.6) 0.55 Platelet, 10 3 /mm 3 118.5 (93.0 229.0) 208.0 (164.0 279.0) 0.03 BUN, mg/dl 20.5 (10.5 26.8) 9.0 (7.0 14.0) 0.06 Creatinine, mg/dl 1.0 (0.80 1.18) 0.8 (0.6 1.0) 0.10 CK, IU/L 119.0 (52.50 247.0) 121.5 (57.3 255.0) 0.92 LD, IU/L 383.0 (264.0 830.0) 267.0 (228.0 431.0) 0.18 CRP initial, mg/dl 14.2 (3.4 24.6) 7.4 (3.5 12.0) 0.12 CRP peak, mg/dl 21.2 (9.5 29.1) 7.38 (3.8 12.0) 0.01 Procalcitonin initial, ng/ml 1.6 (0.2 18.2) 0.18 (0.1 2.3) 0.17 Procalcitonin peak, ng/ml 7.0 (0.2 48.2) 0.18 (0.1 2.3) 0.06 ABGA, ph 7.4 (7.4 7.5) 7.4 (7.4 7.5) 0.21 ABGA, PaO 2 51.5 (34.8 75.8) 72.0 (63.0 83.0) 0.03 Outcome In-hospital mortality 4 (40.0) 0 (0) Values are expressed as median (inter-quartile range) or n (%). MC: major complications, WBC: White blood cell, BUN: blood urea nitrogen, CK: creatinine phosphokinase, LD: lactate dehydrogenase; BNP: B-natriuretic peptide, CRP: C-reactive protein, ABGA: arterial blood gas analysis, PaO 2: partial oxygen tension in arterial blood. 164
Tuberculosis and Respiratory Diseases Vol. 68. No. 3, Mar. 2010 p=0.01), 동반질환이없었던환자에서 MC가발생하였던경우는한예뿐이었다. 내원초기활력징후들은양군간에유의한차이가없었고혈소판과입원중 C-reactive protein 최고치를제외한검사실소견에서도양군에서유의한차이가없었다 (Table 2). 내원시동맥혈산소분압은 MC군 51.5 mm Hg으로 non-mc군 72.0 mm Hg보다유의하게낮았으며 (p=0.03), PaO 2 /FiO 2 ratio도 MC군의경우 230.0 (IQR, 145.0 347.3), non-mc군의경우 350.0 (IQR, 315.0 410.0) 로두군사이에서유의한차이가있었다 (p=0.02). PaO 2 /FiO 2 ratio가 300 미만인경우가 MC군에서 90.0% 로 non-mc군 18.5% 보다흔하였다 (p=0.03). 또한 MC군에서 PSI 중앙값은 141.5 (IQR, 88.3 153.5) 로 non-mc군 33.0 (IQR, 19.0 70.0) 보다높았고유의한차이를보였으며 (p<0.01), 특히지역사회획득폐렴환자에서외래단기추적관찰의기준인 PSI score 70 초과시 MC가발생할경우가의미있게높았다 (p< 0.01). 5일간투약후추적 RT-PCR 을전체 41명의환자중 36명에게서시행되었다. 추적검사한 RT-PCR 에서도여전히양성인경우가 MC군에서 66.7% (6/9) 로 non-mc 군 37.0% (10/27) 보다흔하였으나통계적으로유의한차이는없었다 (p=0.12). 전체 41명의환자중 26명의환자에게서흉부전산화단층촬영이시행되었는데대부분에서양측성침윤 (bilateral infiltration) 이었고 (22/26, 85%) 하엽이가장흔히침윤 (12/26, 46%) 되는부위였다. 고찰본연구의결과신종플루에의한폐렴으로입원한환자들에서주요합병증발생과관련된위험요인으로는고령과악성종양의유무였고예후인자로는내원시저산소증, 급성폐손상 (P/F ratio <300) 그리고 PSI score >70 이었다. 신종플루에취약한연령대에대한보고는캐나다지역에서주요합병증이발생한 168명을대상으로한연구에서평균연령이 32.3세로비교적젊은층에서많았었고, French Institute for Public Health Surveillance 에서도사망연령의중앙값이 37세로기존의계절인플루엔자에비해상대적으로젊다고보고하였다 6,13. Simonsen 등 7 은이러한차이가고령환자들에있어서는인플루엔자감염에대한이전의저항성이있어서비교적감염에덜취약하기때문이며이전의저항성이없는젊은성인에대한면역력획득의필요성을강조하였었다. 그러나본연구에서는 MC군에서 64.0세 (IQR, 48.5 67.5) 로 non-mc군 39.0세 (IQR, 19.0 61.0) 에비해서의미있게높았었고, 특히사망한 4명의환자군에있어서는평균연령은 64.5세로매우높았다. 즉, 신종플루로인한폐렴은 30 40대의젊은성인에서흔히발생하나사망환자들은대부분 65세이상고령환자들이었음에주목해야할것이다. 입원환자의나이의중앙값이 27세임에도사망자의 20% 가 50세이상이었고, 주요합병증발생이 50세이상에서많이발생하였다고보고한캘리포니아지역의결과와사망자의 28% 가고령이었다는호주의보고도본연구결과와유사하였기에고령층도더이상신종플루감염에안전하지않음을알수있고, 특히폐렴으로입원한고령의환자에서는보다많은관심과주의깊은처치가필요할것이다 6,14. 이번연구에서는기저질환에있어서특징적으로악성종양이주요합병증의발생에관련된인자임을알수있었는데, 주요합병증이발생하였던환자들중 50% 가악성종양으로치료받고있었다. 만성심폐질환, 천식등기존의알려진계절독감위험인자들각각에있어서는통계적으로유의하지않았으나, 기저질환이하나라도있는경우는기저질환이없는경우보다주요합병증이발생할가능성이통계적으로유의하게높았기에신종플루로인한폐렴환자에서기저질환유무의확인이중요할것이다. 한문헌에따르면호흡기질환에서비만이질병의이환율에영향을준다고언급하고있다 15. 신체질량지수 (body mass index; kg/m 2 ) 가높을수록동반질환의합병가능성이많아이환율이높고주요합병증의발생가능성이많다는결과를제시하였고, Michigan Department of Community Health 의통계자료를토대로미국질병관리본부가 6월 18일까지신종플루의증으로진단된 655명중급성호흡곤란증후군으로진행하여치료받은 10명에대한증례보고에서는 9명이비만도 30 이상이었고그중 7명이약비만도 40의고도비만환자였다고보고하면서비만이주요합병증의위험인자가될수있음을제시하였다 16. 그러나 168 명의중환자실치료를받은환자군에대한캐나다연구에서는비만과사망률과는관련이없다고보고하였고, 본연구에서도비만과주요합병증발생과의관계는유의하지못한결과를얻었다 (p=0.7) 13. 중앙값의비교에서도유의하지않았지만실제비만도 30 이상의환자가세명밖에되지않았는데, 이는 2009년 OECD Factbook에발표된 30개 OECD 국가비만율에있어서대한민국은 3.5% 로비만율이가장낮은국가인데비하여미국이 34.3% 로비만율이가장높은국가로대한민국의비만인구절대수가적기때문으로사료되 165
SS Choi et al: Associated factor related to complications of H1N1 influenza pneumonia 며호흡기질환에대한위험인자에대한고려에있어비교적자유로울수있을것으로생각된다 17. 내원당시의활력징후에서는양군에서유의한차이가없었으나내원시측정한동맥혈산소분압은 MC군이 51.5 mm Hg로 non-mc군 72.0 mm Hg보다유의하게낮았으며, 초기저산소증 (<60 mm Hg) 이있는경우주요합병증이발생하는경우가많았다 (p<0.01). PaO 2 /FiO 2 ratio 도 MC군에서유의하게낮았었고, 특히급성폐손상 (P/F ratio <300) 발생시주요합병증의발생이증가하였기에신종플루폐렴으로내원한환자에서초기저산소증유무와급성폐손상동반여부를확인하는것이중요할것이다. 또한내원시측정한 PSI score >70 (Class III 이상 ) 일경우도주요합병증발생이많았었기에신종플루폐렴환자에서 PSI score 측정이필요할것으로사료된다. 일반실험실검사상에서백혈구, 적혈구기타간기능검사등에서는 MC, non-mc군에서의미있는차이가없었고혈소판의중앙값이 MC군에서 non-mc군보다유의하게낮은값을보였으나 (p=0.03) 통계적으로어떤특별한기준점을제시할수는없었다. 전체폐렴환자 41명중단 3명에서만 CRP가정상이었으나초기 CRP 값은두군에서큰차이가없었다 (p=0.12). 그러나입원중 CRP 최고값에있어서는 MC군이중앙값 21.2 mg/dl (IQR, 9.5 29.1) 로 non-mc군의중앙값 7.38 (3.8 12.0) 보다높았었기에입원중 CRP 검사의추적관찰이환자의주요합병증을확인하는데도움을줄수있을것이다. 초기림프구감소증 ( 800) 은신종플루폐렴환자 46% 에서관찰되는흔한소견이었으나주요합병증발생과관련인자는아니었다 (50% vs. 46%). 이는림프구감소증이신종플루중증질환으로진행하는관련인자중하나로제시한대만에서의보고와는차이가나는결과였다 18. 폐렴으로진단된전체 41명의환자에게 Oseltamivir 150 mg을하루 2회투약하였고 5일간투약후추적 RT-PCR 을시행한 36명중 16명인 44.4% 에서추적 RT- PCR 양성으로판정되었고 MC군에서 66.7% (6/9) 로 non- MC군 37.0% (10/27) 보다흔히관찰되었으나통계적으로유의한차이는없었다 (p=0.12). 즉, 본연구결과로는추적 RT-PCR 양성이주요합병증발생과관련된인자는아니었으나, 추적검사대상자가많지않았기에추적 RT-PCR 양성과주요합병증과의관계는보다많은수를대상으로한연구로확인이필요할것이다. 전체 41명의환자에서초기흉부단순촬영상이상소 견을보였던경우가 39명이었고나머지 2명은각각 3일, 4일째이상소견이관찰되었다. 이는신종플루폐렴의경우대부분초기에흉부방사선검사상이상을보인다는점을시사한다. 41명의환자중 26명에서흉부전산화단층촬영을시행하였고이중 22명에서양측성침윤이관찰되었고, 하엽에만국한된경우 (12/26, 46%) 가가장많이관찰되었다. 한문헌에서는신종플루폐렴에서경화형소견 (consolidation) 이관찰되면예후가좋지않다는결과를제시하였으나, 본연구결과에서는간유리혼탁 (glass ground opacity) 과경화형소견 (consolidation) 은양군에서큰차이를보이지않았었다 19. 본연구의제한점으로는도시지역의일개대학병원에서시행된연구이기에환자들의대부분이일부지역에국한되어있어전체를일반화하는결과로제시하기에는다소한계가있을수있다는것이다. 또한신종플루폐렴환자중입원이필요한환자만을대상으로하여표본수가 41명으로많지않았었고이로인해관련인자로제시한여러변수들에대해서다변량분석을시행할수없었다. 이는이번연구에서주요합병증발생의관련인자들에대해서독립인자여부를확인할수없는제한점을야기하였다. 신종플루에의한폐렴으로입원한환자들에서고령, 악성종양유무, 내원시저산소증, 급성폐손상 (P/F ratio <300) 그리고 PSI가높을수록병원내사망, 중환자실입원처치혹은기계환기치료같은주요합병증발생비율이높았기에, 신종플루폐렴으로입원하는환자에서이러한주요합병증관련인자들을확인한다면중환자실혹은일반격리실입원등입원계획을설정하는데도움을받을수있을것이다. 참고문헌 1. Dolin R. Chapter 180. Influenza. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, editors. Harrison's principles of internal medicine. 17th ed. New York: McGraw-Hill Co., Inc.; 2008. p. 1127-32. 2. Centers for Disease Control and Prevention (CDC). Swine influenza A (H1N1) infection in two children: Southern California, March-April 2009. MMWR Morb Mortal Wkly Rep 2009;58:400-2. 3. World Health Organization. H1N1 influenza press release [Internet]. Geneva: World Health Organization; c2009 [updated 2009 Dec 23; cited 2009 Dec 28]. Availabe from: http://www.who.int/csr/don/2009_12_23/ 166
Tuberculosis and Respiratory Diseases Vol. 68. No. 3, Mar. 2010 en/index. html. 4. Korea Centers for Disease Control and Prevention. H1N1 influenza A (H1N1) press release [Internet].Seoul: Korea center for Disease Control and Prevention; c2009 [Cited 2009 Dec 28]. Available from: http://flu.cdc.go. kr. 5. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86. 6. Vaillant L, La Ruche G, Tarantola A, Barboza P. Epidemiology of fatal cases associated with pandemic H1N1 influenza 2009. Euro Surveill 2009;14.pii:19309. 7. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998;178:53-60. 8. World Health Organization. New influenza A (H1N1) virus infections: global surveillance summary, may 2009. [Internet]. Geneva: World Health Organization; c2009 [Updated 2009 May 15; cited 2009 Dec 28]. Available from: http://www.who.int/wer/2009/wer8420. pdf. 9. World Health Organization. CDC protocol of realtime RTPCR for influenza A (H1N1) [Internet]. Geneva: World Health Organization; 2009 [updated 2009 Oct 6; cited 2009 Dec 28]. Available from: http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/ en/index.html. 10. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44 Suppl 2:S27-72. 11. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low- risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-50. 12. Marras TK, Gutierrez C, Chan CK. Applying a prediction rule to identify low-risk patients with community-acquired pneumonia. Chest 2000;118:1339-43. 13. Kumar A, Zarychanski R, Pinto R, Cook DJ, Marshall J, Lacroix J, et al. Critically ill patients with 2009 influenza A (H1N1) infection in Canada. JAMA 2009;302: 1872-9. 14. Louie JK, Acosta M, Winter K, Jean C, Gavali S, Schechter R, et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A (H1N1) infection in California. JAMA 2009;302:1896-902. 15. Morris AE, Stapleton RD, Rubenfeld GD, Hudson LD, Caldwell E, Steinberg KP. The association between body mass index and clinical outcomes in acute lung injury. Chest 2007;131:342-8. 16. Centers for Disease Control and Prevention. Intensivecare patients with severe novel influenza A (H1N1) virus infection: Michigan, June 2009. MMWR Morb Mortal Wkly Rep 2009;58:749-52. 17. Source OECD. OECD Factbook 2009: economic, environmental and social statistics [Internet]. Paris: Organisation for Economic Co-operation and Development; c2009 [cited 2009 Dec 20]. Available from: http://puck. sourceoecd.org/vl=18173601/cl=11/nw=1/rpsv/factbook 2009/11/01/04/index.htm. 18. Chien YS, Su CP, Tsai HT, Huang AS, Lien CE, Hung MN, et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect 2010;60:168-74. 19. Marchiori E, Zanetti G, Hochhegger B, Rodrigues RS, Fontes CA, Nobre LF, et al. High-resolution computed tomography findings from adult patients with influenza A (H1N1) virus-associated pneumonia. Eur J Radiol 2009 Dec 3. [Epub ahead of print] 167