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[ Critical Care Original Research ] 56

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Comparison of Hospitalized Patients With 61
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ARDS Caused by COVID-19 and H1N1 63
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Q25 Xiao Tang, MD; Ronghui Du, MD; Rui Wang, MD; Tanze Cao, MD; Lulu Guan, MD; Chengqing Yang, MD; Qi Zhu, MD;
11 66
12 Ming Hu, MD; Xuyan Li, MD; Ying Li, MD; Lirong Liang, MD; Zhaohui Tong, MD, PhD; Bing Sun, MD, PhD; 67
Q1 Peng Peng, MD; and Huanzhong Shi, MD, PhD
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BACKGROUND: Since the outbreak of coronavirus disease 2019 (COVID-19) in China in
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December 2019, considerable attention has been focused on its elucidation. However, it is
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also important for clinicians and epidemiologists to differentiate COVID-19 from other 74
20 respiratory infectious diseases such as influenza viruses. 75
21 RESEARCH QUESTION:The aim of this study was to explore the different clinical presentations 76
22 between COVID-19 and influenza A (H1N1) pneumonia in patients with ARDS. 77
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STUDY DESIGN AND METHODS: This analysis was a retrospective case-control study. Two in-
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dependent cohorts of patients with ARDS infected with either COVID-19 (n ¼ 73) or H1N1
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(n ¼ 75) were compared. Their clinical manifestations, imaging characteristics, treatments, 81
27 and prognosis were analyzed and compared. 82
28 RESULTS: The median age of patients with COVID-19 was higher than that of patients with 83
29 H1N1, and there was a higher proportion of male subjects among the COVID-19 cohort (P < 84
30 .05). Patients with COVID-19 exhibited higher proportions of nonproductive coughs, fatigue, 85
31 and GI symptoms than those of patients with H1N1 (P < .05). Patients with H1N1 had 86
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higher Sequential Organ Failure Assessment (SOFA) scores than patients with COVID-19
33 Q6 88
(P < .05). The PaO2/FIO2 of 198.2 mm Hg in the COVID-19 cohort was significantly
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higher than the PaO2/FIO2 of 107.0 mm Hg in the H1N1 cohort (P < .001). Ground-glass
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opacities was more common in patients with COVID-19 than in patients with H1N1 (P < 91
37 .001). There was a greater variety of antiviral therapies administered to COVID-19 patients 92
38 than to H1N1 patients. The in-hospital mortality of patients with COVID-19 was 28.8%, 93
39 whereas that of patients with H1N1 was 34.7% (P ¼ .483). SOFA score-adjusted mortality of 94
40 H1N1 patients was significantly higher than that of COVID-19 patients, with a rate ratio of 95
41 2.009 (95% CI, 1.563-2.583; P < .001). 96
42 97
INTERPRETATION: There were many differences in clinical presentations between patients
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with ARDS infected with either COVID-19 or H1N1. Compared with H1N1 patients, pa-
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tients with COVID-19-induced ARDS had lower severity of illness scores at presentation and
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lower SOFA score-adjusted mortality. CHEST 2020; -(-):---
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47 Q7 102
KEY WORDS: ARDS; COVID-19; H1N1; influenza A; mortality
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ABBREVIATIONS: COVID-19 = coronavirus disease 2019; ECMO = Beijing Chao-Yang Hospital, Capital Medical University, Beijing
52 extracorporeal membrane oxygenation; H1N1 = influenza A; SARS- Institute of Respiratory Medicine, Beijing Engineering Research Center 107
Q2
53 CoV-2 = severe acute respiratory syndrome coronavirus 2; SOFA = for Diagnosis and Treatment of Respiratory and Critical Care Medicine 108
54 Sequential Organ Failure Assessment (Beijing Chao-Yang Hospital), Beijing Key Laboratory of Respiratory 109
AFFILIATIONS: From the Department of Respiratory and Critical Care and Pulmonary Circulation Disorders, Beijing, China; and the
55 Department of Respiratory and Critical Care Medicine 110
Medicine (Drs Tang, Wang, X. Li, Y. Li, Liang, Tong, Sun, and Shi),

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111 Since December 2019, there has been a cluster of 166
112 patients with pneumonia of previously unknown 167
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cause in Wuhan, China. Research by the Chinese Take Home Point 168
114 169
115
Center for Disease Control and Prevention assessed Study Question: 170
the lower respiratory tracts of these patients and The aim of the study was to explore the different
116 171
discovered a novel coronavirus, which has since been clinical presentations between COVID-19 and H1N1
117 172
118
named the 2019 novel coronavirus.1 On February 11, pneumonia in patients with ARDS. 173
119 2020, the World Health Organization officially named 174
120 this novel coronavirus pneumonia as coronavirus Results: 175
121 disease 2019 (COVID-19), whereas the International 176
There were many differences between COVID-19-
122 Committee on Taxonomy of Viruses has named it 177
induced ARDS patients and H1N1-induced ARDS
123 severe acute respiratory syndrome coronavirus 2 178
patients in clinical presentations and outcome.
124 (SARS-CoV-2). Huang et al2 reported that the first 41 179
125 patients with COVID-19 exhibited fever, cough, 180
126 Interpretation: 181
myalgia, and/or fatigue as common symptoms, 29% of
127 Compared with H1N1, patients with COVID-19- 182
whom had ARDS and six of whom died (15%). The
128 induced ARDS had lower severity of illness scores at 183
typical findings from chest CT scans were bilateral
129 presentation and lower SOFA score adjusted 184
ground-glass opacity and subsegmental areas of
130 mortality. 185
131
consolidation. At earlier times during the COVID-19 186
132 outbreak, patients with COVID-19 were more likely to 187
133 report exposure to food from the Huanan Seafood 188
134 Wholesale Market. With the epidemic gradually 189
135 growing, it is now clear that human-to-human 190
present-day, there have been > 170,000 patients with
136 transmission has been prevalent.3 As of March 10, 191
137
influenza in the United States, more than one-half of 192
2020, there have been a total of 113,702 confirmed
138 whom have been infected with the influenza A (H1N1) 193
cases and 4,012 related deaths, among which 80,924
139 virus. The percentage of deaths attributed to pneumonia 194
cases have occurred in China.4
140 induced by influenza is 6.8%.6 During the H1N1 global 195
141 Importantly, when assessing COVID-19, it is epidemic in 2009, Jain et al7 found that 5% of patients 196
142 noteworthy that influenza viruses share common with H1N1 influenza were admitted to ICUs and 197
143 etiologies and occur in the same season. Recently, global 7% died. Another study from Canada showed that the 198
144 influenza associated with respiratory mortality is overall mortality among patients critically ill with H1N1 199
145 200
occurring at a higher frequency than what has been at 28 days was 14.3%.8 The common symptoms of H1N1
146 201
previously reported.5 From September 2019 through infection include fever and productive cough, whereas
147 202
GI symptoms (eg, nausea, vomiting, diarrhea) are less
148 203
common. Furthermore, ground-glass opacities are not
149 204
(Drs Du, Cao, Guan, Yang, Zhu, Hu, and Peng), Wuhan Pulmonary commonly found on chest CT scans from patients with
150 Hospital, Wuhan, China. 205
151 H1N1.9 206
Drs Tang and Du contributed equally to this study.
152 Q3 FUNDING/SUPPORT: This work was supported by the Beijing Q8 207
Although these two respiroviruses have loomed as
153 Municipal Administration of Hospitals’ Mission Plan [SML20150301], 208
the 1351 Talents Program of Beijing Chao-Yang Hospital [WXZXZ- epidemics in different regions at present, such
154 209
2017-01], and Novel Coronavirus Pneumonia Key Technology epidemics can easily propagate to further regions over
155 Q24 Research and Development Funding of the Beijing Hospital Authority. 210
time due to climate change and global travel by
156 CORRESPONDENCE TO: Huanzhong Shi, MD, PhD, Department of 211
157 Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, individuals. Because of their distinct treatments and 212
Q4 Capital Medical University, No. 8 Gongtinan Rd, Chao-Yang District, prognoses, it is important for clinicians and
158 Q5 Beijing, China, 100020; e-mail: shihuanzhong@sina.com; or Peng Peng, 213
159 MD, Department of Respiratory and Critical Care Medicine, Wuhan epidemiologists to accurately identify these two 214
160 Pulmonary Hospital, No. 28 Baofeng Rd, Wuhan, China, 430030; respiroviral infections via their differential clinical 215
e-mail: pengpengwg@126.com; or Bing Sun, MD, PhD, Department of
161 Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, manifestations. The aim of the current study therefore 216
162 Capital Medical University, No. 8 Gongtinan Rd, Chao-Yang District, was to compare the different clinical presentations 217
163 Beijing, China, 100020; e-mail: ricusunbing@126.com 218
between ARDS patients infected with COVID-19
Copyright Ó 2020 Published by Elsevier Inc under license from the
164 vs those infected with H1N1 to provide some guidance 219
American College of Chest Physicians.
165 220
DOI: https://doi.org/10.1016/j.chest.2020.03.032 for their differential diagnoses.

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221 276
222 Patients and Methods Data Collection 277
223 Study Design Demographic and clinical data of the patients were entered into an 278
electronic case report form. The data included the following:
224 This analysis was a retrospective case-control study. All of the COVID- 279
demographic characteristics (age and sex), underlying diseases,
225 19 subjects were confirmed by using results of laboratory tests and were
comorbidities, clinical symptoms (fever, cough, sputum, dyspnea, 280
226 hospitalized at Wuhan Pulmonary Hospital (Hubei Province of China) 281
chest pain, rash, nausea, vomiting, abdominal pain, diarrhea, and
between December 24, 2019, and February 7, 2020. The H1N1
227 headache), signs (body temperature, heart rate, respiratory frequency, 282
pneumonia cases were from a single-center prospective cohort
228 and BP), laboratory tests (blood routine test, arterial blood gas 283
study10 of patients with H1N1-induced ARDS at Beijing Chao-Yang
analysis, and blood chemistry), and microbiologic findings/images of
229 Hospital (China). All of the H1N1 cases were confirmed by using 284
the lung (chest CT scan). Antimicrobiologic therapy, respiratory
230 laboratory test results, and corresponding patients were hospitalized
support, complications, and outcomes were also recorded. 285
231 from March 2016 to December 2019. All of the patients met the 286
criteria of the Berlin definition11 for diagnosis of ARDS. Following Diagnoses of patients infected with COVID-19 or H1N1 were based on
232 287
fulfillment of these criteria, all of the patients with COVID-19- clinical presentations, imaging characteristics, and the presence of
233 induced or H1N1-induced ARDS were included in this study. either SARS-CoV-2 or H1N1 detected in samples from either the 288
234 respiratory tract or blood. 289
235
The Ethics Committee of Beijing Chao-Yang Hospital (2017-KE- 290
61) and Wuhan Pulmonary Hospital (wufeilunli-2020-02) Statistical Analysis
236 291
approved the collection of clinical data from the included
237 Data analysis was performed by using SPSS 23.0 (IBM SPSS Statistics, 292
patients with H1N1 or COVID-19 infections, respectively. For
IBM Corporation) software. Categorical variables were summarized by
238 the H1N1 cohort, written informed consent was obtained from 293
using frequencies and percentages, and continuous data are presented
239 all of the patients or their legal guardians. For the COVID-19 294
as the medians (interquartile ranges). The Mann-Whitney U test was
cohort, informed consent from each patient was waived
240 used for continuous variables, and the c2 test or the Fisher exact test 295
because we prospectively collected and analyzed all of the data
241 was used for categorical variables. Variables with a P value < .05 in 296
from each patient according to the policy for public health
242 the univariate analysis were entered into multivariate logistic 297
outbreak investigation of emerging infectious diseases issued by
regression analysis to identify independent risk factors associated
243 the National Health Commission of the People’s Republic of 298
with COVID-19 or H1N1. All P values < .05 are considered
244 China. 299
statistically significant.
245 300
246 301
247 Results (13.3%; P < .001). However, the median Sequential 302
248 From December 24, 2019, to February 7, 2020, there Organ Failure Assessment (SOFA) score and the Acute 303
249 Physiology and Chronic Health Evaluation II (APACHE 304
were a total of 179 patients infected with COVID-19
250 305
admitted to the Department of Pulmonary and Critical II) score of COVID-19 patients were 2 and 11,
251 306
Care at Wuhan Pulmonary Hospital in Hubei Province respectively, which were lower than the scores of 5 (P <
252 307
of China, among which 73 cases included ARDS. There .001) and 14 (P ¼ .019) for H1N1 patients. There was no
253 308
254 were 345 patients with ARDS induced by pneumonia of significant difference in the duration of onset to ARDS 309
255 various etiologies admitted to the respiratory ICU at or duration of onset to diagnosis (Table 1). 310
256 Beijing Chao-Yang Hospital from March 2016 to 311
257 December 2019, among whom 75 patients were infected Clinical Symptoms and Laboratory Examinations 312
258 with H1N1. 313
Both COVID-19 and H1N1 groups presented with fever,
259 314
COVID-19 and H1N1 Patient Characteristics cough, and dyspnea, whereas hemoptysis was less
260 315
261
common. Furthermore, 53.4% of patients with COVID- 316
The median age of patients with COVID-19 was 67
262 19 had productive cough, which was significantly less 317
years, which was significantly higher than that of
263 than that of patients with H1N1 (78.7%; P ¼ .002). The Q9318
patients with H1N1 (52 years; P < .001). The proportion
264 proportions of fatigue (63.0%), myalgia (37.0%), and GI 319
of male subjects in the COVID-19 group was 61.5%,
265 symptoms (34.2%) in patients with COVID-19 were 320
which was significantly lower than that of the H1N1
266 higher than those of patients with H1N1 (18.7%, P < 321
group (80.0%; P ¼ .011). In terms of underlying
267 .001; 6.7%, P < .001; and 14.7%, P ¼ .007, respectively) 322
268 diseases, 31.5% of COVID-19 patients has a history of 323
(Table 2).
269 cardiovascular disease, whereas that of H1N1 patients 324
270 was significantly lower (10.7%; P ¼ .002). There was no The median PaO2/FIO2 in patients with COVID-19 was 325
271 significant difference in the history of hypertension, 198.2 mm Hg, which was significantly higher than the 326
272 diabetes, or chronic airway diseases between the two 107.0 mm Hg of patients with H1N1 (P < .001). 327
273 groups. At the time of admission, septic shock had Following biochemical testing, aspartate transaminase, 328
274 occurred in 31.5% of patients with COVID-19, which lactate dehydrogenase, and troponin I levels in patients 329
275 330
was greater than that reported in patients with H1N1 with COVID-19 were all significantly lower than those

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331 TABLE 1 ] Characteristics of Patients With COVID-19 or H1N1 Q21 386
332 387
Characteristic Total (N ¼ 148) COVID-19 (n ¼ 73) H1N1 (n ¼ 75) P Value
333 388
Age, y 62 (47, 69) 67 (57, 72) 52 (41, 64) < .001
334 389
335 Male sex 105 (70.9) 45 (61.6) 60 (80.0) .011 390
336 Onset to ARDS, d 8 (6, 11) 8 (6, 10) 8 (6, 12) .755 391
337 Onset to confirm diagnosis, d 10 (7, 14) 11 (8, 14) 9 (7, 13) .079 392
338 CURB-65 score 1 (1, 2) 1 (1, 2) 1 (1, 2) .255 393
339 SOFA score 4 (2, 6) 2 (2, 4) 5 (4, 8) < .001
394
340 395
APACHE II score 12 (8, 15) 11 (8, 13) 14 (9, 19) .019
341 396
Highest temperature,  C 38.5 (36.8, 39.3) 36.8 (36.5, 38.2) 39 (38.7, 39.8) < .001
342 397
343 Systolic BP, mm Hg 127 (110, 140) 123 (118, 128) 128 (108, 143) .626 398
344 Diastolic BP, mm Hg 70 (62, 82) 76 (70, 84) 70 (60, 82) .554 399
345 Respiratory rate, breaths/min 22 (20, 31) 21 (20, 30) 26 (21, 33) .021 400
346 Heart rate, beats/min 90 (80, 104) 86 (78, 101) 96 (81, 112) .006 401
347 Underlying diseases 402
348 403
Smoke 43 (29.3) 8 (11.0) 35 (47.3) < .001
349 404
Hypertension 70 (47.3) 38 (52.1) 32 (42.7) .323
350 405
Diabetes 35 (23.6) 20 (27.4) 15 (20.0) .336
351 406
352 Cardiovascular disease 31 (20.9) 23 (31.5) 8 (10.7) .002 407
353 Chronic kidney failure 9 (6.1) 3 (4.1) 6 (8.0) .494 408
354 Chronic respiratory disease 2 (1.4) 1 (1.4) 1 (1.3) .745 409
355 Complications 410
356 Leukocytopenia 125 (84.5) 60 (82.2) 65 (86.7) .502
411
357 412
Septic shock 33 (22.3) 23 (31.5) 10 (13.3) .010
358 413
Acute kidney injury 21 (14.2) 13 (17.8) 8 (10.7) .245
359 414
360 Liver disfunction 67 (45.3) 33 (45.2) 34 (45.3) .999 415
361 Data are presented as medians (interquartile ranges) or No. (%). APACHE ¼ Acute Physiology and Chronic Health Evaluation; COVID-19 ¼ coronavirus Q22 416
362 disease 2019; CURB-65 ¼ confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older; HINI ¼ influenza A; SOFA ¼ Sequential Q23 417
363 Organ Failure Assessment. 418
364 419
365 in patients with H1N1 (25.5 vs 70.0 U/L, 483 vs 767 U/L, mL, which were significantly lower than those in patients 420
366 and 0.03 vs 0.14 ng/mL, respectively; P < .001 for each). with H1N1 (303 cells/mL, P ¼ .007; and 185 cells/mL, 421
367 Both COVID-19 and H1N1 cohorts exhibited P < .001) (Table 3). 422
368
Q10 impairments in cellular immune function. However, the 423
369 median CD3þ T lymphocyte concentration in patients In terms of imaging characteristics, ground-glass opacity 424
370 with COVID-19 was 193 cells/mL, and the median 425
on chest CT scans was more common in patients with
371 426
CD4þCD3þ T lymphocyte concentration was 97 cells/ COVID-19 (94.5%) than in patients with H1N1 (45.3%;
372 427
373 TABLE 2 ] Clinical Symptoms of Patients With COVID-19 or H1N1 428
374 429
Symptom Total (N ¼ 148) COVID-19 (n ¼ 73) H1N1 (n ¼ 75) P Value
375 430
376 Fever 141 (95.3) 72 (98.6) 69 (92.0) .116 431
377 Cough 125 (84.5) 58 (79.5) 67 (89.3) .115 432
378 Sputum 98 (66.2) 39 (53.4) 59 (78.7) .002 433
379 Dyspnea 108 (73.0) 52 (71.2) 56 (74.7) .712 434
380 435
Fatigue 60 (63.0) 46 (63.0) 14 (18.7) < .001
381 436
GI symptoms 32 (21.6) 27 (37.0) 5 (6.7) < .001
382 437
Myalgia 36 (24.3) 25 (34.2) 11 (14.7) .007
383 438
384 Hemoptysis 9 (6.1) 4 (5.5) 5 (6.7) .517 439
385 440
Data are presented as No. (%). See Table 1 legend for expansion of abbreviations.

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441 TABLE 3 ] Laboratory Examinations and Imaging Characteristics at Admission in Patients With COVID-19 or H1N1 496
442 497
Variable Total (N ¼ 148) COVID-19 (n ¼ 73) H1N1 (n ¼ 75) P Value
443 498
Blood routine test
444 499
445 WBC (109/L) 6.9 (4.6, 10.0) 7.2 (4.8, 10.0) 6.6 (4.3, 10.1) .511 500
446 Neutrophil granulocyte 6.0 (3.3, 9.1) 6.3 (3.2, 9.2) 5.5 (3.4, 9.0) .511 501
447 (109/L) 502
448 Neutrophil granulocyte, % 86.0 (77.9, 91.2) 85.4 (75.4, 90.2) 86.6 (80.0, 92.0) .439 503
449 Lymphocyte (109/L) 0.6 (0.4, 0.8) 0.7 (0.5, 0.9) 0.5 (0.4, 0.8) .251 504
450 Lymphocyte, % 9.2 (5.0, 13.8) 9.2 (6.1, 16.0) 9.2 (4.8, 12.3) .930 505
451 Hemoglobin, g/L 126.0 (105.5, 138.5) 136.0 (127.5, 147.0) 124 (104.5, 138.0) .094 506
452 507
Platelet (109/L) 129.0 (99, 176.5) 166.5 (145.5, 192.5) 123.0 (96.5, 173.0) .117
453 508
Coagulation function
454 509
Prothrombin time, s 13.0 (12.0, 14.8) 14.2 (12.6, 15.6) 12.1 (11.5, 13.8) < .001
455 510
456 Activated partial 33.8 (28.8, 39.9) 36.2 (30.4, 40.8) 31.6 (26.2, 37.8) .020 511
thromboplastin time, s
457 512
458 D-dimer, ng/mL 2.4 (0.6, 6.6) 0.6 (0.4, 3.4) 4.2 (1.8, 9.2) < .001 513
459 Biochemical test 514
460 Albumin, g/L 30.7 (26.8, 33.4) 33.2 (30.8, 36.2) 27.3 (24.8, 30.8) < .001 515
461 AST, U/L 29.5 (21.0, 51.0) 25.5 (20.0, 42.5) 70.0 (49.0, 123.0) < .001 516
462 ALT, U/L 52.0 (31.0, 88.0) 34.5 (24.0, 61.0) 35.0 (23.0, 55.0) .742
517
463 518
Total bilirubin, mmol/L 11.1 (8.2, 16.8) 9.8 (8.0, 14.5) 12.1 (9.1, 18.5) .208
464 519
Direct bilirubin, mmol /L 4.6 (2.7, 7.2) 3.1 (2.2, 5.4) 6.2 (3.4, 10.3) < .001
465 520
466 Urea nitrogen, mmol/L 5.3 (7.4, 10.8) 7.5 (6.1, 8.6) 8.1 (5.6, 12.5) .247 521
467 Creatinine, mmol /L 81.0 (59.0, 107.0) 81.0 (62.0, 95.0) 84.3 (57.7, 116.4) .320 522
468 Lactate dehydrogenase, U/L 577.0 (440.0, 826.0) 483.0 (351.0, 602.0) 767.0 (504.0, 1026.0) < .001 523
469 Troponin I, ng/mL 0.04 (0.02, 0.20) 0.03 (0.03, 0.05) 0.14 (0.02, 0.37) .014 524
470 Type B natriuretic peptide, 217.0 (60.0, 1072.0) 619.0 (264.0, 2159.0) 169 (46.5, 649) .009 525
471 pg/mL 526
472 Infection and immunity 527
473 528
Procalcitonin, ng/mL 0.4 (0.1, 2.6) 0.1 (0.0, 0.24) 1.0 (0.5, 5.9) < .001
474 529
C-reactive protein, mg/dL 22.8 (10.0, 88.9) 87.2 (32.6, 104.5) 11.7 (7.9, 19.8) < .001
475 530
CD3þ T lymphocyte (/mL) 243 (141, 363) 193 (98, 295) 303 (198, 495) .007
476 531
477 CD4þCD3þ T lymphocyte 150 (75, 240) 97 (57, 194) 185 (119, 299) < .001 532
(/mL)
478 533
479 CD8þCD3þ T lymphocyte 82 (46, 136) 70 (36, 116) 89 (58, 150) .073 534
(/mL)
480 535
CD4þ/CD8þ T lymphocyte 1.8 (1.3, 2.6) 1.6 (1.0, 2.3) 2.2 (1.5, 2.8) .125
481 536
482 Arterial blood gas analysis 537
483 pH 7.42 (7.36, 7.45) 7.48 (7.45, 7.52) 7.42 (7.36, 7.45) .099 538
484 PaO2, mm Hg 74.6 (64.0, 89.0) 58.0 (49.0, 67.0) 74.6 (64.0, 89.0) .018 539
485 PaCO2, mm Hg 38.0 (32.0, 44.0) 35.0 (31.5, 39.5) 38.0 (32.0, 43.9) .253 540
486 541
PaO2/FIO2, mm Hg 138.0 (92.0, 207.3) 198.5 (147.6, 255.2) 107.0 (76.0, 148.0) < .001
487 542
Lung CT scan
488 543
Ground-glass opacity 103 (69.6) 69 (94.5) 34 (45.3) < .001
489 544
490 Consolidation 55 (37.2) 21 (28.8) 34 (45.3) .042 545
491 Mixed manifestationa 37 (25.0) 21 (28.8) 16 (21.3) .345 546
492 547
Data are presented as medians (interquartile ranges) or No. (%). ALT ¼ alanine aminotransferase; AST ¼ aspartate transaminase. See Table 1 legend for
493 expansion of other abbreviations. 548
494 a
Ground-glass opacity with consolidation. 549
495 550

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551 P < .001). In contrast, consolidation was more common than that administered to patients with H1N1 (29.3%; 606
552 in patients with H1N1 than in those with COVID-19 P < .001) (Table 4). 607
553 608
(P ¼ .042) (Fig 1, Table 3).
554 In terms of respiratory support, 67.1% of patients with 609
555 COVID-19 received conventional oxygen therapy as 610
Treatment Process and Prognosis
556 initial support, whereas 89.7% of patients with H1N1 611
557 All of the patients received antiviral therapies. received mechanical ventilation (P < .001). However, 612
558 Oseltamivir was administered in all of the patients with the failure rates of conventional oxygen therapy, high- 613
559 H1N1. However, patients with COVID-19 were flow nasal cannula oxygen therapy, and noninvasive 614
560 administered a variety of antiviral treatments, including 615
mechanical ventilation were higher than those in
561 83.6% with lopinavir/ritonavir, 62.7% with interferon- 616
patients with COVID-19. During the entire process of
562 a2b, 46.6% with oseltamivir, 32.9% with ganciclovir, and treatment, the proportions of patients with H1N1 who
617
563 618
27.4% with traditional Chinese medicines. In addition to received high-flow nasal cannula oxygen therapy,
564 619
antiviral treatments, 79.5% of patients with COVID-19 noninvasive mechanical ventilation, invasive mechanical
565 620
received glucocorticoids, which was significantly higher ventilation, and extracorporeal membrane oxygenation
566 621
567
than the proportion of 49.3% in patients with H1N1 (ECMO) were significantly higher than those of patients 622
568 (P < .001). In contrast, there were no differences in the with COVID-19 (P < .05) (Table 4). 623
569 dosage or course of glucocorticoid treatments between 624
570 the two groups. Immunoglobulin was administered in In terms of prognoses, 26 patients (17.6%) with COVID- Q11 625
571 58.9% of patients with COVID-19, which was higher 19 were not discharged by the time that the current 626
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601 656
602 657
Figure 1 – A-D, Imaging characteristics of chest CT scans from patients with coronavirus disease 2019 (COVID-19) and influenza A (H1N1) . A, A 60-
603 year-old man with COVID-19 exhibited multiple ground-glass opacities in both lungs. B, A 75-year-old man with COVID-19 exhibited diffuse ground- 658
604 glass opacities in both lungs. C, A 46-year-old woman with H1N1 exhibited exudation and consolidation distributed with bronchus in multiple lobes 659
and segments. D, A 66-year-old man with H1N1 exhibited ground-glass opacities with little exudation and consolidation distributed diffusely in both
605 660
lungs. Q20

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661 TABLE 4 ] Treatments and Prognoses of the Patients With COVID-19 or H1N1 716
662 717
Variable Total (N ¼ 148) COVID-19 (n ¼ 73) H1N1 (n ¼ 75) P Value
663 718
Oxygenation stratification < .001
664 719
665 PaO2/FIO2 > 200 mm Hg 41 (27.7) 32 (43.8) 9 (12.0) 720
666 100 mm Hg < PaO2/FIO2 # 200 mm Hg 66 (44.6) 36 (49.3) 30 (40.0) 721
667 PaO2/FIO2 # 100 mm Hg 41 (27.7) 5 (6.8) 36 (48.0) 722
668 Initial respiratory support < .001 723
669 COT 54 (38.3) 49 (67.1) 5 (7.4)
724
670 725
HFNC 16 (11.3) 14 (19.2) 2 (2.9)
671 726
NIV 29 (20.6) 5 (6.8) 24 (35.3)
672 727
673 IMV 42 (29.8) 5 (6.8) 37 (54.4) 728
674 Initial respiratory support failure 729
675 COT failure 20/54 (37.0) 20/49 (40.8) 0/5 (0.0) .145 730
676 HFNC failure 3/16 (18.8) 3/14 (21.4) 0/2 (0.0) .650 731
677 NIV failure 11/29 (37.9) 5/5 (100.0) 6/24 (25.0) .004 732
678 733
Respiratory support during hospitalization
679 734
COT 61 (47.3) 29 (39.7) 32 (57.1) .053
680 735
HFNC 54 (40.6) 22 (30.1) 32 (53.3) .008
681 736
682 NIV 42 (31.3) 8 (11.0) 34 (55.7) < .001 737
683 IMV 73 (51.4) 14 (19.2) 59 (85.5) < .001 738
684 ECMO 35 (25.2) 10 (13.7) 25 (25.2) .002 739
685 Antiviral therapy 740
686 Interferon-a2b 42 (29.8) 42 (62.7) . .
741
687 742
Ganciclovir 24 (16.2) 24 (32.9) . .
688 743
Lopinavir/ritonavir 61 (47.3) 61 (83.6) . .
689 744
690 Oseltamivir 102 (68.9) 34 (46.6) 68 (90.7) < .001 745
691 Chinese traditional medicine 20 (13.5) 20 (27.4) . . 746
692 Glucocorticoid 94 (64.4) 58 (79.5) 36 (49.3) < .001 747
693 Initial dosage, mg/d 80 (40, 80) 80 (40, 80) 80 (40, 80) .770 748
694 Duration, d 8 (5, 11) 8 (5, 11) 6 (5, 13) .502 749
695 750
Immunoglobulin 65 (43.9) 43 (58.9) 22 (29.3) < .001
696 751
Outcome
697 752
Discharge 75 (50.7) 26 (35.6) 49 (65.3) .001
698 753
699 Death 47 (31.8) 21 (28.8) 26 (34.7) .483 754
700 In-hospital 26 (17.6) 26 (35.6) . . 755
701 Hospital stay, d 14 (9, 21) 13 (10, 18) 16 (9, 30) .247 756
702 757
Data are presented as medians (interquartile ranges) or No. (%). COT ¼ conventional oxygen therapy; ECMO ¼ extracorporeal membrane oxygenation;
703 758
HFNC ¼ high-flow nasal cannula oxygen therapy; IMV ¼ invasive mechanical ventilation; NIV ¼ noninvasive mechanical ventilation. See Table 1 legend for
704 expansion of other abbreviations. 759
705 760
706 761
707
Q12 study was published. The in-hospital mortality of hospitalization between patients with COVID-19 762
708 patients with COVID-19-induced ARDS was 28.8%, (13 days) and patients with H1N1 (16 days) (Table 4). 763
709 whereas that of patients with H1N1-induced ARDS was 764
34.7% (P ¼ .483). The SOFA score was then used to Multivariate Analysis
710 765
711 adjust the mortality of these patients. SOFA score- Variables with a P value< .05 in the univariate analysis 766
712 adjusted mortality of patients with H1N1 was were entered into multivariate logistic regression 767
713 significantly higher than that of patients with COVID- analysis. Compared with parameters in patients with 768
714 19; the rate ratio was 2.009 (95% CI, 1.563-2.583; P < COVID-19, patients with H1N1 were more inclined to 769
715 770
.001). There was no difference in the duration of have productive cough (OR, 9.576; 95% CI, 1.729-

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771 64.711; P ¼ .011), consolidation manifested on chest CT although the conditions of patients with H1N1 seemed 826
772 imaging (OR, 4.956; 95% CI, 1.518-16.176; P ¼ .008), to be more critical than those of patients with COVID- 827
773 828
and higher SOFA scores (OR, 2.263; 95% CI, 1.124- 19, there was no difference in the prognoses between
774 829
3.574; P ¼ .006). Furthermore, compared with ARDS patients infected with COVID-19 vs those
775 830
additional parameters in patients with H1N1, patients infected with H1N1.
776 831
with COVID-19 had a greater disposition to be older
777 Huang et al reported that 93% of the first 41 patients
2 832
778
(OR, 0.908; 95% CI, 0.843-0.978; P ¼ .011), exhibit 833
with COVID-19 received oseltamivir as an antiviral
779 symptoms of fatigue (OR, 0.117; 95% CI, 0.021-0.941]; 834
therapy, which indicated that it was difficult to
780 P ¼ .013), exhibit GI symptoms (OR, 0.100; 95% CI, 835
differentiate COVID-19 from influenza via only clinical
781 0.009-0.984; P ¼ .044), and present with ground-glass 836
manifestations prior to viral identification. Similar to
782 opacities on chest CT scans (OR, 0.086; 95% CI, 0.015- 837
H1N1, SARS-CoV-2 exhibits prevalent human-to-
783 0.490; P ¼ .006) (Fig 2, Table 5). 838
784
human transmission through close contact, and its basic 839
785 reproductive number is estimated to be 2.2.3 However, 840
786
Discussion the basic reproductive number estimated during the 841
787 The outbreak of COVID-19 began in December 2019, H1N1 outbreak in Mexico in 2009 ranged from 1.3 to 842
788 which also corresponded with the flu season. The 1.7.12 Acute respiratory infection is always the initial 843
789 current study compares the clinical courses between manifestation of these two respiratory infectious 844
790 patients with COVID-19-induced ARDS and those with diseases. Because of their different therapies, prognoses, 845
791 H1N1-induced ARDS. We found that, compared with and protective measures, it is important to differentiate 846
792 847
features in patients with H1N1, patients with COVID-19 these two diseases via early clinical presentations. The
793 848
were more likely to exhibit nonproductive cough with current study revealed that COVID-19 manifested as
794 849
obvious constitutional symptoms such as fatigue, GI nonproductive cough with nonspecific systemic
795 850
symptoms, and a prevalence in the elderly. In addition, symptoms, which is consistent with previous studies.
796 851
797 imaging results more commonly presented as ground- Wang et al13 analyzed the clinical characteristics of 138 852
798 glass opacities in patients with COVID-19. However, hospitalized COVID-19 patients and reported that fever, 853
799 854
800 855
OR (95% CI)
801 856
802 Age 0.908 (0.843-0.978) 857
803 858
804 Cardiovascular disease 0.631 (0.083-4.577) 859
805 SOFA score 2.263 (1.124-3.574) 860
806 861
APACHE II score 1.124 (0.932-1.355)
807 862
808 Fatigue 0.117 (0.021-0.941) 863
809 864
Sputum 9.576 (1.729-64.711)
810 865
811 GI symptoms 0.100 (0.009-0.984) 866
812 867
Myalgia 1.832 (0.512-6.555)
813 868
814 Prothrombin time 0.627 (0.458-0.858) 869
815 870
AST 1.021 (0.998-1.044)
816 871
817 Lactate dehydrogenase 1.007 (1.000-1.014) 872
818 Ground glass opacity 0.086 (0.015-0.490) 873
819 874
print & web 4C=FPO

820 Consolidation 4.956 (1.518-16.176) 875

821 876
0 1 5 10
822 877
COVID-19 Influenza A H1N1 pneumonia
823 878
824 Figure 2 – Multivariate model of the specific risk factors for COVID-19 or H1N1. Plots reporting variables independently associated with the risk for Q26
879
COVID-19 or H1N1 in the final model, with their 95% CIs. APACHE ¼ Acute Physiology and Chronic Health Evaluation; AST ¼ aspartate
825 880
transaminase; SOFA ¼ sequential organ failure assessment. See Figure 1 legend for expansion of other abbreviations.

8 Original Research [ -#- CHEST - 2020 ]

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881 TABLE 5 ] Multivariate Analysis of Independent Risk Factors for Differentiating COVID-19 From H1N1 936
882 937
Univariate Analysis Multivariate Analysis
883 938
Variable OR 95% CI P Value OR 95% CI P Value
884 939
885 Age 0.928 0.092-0.956 < .001 0.908 0.843-0.978 .011 940
886 Cardiovascular disease 0.260 0.107-0.628 .003 0.631 0.083-4.577 .649 941
887 Septic shock 0.334 0.146-0.766 .010 . . . 942
888 Respiratory rate 1.018 0.983-1.054 .325 . . . 943
889 944
Heart rate 1.021 1.004-1.039 .015 . . .
890 945
SOFA score 1.820 1.462-2.266 < .001 2.263 1.124-3.574 .006
891 946
APACHE II score 1.136 1.062-1.214 < .001 1.124 0.932-1.355 .221
892 947
893 Fatigue 0.135 0.064-0.285 < .001 0.117 0.021-0.941 .013 948
894 Sputum 3.215 1.567-6.597 .001 9.576 1.729-64.711 .011 949
895 GI symptoms 0.122 0.044-0.339 < .001 0.100 0.009-0.984 .044 950
896 Myalgia 0.330 0.148-0.736 .007 1.832 0.512-6.555 .352 951
897 Prothrombin time 0.673 0.555-0.817 < .001 0.627 0.458-0.858 .004
952
898 953
APTT 0.986 0.954-1.019 .409 . . .
899 954
D-dimer 1.036 0.993-1.080 .100 . . .
900 955
901 AST 1.035 1.021-1.049 < .001 1.021 0.998-1.044 .074 956
902 Direct bilirubin 1.155 1.055-1.265 .002 . . . 957
903 Lactate dehydrogenase 1.004 1.002-1.005 < .001 1.007 1.000-1.014 .025 958
904 Troponin I 1.517 0.883-2.605 .131 . . . 959
905 þ
CD3 T lymphocyte 1.004 1.002-1.006 .001 . . . 960
906 þ þ 961
CD4 CD3 T lymphocyte 1.007 1.003-1.010 < .001 . . .
907 962
Ground-glass opacity 0.048 0.016-0.145 < .001 0.086 0.015-0.490 .006
908 963
Consolidation 2.053 1.039-4.056 .038 4.956 1.518-16.176 .008
909 964
910 APTT ¼ activated partial thromboplastin time. See Table 1 and 3 legends for expansion of abbreviations. 965
911 966
912 967
913 fatigue, and dry cough were the most common consolidation on CT imaging, with or without ground- 968
914 symptoms, and that the mean incubation period was glass opacities.15,16 In addition to diffuse alveolar 969
915 5.2 days. However, in addition to fever and productive damage in pathologic findings of lungs indicating ARDS, 970
916 cough, rhinorrhea is more common in patients with COVID-19 is accompanied by cellular fibromyxoid 971
917 H1N1, and the median incubation period of this virus is exudates,17 whereas H1N1 is accompanied by 972
918 2 days.9 Therefore, we speculate from previous research necrotizing bronchiolitis and extensive hemorrhage.18 973
919 and our current findings that COVID-19 infection may Therefore, these differential pathologic changes may 974
920 present as a slow onset with fewer productive coughs present as distinguishing imaging characteristics during 975
921 976
and more obvious systemic symptoms compared with clinical assessments.
922 977
the clinical presentations of H1N1 infection.
923 We also found that patients with COVID-19 received a 978
924 The current study found that ground-glass opacity was wider variety of treatments compared with patients with 979
925 more common in patients with COVID-19 than in H1N1. In contrast to definitive treatment measures for 980
926 patients with H1N1, whereas consolidation was more H1N1,19 there is no evidence to approve the 981
927 982
frequent in H1N1 patients, which is consistent with effectiveness of any therapy for COVID-19. More than
928 983
previous studies. The radiologic findings of 81 patients one hundred clinical studies have been conducted by
929 984
with COVID-19 pneumonia from Shi et al14 showed Chinese researchers, and the interim research data may
930 985
931
that diffused bilateral ground-glass opacities were the provide some help for the current urgent demand for 986
932 most predominant pattern of abnormalities on chest CT COVID-19 drug treatments.20 The application of 987
933 scans within 1 to 3 weeks following disease onset. In glucocorticoids was common in both COVID-19 and 988
934 addition, studies on H1N1-associated pneumonia have H1N1 patients in the current study, but the proportion 989
935 shown that critical cases present as areas of in COVID-19 patients was greater than that in H1N1 990

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991 patients. However, there was no difference in the dosage H1N1 had a significantly worse prognosis than patients 1046
992 or duration of glucocorticoids between these two groups. with COVID-19. All of the included COVID-19 cases in 1047
993 1048
The observational data currently available suggest that the current study were at the early stage of this epidemic.
994 1049
glucocorticoids for the treatment of respiratory The rapidly growing cases of unknown diseases,
995 1050
infections increase mortality and secondary infection inadequate responses, insufficient medical staff, and lack
996 1051
rates in influenza, impair clearance of SARS-CoV and of medical supplies have adversely affected the
997 1052
998
Middle East respiratory syndrome coronavirus, and treatments and prognoses of COVID-19 cases. 1053
999 complicate corticosteroid therapies in survivors.21 Therefore, as a novel respiratory infectious disease, 1054
1000 Therefore, indications for glucocorticoids should be the relatively higher mortality rate of COVID-19 cases 1055
1001 carefully evaluated in such patients. is to be expected. From the experiences gained from 1056
1002 treating early COVID-19 patients, subsequent cases 1057
Both COVID-19 and H1N1 infections may be
1003 may benefit from better and more standard therapies, 1058
accompanied by ARDS. Respiratory support in such
1004 including specific medical treatments and respiratory 1059
1005
cases should be in accordance with therapeutic strategies 1060
support.
1006 for ARDS.22 In the current study, we found that the 1061
1007 severity of respiratory failure was not equal between The current study had some limitations. First, this was a 1062
1008 COVID-19 and H1N1 patients. The PaO2/FIO2 levels in retrospective study that included data from two 1063
1009 patients with COVID-19 were higher than those in independent single-center cohorts, which may have 1064
1010 patients with H1N1, such that respiratory support in resulted in unavoidable bias. Second, the conditions of 1065
1011 COVID-19 patients was initially via noninvasive patients with H1N1 was more severe than those of the 1066
1012 methods and ultimately yielded higher failure rates. The COVID-19 cohort, which may have led to statistical 1067
1013 1068
ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) disequilibrium. Third, 35.6% of the patients with
1014 1069
trial23 provided information about the posterior COVID-19 were still hospitalized at the time of
1015 1070
probability of a mortality benefit for patients with acute manuscript submission, meaning that the mortality rate
1016 1071
respiratory failure,24 especially in terms of reporting the presented in COVID-19 is likely an underestimate of the
1017 1072
1018
success of the application of ECMO in ARDS patients real overall hospital mortality rate. Finally, the data from 1073
1019 with influenza.25 We speculate that ECMO may also the H1N1 cohort originated from a 3-year span, whereas 1074
1020 have potential in treating patients with COVID-19. the data from the COVID-19 cohort originated from 1075
1021 However, the rapid growth of cases and lack of medical only a 1-month span, which may also have affected the 1076
1022 resources and medical staff have limited standardized study’s results. 1077
1023 respiratory support in accordance with related 1078
1024 guidelines. 1079
Interpretation
1025 1080
1026 In the current study, the mortality of ARDS patients There were many differences in clinical presentations 1081
1027 infected with COVID-19 was 28.8%. According to the between patients with ARDS infected with either 1082
1028 median PaO2/FIO2 of 198.5 mm Hg in patients with COVID-19 or H1N1. Compared with H1N1, patients 1083
1029 COVID-19 in the current study, the corresponding with COVID-19-induced ARDS had lower severity of 1084
1030 mortality rate was consistent with the definition of illness scores at presentation and lower SOFA score- 1085
1031 ARDS.11 Although patients with H1N1 in this study adjusted mortality. Future studies investigating COVID- 1086
1032 exhibited significantly lower oxygenation than that of 19 should focus on well-designed, prospective, case- 1087
1033 1088
patients with COVID-19, there was no difference in the controlled trials with large sample sizes, which could
1034 1089
mortality rate between the two groups. From the provide more experience and evidence regarding
1035 1090
adjusted mortality analysis, we found that patients with COVID-19 treatment measures.
1036 1091
1037 1092
1038 1093
1039 1094
1040 1095
1041 1096
1042 1097
1043 1098
1044 1099
1045 1100

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1101 Acknowledgments influenza in the United States, April-June 18. Mauad T, Hajjar LA, Callegari GD, 1149
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