DOI: 10.4046/trd.2011.70.4.285 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2011;70:285-292 CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 인플루엔자연관폐렴 Review 중앙대학교의과대학호흡기내과학교실 김재열 Influenza Associated Pneumonia Jae Yeol Kim, M.D. Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea After an outbreak of H1N1 influenza A virus infection in Mexico in late March 2009, the World Health Organization raised its pandemic alert level to phase 6, and to the highest level in June 2009. The pandemic H1N1/A influenza was caused by an H1N1 influenza A virus that represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza. After the first case report of H1N1/A infection in early May 2009, South Korea was overwhelmed by this new kind of influenza H1N1/A pandemic, which resulted in a total of 700,000 formally reported cases and 252 deaths. In this article, clinical characteristics of victims of H1N1/A influenza infection, especially those who developed pneumonia and those who were cared for in the intensive care unit, are described. In addition, guidelines for the treatment of H1N1/A influenza virus infection victims in the ICU, which was suggested by the Korean Society of Critical Care Medicine, are introduced. Key Words: Influenza A Virus, H1N1 Subtype; Pneumonia; Intensive Care Units 역사속에서의 Influenza 유행 언제부터인간사회에서독감이유행하였는지그기원을정확히밝히는것은어렵지만, 역사적으로발한병 (sweat disease) 등으로불리던유행병이독감에의하였을가능성이있으며, 16세기에유럽에유행했던전염병은질병의특징과전파양상을고려할때독감에의한것일가능성이높다. 과거에는독감이왜발생하는지를잘몰랐기때문에나쁜별의영향 (influence) 이라고여기던시기가있었으며, 여기에서인플루엔자 (influenza) 라는이름이유래되었다고한다. Address for correspondence: Jae Yeol Kim, M.D. Department of Internal Medicine, Chung-Ang University College of Medicine, 224-1, Heukseok-dong, Dongjak-gu, Seoul 156-755, Korea Phone: 82-2-6299-1396, Fax: 82-2-825-7571 E-mail: jykimmd@cau.ac.kr Received: Dec. 3, 2010 Accepted: Dec. 3, 2010 2009 2010 년사이에범세계적으로유행한 H1N1 A 형인플루엔자의역학 2009년 3월에멕시코에서호흡기전염병이대규모로발생하였으며, 이것이결국 H1N1 A형인플루엔자에의한것으로확인되었다. 멕시코에서유래한 H1N1 A형인플루엔자는빠른속도로전세계적으로전파되었으며, 검사를통해확인된감염사례를발표한나라만해도 214개국가에달한다. 2009년 6월 11일에 WHO는감염경보를최고단계인 6단계로격상시켰다. 모델링기법에의하면미국에서 H1N1 A형인플루엔자에감염된사람은 6천백만명정도일것으로추정된다 1. 이를연령별로나눠서살펴보면 0세에서 17세까지감염된사람은 2천만명, 18세에서 64세사이에서감염된사람은 3천 5백만명, 그리고 65세이상에서감염된사람은 6백만명일것으로추산된다. 이렇게나이에따라이환율에차이가나는것은노년층에서인플루엔자에대한항체율이높기때문으로해석된다. 2008년에획득된 14,000명의혈청을이용하여 2009년형 H1N1 A형인플루엔자에대한교차항체반응검사를시행하였을때, 4세이하의어린이에서는항체양성률이 1.8% 285
JY Kim: Influenza associated pneumonia 인반면에 80세이상인사람에서의항체양성률은 31% 였다 2. H1N1 A형인플루엔자로입원한환자수는 274,000명이고, 이로인해사망한환자수는 12,470명이다 3. 우리나라에서는약 70만명의환자가발생하여 252명의환자가이로인하여사망한것으로공식발표되었다. H1N1 A형인플루엔자의유전적특징 세계적인유행이없는시기의계절성인플루엔자에의한사망자수보다는적지만, H1N1 A형인플루엔자에의한사망이주로젊은층에서많이일어났기때문에그손실은더막대한것으로추산된다 6. H1N1 A형인플루엔자감염에의한사망의위험을높이는위험인자로는만성호흡기질환, 면역억제질환, 심질환등의동반질환존재 7, 임산부 8, 신생아 9, 고령 7, 그리고비만 10 등이었다. 2009년과 2010년사이에걸쳐서범세계적인유행을몰고온 H1N1 A형인플루엔자바이러스는두개의돼지계통유전자 (swine strain), 한개의사람계통유전자 (human strain), 그리고한개의조류계통유전자 (avian strain) 의복합체로과거에는분리된적이없는새로운형태의유전적구조를가지고있다 (Figure 1) 4. 이때문에신종인플루엔자라고불렸다. H1N1 A형인플루엔자로인한사망률 H1N1 A형인플루엔자에의한사망률은 0.5% 미만 (0.0004 1.47%) 인것으로추정된다 5. 수학적모델링에의거하여미국질병관리국 (CDC) 은미국에서 H1N1 A형인플루엔자로인하여사망한숫자를 12,470명으로추산하였다 3. 비록 H1N1 A형인플루엔자에의한사망자수가범 H1N1 A형인플루엔자와연관된폐렴국내의 14개종합병원에서 2009 년 6월부터 2010 년 2월까지 H1N1 A형인플루엔자로확진된환자중에서폐렴이발생한환자 269명에대하여후향적분석을시행한연구에따르면 (unpublished data), 환자들의평균나이는 48세 (15 93세 ) 였으며, 남성이 143명으로 53.2% 였다. 동반질환은천식이 36명 (13.4%), 만성폐쇄성폐질환이 14명 (5.2%), 기관지확장증이 12명 (4.5%), 그리고악성질환이 29명 (10.8%) 이었다. 사망한환자는 19명으로 7.2% 의사망률을보였다. 사망한환자의연령대를살펴보면 40대에서 2명, 50대에서 5명, 60대에서 4명, 70대에서 5명, 그리고 80대이상에서 3명이사망하였다. 다중회귀분석 (multivariate logistic regression analysis) 에서사망에영향을미치는인자는악성종양 (odd ration [OR], 12.0; 95% confidence interval [CI], 2.8 51.5; p=0.001), 추적한가슴 X선사진에서병변의범위가 50% 이상증가하는경우 (OR, 4.00; 95% CI, 1.05 15.2; p=0.033), 그리고폐렴중증도지표인 pneumonia severity index (OR, 1.03; 95% CI, 1.01 1.04; p=0.008) 였다 (Table 1). Table 1. Multivariate analysis for survival predictors of patients with H1N1-associated pneumonia Variables Adjusted OR (95% CI) p-value Figure 1. History of reassortment events in the evolution of the 2009 influenza A (H1N1) virus. Malignancy 12.0 (2.8 51.5) 0.001 PSI score 1.03 (1.01 1.04) 0.008 >50% increased extent of 4.00 (1.05 15.2) 0.033 infiltrate on follow-up chest X ray BUN>7 mmol/l 4.64 (0.93 23.2) 0.062 Male gender 0.28 (0.07 1.16) 0.080 CI: confidence interval; BUN: blood urea nitrogen. 286
Tuberculosis and Respiratory Diseases Vol. 70. No. 4, Apr. 2011 중환자실에입원한 H1N1 A 형인플루엔자환자의특징 국내의 28개종합병원에서 H1N1 A형인플루엔자로입원치료를받았던환자들의특징을살펴보면 (Hong et al, unpublished data), 총 245명의환자중에서사망한경우는 99예 ( 사망률, 40.4%) 였다. 사망군에서평균나이, 질환의중증도 (APACHE II, SOFA score) 가높았고, 동반질환의수가많았으며, 특히악성질환과간경변의빈도가높았다 (Table 2). 중환자실에입원한 H1N1 A 형인플루엔자환자의치료지침 ( 대한중환자의학회제공 ) 1. ICU admission criteria 1) Acute respiratory failure (1) An arterial oxygen tension (PaO 2 ) of <60 mm Hg with normal or low PaCO 2 at FiO 2 more than 0.5 (2) An arterial carbon dioxide tension (PaCO 2 ) of > 50 mm Hg accompanied by a fall in ph<7.3 in addition to hypoxaemia (3) Respiratory rate >35 breaths/minute with accessory muscle use 2) Hemodynamic instability (1) Pulse <40 or >50 beats/minute (2) Systolic arterial pressure <90 mm Hg or 40 mm Hg below the patient's usual pressure, or mean arterial pressure <60 mm Hg, or diastolic arterial pressure >120 mm Hg 2. ICU discharge criteria When a patient's physiologic status has stabilized and the need for intensive patient monitoring is no longer necessary and the patient can be cared for on a general unit. 3. Treatment protocol 1) Antibacterial+antiviral treatment (1) Initial antibiotics: 3rd generation cephalosporine+ respiratory quinolone (2) Antiviral: tamiflu 150 mg po bid+amantidine 100 mg po bid+ribavirin 300 mg po tid ㆍRibavirin-induced hemolysis and anemia should be monitored. ㆍRibavirin is contraindicated in patients with CrCl <50 ml/min. Ribavirin is not effectively removed by hemodialysis. (3) Others: follow ATS/IDSA guideline 11 2) Respiratory support (1) General principles 1 NPPV (noninvasive positive pressure ventilation) - generally not recommended, selected patients only 2 Bronchodilator delivery: 6 puffs of metered dose inhaler of ventolin at the inspiratory limb of ventilatory tubing using a spacer or nebulizer 3 Moderate case - follow usual respiratory failure management 4 Severe case (PaO 2 /FiO 2 100 200) - mechanical Table 2. Baseline characteristics of critically ill patients with pandemic influenza A/H1N1 All patients (n=245) Survivors (n=146) Non-survivors (n=99) p-value Age, yr 55.5±18.4 51.8±19.9 60.5±14.5 0.000 Male sex 134 (54.7) 84 (57.5) 50 (50.5) 0.278 Nosocomial acquisition 33 (13.5) 9 (6.2%) 24 (24.2) 0.000 APACHE II score 19.1±8.4 15.9±7.4 23.7±7.4 0.000 SOFA score 7.7±3.7 6.3±3.1 9.9±3.5 0.000 No. of comorbodity 2 (1 3) 1 (1 3) 2 (1 3) 0.000 Malignancy, solid tumor 49 (20.0) 19 (13.0) 30 (30.3) 0.001 Liver cirrhosis 9 (3.7) 0 (0) 9 (9.1) 0.000 Values are presented as number (%) or mean±sd unless otherwise indicated. SD: standard deviation. 287
JY Kim: Influenza associated pneumonia ventilation with or without NO inhalation, consider prone position or ARM (alveolar recruitment maneuver) 5 Very severe case (PaO 2 /FiO 2 <100) - consider early ECMO 6 With unstable vital signs: heavy sedation with fentanyl or ketamine, and consider use neuromuscular blockades (2) Ventilaror setting 1 In case of FiO 2 requirement less or equal than 0.6: Lung protective ventilation (tidal volume 6 ml/predicted body weight; if Pplat >30 cm H 2 O, consider reduce tidal volume further, PEEP setting as ARDSnet PEEP table, I:E=1:1). Consider permissive hypercapnea strategy (do not overventilate) 2 In case of FiO 2 >0.6 - if hemodynamic stable: decremental PEEP setting after ARM - if case of hemodynamic unstable: prone ventilation with or without NO inhalation (nitric oxide should be titrated the dose daily) (3) Indication of early ECMO: Consider ECMO at early stage of ARDS if ARDS patients not be maintained appropriately (optional treatment) 1 If FiO 2 requirement is still higher 0.7 after decremental PEEP titration with alveolar recruitment maneuver and/or Prone ventilation & NO inhalation 2 Refractory hypercapnea (ph <7.2) under mechanical ventilation 3 Blood pressure could not be maintained with appropriate vasopressor use 4 Rapid progression of lung fibrosis (4) Criteria for Ventilator Weaning 1 Stability/reversal of acute respiratory failure 2 PaO 2 /FiO 2 >150 200, PEEP <5 8 cm H 2 O, FIO 2 <0.4 0.5, ph >7.25 3 Hemodynamic stability (dop/dob <5) 4 Capable of reliable inspiratory efforts 3) Shock managements Principle: follow early goal-directed therapy protocol If needed vasopressors, (1) Norepinephrine (NE) with Dobutamine (2) If the dose of NE >0.4μg/kg/min --- add low dose of vasopressin (0.01 0.04 IU/hr) and low dose steroid (hydrocortisone 50 mg q 6 hr or continuous infusion 10 mg/hr) (3) If the dose of NE >1μg/kg/min --- consider early ECMO 4) Renal replacement therapy: early CRRT or daily hemodialysis Principle: follow early goal-directed therapy protocol (1) In case of urine output <0.5 ml/hour/kg even after intravenous Lasix 1 mg/kg injection over 20 min (2) In case of serum creatinine elevation more than 2.0 3.0 times compared with the baseline value (3) Dialysis is better than high dose furosemide infusion in acute kidney injury 5) Steroid (1) Generally not recommended (2) It may be applied only in refractory shock and ARDS 6) Transmission prevention (1) All health care workers; eye protection google, gown, gloves, N95 mask during aerosol-generating procedure, handwahsing before and after patient's management or touching patient's related equipments (2) Patient's bed; single mechanically or naturally ventilated room (12 air exchanges/hour), or negative pressure room if available (3) Closed tracheal suction system (4) In open spaced icu beds: the space between patient's bed should be wider than 3 meter to prevent spread of H1N1 influenza via H1N1 influenza infected patient's droplet 7) Other general prophylaxis guideline (1) Deep vein thrombosis prophylaxis (2) Stress ulcer prophylaxis (3) Bed head elevation (higher than 30 degree) to prevent aspiration (4) Subglottic aspiration in case of intubated patients, if available (5) Serum glucose control around 150 mg/dl 288
Tuberculosis and Respiratory Diseases Vol. 70. No. 4, Apr. 2011 4. 참고자료 1) 진단적검사 Laboratory of H1N1 RT-PCR in brocnoalveolar lavage (BAL) fluid or endotracheal aspiration : can be repeated twice for false negative 2) PEEP setting: Use PEEP table or decremental PEEP titration after ARM (1) PEEP titraton PEEP and FiO 2 in ARDS Net study FiO 2 0, 3 0, 3 0, 3 0, 3 0, 3 0, 4 0, 4 0, 5 0, 5 0, 5 0, 8 0, 8 0, 9 1, 0 1, 0 PEEP 5 8 10 12 14 14 16 16 18 20 22 22 22 24 (2) Alveolar recruitment maneuver - an example Initial Lung Recruitment Procedure 1 Before beginning recruitment maneuver, follow steps a f in order: a. Ensure patient is ventilated on 100% O 2. b. Sedate patient to produce apnea c. Administer neuromuscular blockade if necessary d. Measure S O 2, pulse pressure or CVP. e. Determine if intravascular volume status is acceptable. ㆍS O 2 >70% or ㆍPulse pressure variation <10% or ㆍCVP >12 mm Hg f. Administer IV fluids for low S O 2 or CVP and/or high pulse pressure 2 Ventilator settings for the initial recruitment maneuver a. Pressure A/C mode b. PEEP=25 cm H 2 O initially c. Pressure control (PC)=15 cm H 2 O d. Peak inspiratory pressure (PIP)=40 cm H 2 O e. Inspiratory time=3.0 sec f. Ventilator rate=10 breaths/min g. F I O 2 =1.0 (Ventilator should already be set on 100% O 2 ) 3 After 5 breaths, increase PC to 20 cm H 2 O (PIP=45 cm H 2 O) 4 After 5 breaths, increase PEEP to 30 cm H 2 O (PIP=0 cm H 2 O) 5 Continue for 20 breaths 6 Important: Abort lung recruitment procedure and immediately change ventilator to pre-recruitment settings if any of the following occur ㆍMean arterial pressure <60 mm Hg or decreases by >20 mm Hg from baseline ㆍSpO 2 <88% ㆍHeart rate >130 or <60/min ㆍNew onset of cardiac arrhythmias ㆍSvO 2 <65% or decreases by >20% or more 7 Change ventilator to Post-Recruitment settings ㆍVolume A/C mode ㆍF I O 2 =1.0 ㆍPEEP=25 cm H 2 O ㆍV T =6 ml/kg ㆍP plat <45 cm H 2 O ㆍDecrease V T to 5 or 4 ml/kg if needed to keep P plat <45 cm H 2 O ㆍInspiratory time=0.6 seconds ㆍVentilator rate 40 breaths/min (highest possible without auto-peep) 8 Begin Decremental PEEP Trial Procedure immediately 3) Prone positioning ( 복와위 ) (1) 복와위시행방법 1 복와위를함께수행할사람들에게체위변경의목적과절차를설명한다. 2 손을씻는다. 3 필요한물품 (electrode, air ring, 욕창방지용 pad, 베개등 ) 을준비한다. 4 필요시기관절개관은유연하고긴인공기도관으로교체한다. 5 욕창호발부위 ( 앞가슴, 어깨 ) 에욕창방지용 pad를붙인다. 6 인공호흡기 tube, 말초동맥관, 중심정맥관, Swanganz catheter. IV-line, chest-tube 및 L-tube 등환자가가지고있는모든 line 이빠지지않도록충분히길게정리한다. 7 주치의와간호직원에게알리고도움을요청한다. 8 상지부분 2명, 하지부분 2명, 모두 4명이침대양쪽에마주보며선다. 289
JY Kim: Influenza associated pneumonia 9 환자를침대가장자리로옮긴후체위를측위로돌린다. 10 Foley catheter, chest-tube 는복와위자세에맞게이동한다. 11 가슴위의 electrode를제거한다. 12 환자를침상에서 10 cm 정도들어올린상태에서동시구호를외치면서신속하게돌린다. ㆍ머리쪽의사 / 간호사 (I) 는기도유지와인공호흡기를담당하는데한손으로인공기도를지지하고다른한손으로목뒷부분 ( 경추 ) 을지지한다. ㆍ상지쪽간호사 (II) 는상지부분의모든 line 을지지하고양팔의관절에무리가없도록지지한다. ㆍ복부쪽선간호사 (III) 는복부와하지부분에있는 line과 foley catheter를지지한다. ㆍ하지쪽선간호사 (IV) 는양다리의관절을지지한다. 13 인공기도의위치를확인하고인공호흡기를연결한후호흡상태를확인한다. 14 Electrode 를등쪽의올바른위치에붙인후심전도를확인한다. 15 Sore 가잘생길수있는부위에 air ring 이나베개로지지한다 ( 귓볼, 뺨, 앞가슴, 팔꿈치, 회음부, 무릎등 ). 16 침상상부를 10 15 도올린후환자를편안한자세로취해준다. 17 모든 line을정리한다. 18 환자의상태를관찰하고기록한다 ( 활력징후, SPO 2, ABGA 결과변화등 ). 4) ARDS환자에서의 NO 투여및사용원칙 (1) 사용원칙 1 NO는흡입되었을때선택적으로폐동맥압을감소시키며, venous admixture (QVA/Qt) 의감소를통해서산소화를개선시키나환자의사망률을개선시키지는못한다. 또한 NO의 dose-response curve 는투여일수가지나갈수록변화하므로매일 SaO 2 가최대화되는용량으로조정하고 ( 흔히용량을줄여야함 ) 가능한 1주일이상은사용하지않도록한다. 2 산소화개선을위한효과적인농도는 10 ppm 미만이나폐동맥압감소를목적으로하는경우는흡입용량에비례하여폐동맥감소가나타나나 30 ppm 이상은사용하지않도록하고 10 ppm 이상의용량이흡입될때는호기내 NO 2 농도를지속적으로감시하여야하고환기에유의하여야한다. 3 NO에대한반응성 : 패혈증이없는 ARDS가패혈성쇽에동반된 ARDS 에비해 NO에대한반응이좋다. 또한폐혈관저항이증가된경우폐포모집이많이된경우에서 NO에대한반응이좋다. 4 흡입 NO의유지및중단 : NO는우선 2 10 ppm 의농도로시작하고 SaO 2 를보면서그흡입용량을매일적정화하여야한다. 대부분의경우투여시간이경과할수록투여량을줄여나가야한다. 투여량을급격히끊으면저산소증및폐고혈압의갑작스런악화가발생할수있다. (2) NO의흡입 1 가장간단한방법 : NO는 inspiratory limb 으로지속적으로주입한다. 호기동안에 inspiratory limb에는 flow 가없기때문에 NO만이흘러가게된다. 따라서환자는흡기시에고농도의 NO를흡입할수있게된다. 2 Y piece 나 endotracheal tube 에직접 NO를주입했을때 : NO가호기시 exhalation limb으로빠져나갈수있고정확한 NO의농도를측정하는것이불가능하다. Tube 에직접주입하는경우에는환자가무호흡상태일때 anoxic gas를흡입하게되어질식할수도있다. 3 Nebulizer 이용법 : 흡기시에만작동하는 nebulizer drive mechanism 을통해흡기시에만 NO가투입되게할수있다. 4 Premix 법 : NO를공기나 nitrogen 과미리혼합하여인공환기기 gas inlet 의근위부나 breathing circuit 에주입하는법이다. NO의농도가일정하게유지되고분당환기량이나흡기 waveform 에영향을받지는않는다. 5) ECMO (1) V-V ECMO 주로폐질환으로인해서 ECMO 를사용한다. 우선, 환자의폐질환이호전되는양상을보여야한다. ECMO를하고자할때운용하는동안환자의 ventilator 는가능한폐손상을줄이기위해서 low tidal volume, low pressure, low FiO 2 를유지하게되고, 환자의 PaO 2 를 60 mm Hg 이상유지해야한다. 환자의산소가증가하거나방사선사진이호전되는경우 "trial off ECMO" 를시도하게되는데이것은 pump flow 를줄이는방법과 ECMO 산화기의산소를줄이는방법을이용할수있다. ECMO oxygenator FiO 2 를줄이는방법이 pump flow 를줄이는방법에비해서간편할수있다. Oxygentor FiO 2 를줄여서 Oxygenator 를통과하고환자의몸으로들어가는혈액의산소농도가 mixed venous O 2 만큼감소하였는데환자혈액의산소농도가 60 mm 290
Tuberculosis and Respiratory Diseases Vol. 70. No. 4, Apr. 2011 Hg 이상으로유지되는경우 "Oxygen challenge" 의방법을이용하여환자 ventialtor 의 FiO 2 를 1.0으로하여 PaO 2 가 100 mm Hg 이상으로증가하는경우 ECMO 를제거할수있다. 제거하는방법은 continuous infusion 되고있는 heparin을중단하고, pump flow를낮추고 stop한다음 catheter line을 clamp하고 catheter 를제거한다. 제거후에 protamine 을주입하여 heparin을 reversal시킨다. (2) V-A ECMO 대부분심장기능의저하나 septic shock 으로인해서혈압을유지할수없는경우에사용한다. 72시간이후심장기능회복여부를평가한다. 심초음파검사상에서심장기능이회복되거나 pulse pressure 가나타나는것으로알수있다. 정확한검사를위해서 pump flow를 50% 미만으로감소한상태에서확인해야한다. Catheter 를제거하기위해서는심장기능이회복된후에시도해야한다. Pump flow를 10 20% 씩감소시키면서혈압의변화를확인해야하고, pump assist 를중단한다음 30분에서 1시간정도유지할수있는지를본다. 이때에는 thrombus의위험이높기때문에 heparin 을증량하거나 bolus injection 을통해서 ACT를 200초이상유지해야한다. 환자의상태가 pump flow를중단한상태에서잘견디는경우제거하면된다. 그러나, 환자의상태가점점악화되고, 강압제를증량하면서도혈압의유지가어려운경우에는다시 pump assist 를하게되고, 위와같은과정을통해서 weaning 을 2 3일마다할수있다. 가장중요한것은환자의심장에교정할다른문제가없어야한다. (3) Stopping support for futility of ECMO ECLS should be discontinued promptly if there is no hope for healthy survival (severe brain damage, no or heart or lung recovery, and no hope of organ replacement by VAD or transplant). The definition of irreversible heart or lung damage For cardiac failure, three days of no cardiac function in a patient who is not a VAD or transplant candidate is considered futile in most centers. For lung failure, two weeks of no lung function in a patient who is not a transplant candidate is considered futile. The possibility of stopping for futility will be explained to the family before ECLS is begun. 6) Other rescue therapy Refractory hypoxemia - consider induced mild hypothermia 참고문헌 1. Reed C, Angulo FJ, Swerdlow DL, Lipsitch M, Meltzer MI, Jernigan D, et al. Estimates of the prevalence of pandemic (H1N1) 2009, United States, April-July 2009. Emerg Infect Dis 2009;15:2004-7. 2. Miller E, Hoschler K, Hardelid P, Stanford E, Andrews N, Zambon M. Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study. Lancet 2010;375:1100-8. 3. Centers for Disease Control and Prevention. Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009-April 10, 2010. Atlanta, GA: Centers for Disease Control and Prevention; c2010 [cited 2010 June 7]. Available from: http://www.cdc.gov/h1n1flu/estimates_ 2009_h1n1.htm. 4. Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605-15. 5. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, Bautista E, Chotpitayasunondh T, Gao Z, Harper SA, Shaw M, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362: 1708-19. 6. Butler D. Portrait of a year-old pandemic. Nature 2010; 464:1112-3. 7. 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. 8. Hewagama S, Walker SP, Stuart RL, Gordon C, Johnson PD, Friedman ND, et al. 2009 H1N1 influenza A and pregnancy outcomes in Victoria, Australia. Clin Infect Dis 2010;50:686-90. 9. Creanga AA, Johnson TF, Graitcer SB, Hartman LK, Al-Samarrai T, Schwarz AG, et al. Severity of 2009 pandemic influenza A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010;115:717-26. 10. ANZIC Influenza Investigators, Webb SA, Pettilä V, Seppelt I, Bellomo R, Bailey M, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361:1925-34. 291
JY Kim: Influenza associated pneumonia 11. 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. 292