今日の臨床サポート

COVID-19(新型コロナウイルス感染症)

著者: 石川和宏 聖路加国際病院 感染症科

著者: 松尾貴公 聖路加国際病院 感染症科

著者: 森信好 聖路加国際病院 感染症科

監修: 上原由紀 藤田医科大学医学部感染症科

著者校正/監修レビュー済:2022/03/30
参考ガイドライン:
  1. 厚生労働省新型コロナウイルス 感染症(COVID-19) 診療の手引き 第6.2版
  1. 国立感染症研究所:新型コロナウイルス感染症に対する感染管理新型コロナウイルス感染症に対する感染管理(2020年6月2日改訂版)
  1. 国立感染症研究所:新型コロナウイルス感染症、自宅療養時の健康・感染管理(2020年4月2日)
  1. 厚生労働省:新型コロナウイルス感染症について
  1. WHO:Coronavirus
  1. CDC:Coronavirus (COVID-19)
  1. IDSA:Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19
患者向け説明資料

概要・推奨   

※本項は、2022年2月4日時点で得られた情報を元に作成しています。最新情報につきましては、厚生労働省ホームページ等でご確認ください。
 
  1. COVID-19はコロナウイルスの一種であるSARS-CoV-2による感染症で、2019年12月頃に中国湖北省武漢市で発生したが、現在は世界中に広がっている。
  1. COVID-19の症状は、その他のウイルス性上気道炎と同様に、発熱、咽頭痛、鼻汁、咳嗽、喀痰、倦怠感などが現れるが、症状が7日ほど続く。また、結膜炎や味覚障害、嗅覚障害、下痢や嘔吐などの消化器症状が現れることもある。
  1. 新型コロナウイルス感染症の後遺症は、感染後3カ月以内に発症し、少なくとも2カ月続き、症状で最も多いのは倦怠感、呼吸困難、認知機能障害、胸痛、嗅覚障害、味覚障害、動悸などがあり、日常生活に影響を及ぼしている。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石川和宏 : 特に申告事項無し[2022年]
松尾貴公 : 未申告[2022年]
森信好 : 特に申告事項無し[2022年]
監修:上原由紀 : 特に申告事項無し[2022年]

改訂のポイント:
  1. ウイルス変異株についての記載を追記した。
  1. 治療学やワクチンについてのアップデートを行った。

病態・疫学・診察

イントロダクション  
  1. 新型コロナウイルス(以下、SARS-CoV-2)は、2019年12月以降中華人民共和国湖北省武漢市で発生した原因不明の肺炎患者から検出された新種のコロナウイルスである。
  1. 世界保健機関(WHO)は新型コロナウイルス感染症の正式名称を「COVID-19(coronavirus disease 2019)」と定めた(以下、COVID-19)。
疫学  
  1. コロナウイルスはプラス鎖一本鎖のRNAをウイルスゲノムとして有するエンベロープウイルスである。

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文献 

Stephen A Lauer, Kyra H Grantz, Qifang Bi, Forrest K Jones, Qulu Zheng, Hannah R Meredith, Andrew S Azman, Nicholas G Reich, Justin Lessler
The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application.
Ann Intern Med. 2020 Mar 10;. doi: 10.7326/M20-0504. Epub 2020 Mar 10.
Abstract/Text Background: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in China in December 2019. There is limited support for many of its key epidemiologic features, including the incubation period for clinical disease (coronavirus disease 2019 [COVID-19]), which has important implications for surveillance and control activities.
Objective: To estimate the length of the incubation period of COVID-19 and describe its public health implications.
Design: Pooled analysis of confirmed COVID-19 cases reported between 4 January 2020 and 24 February 2020.
Setting: News reports and press releases from 50 provinces, regions, and countries outside Wuhan, Hubei province, China.
Participants: Persons with confirmed SARS-CoV-2 infection outside Hubei province, China.
Measurements: Patient demographic characteristics and dates and times of possible exposure, symptom onset, fever onset, and hospitalization.
Results: There were 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection. These estimates imply that, under conservative assumptions, 101 out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine.
Limitation: Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases.
Conclusion: This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases.
Primary Funding Source: U.S. Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, and Alexander von Humboldt Foundation.

PMID 32150748
Xi He, Eric H Y Lau, Peng Wu, Xilong Deng, Jian Wang, Xinxin Hao, Yiu Chung Lau, Jessica Y Wong, Yujuan Guan, Xinghua Tan, Xiaoneng Mo, Yanqing Chen, Baolin Liao, Weilie Chen, Fengyu Hu, Qing Zhang, Mingqiu Zhong, Yanrong Wu, Lingzhai Zhao, Fuchun Zhang, Benjamin J Cowling, Fang Li, Gabriel M Leung
Temporal dynamics in viral shedding and transmissibility of COVID-19.
Nat Med. 2020 Apr 15;. doi: 10.1038/s41591-020-0869-5. Epub 2020 Apr 15.
Abstract/Text We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector-infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25-69%) of secondary cases were infected during the index cases' presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.

PMID 32296168
Roman Wölfel, Victor M Corman, Wolfgang Guggemos, Michael Seilmaier, Sabine Zange, Marcel A Müller, Daniela Niemeyer, Terry C Jones, Patrick Vollmar, Camilla Rothe, Michael Hoelscher, Tobias Bleicker, Sebastian Brünink, Julia Schneider, Rosina Ehmann, Katrin Zwirglmaier, Christian Drosten, Clemens Wendtner
Virological assessment of hospitalized patients with COVID-2019.
Nature. 2020 May;581(7809):465-469. doi: 10.1038/s41586-020-2196-x. Epub 2020 Apr 1.
Abstract/Text Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.

PMID 32235945
Neeltje van Doremalen, Trenton Bushmaker, Dylan H Morris, Myndi G Holbrook, Amandine Gamble, Brandi N Williamson, Azaibi Tamin, Jennifer L Harcourt, Natalie J Thornburg, Susan I Gerber, James O Lloyd-Smith, Emmie de Wit, Vincent J Munster
Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1.
N Engl J Med. 2020 Apr 16;382(16):1564-1567. doi: 10.1056/NEJMc2004973. Epub 2020 Mar 17.
Abstract/Text
PMID 32182409
Jane Y Tong, Amanda Wong, Daniel Zhu, Judd H Fastenberg, Tristan Tham
The Prevalence of Olfactory and Gustatory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis.
Otolaryngol Head Neck Surg. 2020 Jul;163(1):3-11. doi: 10.1177/0194599820926473. Epub 2020 May 5.
Abstract/Text OBJECTIVE: To determine the pooled global prevalence of olfactory and gustatory dysfunction in patients with the 2019 novel coronavirus (COVID-19).
DATA SOURCES: Literature searches of PubMed, Embase, and Scopus were conducted on April 19, 2020, to include articles written in English that reported the prevalence of olfactory or gustatory dysfunction in COVID-19 patients.
REVIEW METHODS: Search strategies developed for each database contained keywords such as anosmia, dysgeusia, and COVID-19. Resulting articles were imported into a systematic review software and underwent screening. Data from articles that met inclusion criteria were extracted and analyzed. Meta-analysis using pooled prevalence estimates in a random-effects model were calculated.
RESULTS: Ten studies were analyzed for olfactory dysfunction (n = 1627), demonstrating 52.73% (95% CI, 29.64%-75.23%) prevalence among patients with COVID-19. Nine studies were analyzed for gustatory dysfunction (n = 1390), demonstrating 43.93% (95% CI, 20.46%-68.95%) prevalence. Subgroup analyses were conducted for studies evaluating olfactory dysfunction using nonvalidated and validated instruments and demonstrated 36.64% (95% CI, 18.31%-57.24%) and 86.60% (95% CI, 72.95%-95.95%) prevalence, respectively.
CONCLUSIONS: Olfactory and gustatory dysfunction are common symptoms in patients with COVID-19 and may represent early symptoms in the clinical course of infection. Increased awareness of this fact may encourage earlier diagnosis and treatment, as well as heighten vigilance for viral transmission. To our knowledge, this is the first meta-analysis to report on the prevalence of these symptoms in COVID-19 patients.

PMID 32369429
Christopher S von Bartheld, Molly M Hagen, Rafal Butowt
Prevalence of Chemosensory Dysfunction in COVID-19 Patients: A Systematic Review and Meta-analysis Reveals Significant Ethnic Differences.
ACS Chem Neurosci. 2020 Sep 17;. doi: 10.1021/acschemneuro.0c00460. Epub 2020 Sep 17.
Abstract/Text A significant proportion of people who test positive for COVID-19 have chemosensory deficits. However, the reported prevalence of these deficits in smell and taste varies widely, and the reason for the differences between studies is unclear. We determined the pooled prevalence of such chemosensory deficits in a systematic review and meta-analysis. We searched the COVID-19 portfolio of the National Institutes of Health for studies that reported the prevalence of smell or taste deficits or both in patients diagnosed with COVID-19. One-hundred-four studies reporting on 38 198 patients qualified and were subjected to a systematic review and meta-analysis. Estimated random prevalence of olfactory dysfunction was 43.0%, that of taste dysfunction was 44.6%, and that of overall chemosensory dysfunction was 47.4%. We examined the effects of age, gender, disease severity, and ethnicity on chemosensory dysfunction. Prevalence of smell or taste dysfunction or both decreased with older age, male gender, and disease severity. Ethnicity was highly significant: Caucasians had a three times higher prevalence of chemosensory dysfunctions (54.8%) than Asians (17.7%). The finding of geographic differences points to two causes that are not mutually exclusive. A virus mutation (D614G) may cause differing infectivity, while at the host level genetic, ethnicity-specific variants of the virus-binding entry proteins may facilitate virus entry in the olfactory epithelium and taste buds. Both explanations have major implications for infectivity, diagnosis, and management of the COVID-19 pandemic.

PMID 32870641
Joshua M Levy
Treatment Recommendations for Persistent Smell and Taste Dysfunction Following COVID-19-The Coming Deluge.
JAMA Otolaryngol Head Neck Surg. 2020 Jul 2;. doi: 10.1001/jamaoto.2020.1378. Epub 2020 Jul 2.
Abstract/Text
PMID 32614399
CDC COVID-19 Response Team
Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020.
MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-346. doi: 10.15585/mmwr.mm6912e2. Epub 2020 Mar 27.
Abstract/Text Globally, approximately 170,000 confirmed cases of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) have been reported, including an estimated 7,000 deaths in approximately 150 countries (1). On March 11, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic (2). Data from China have indicated that older adults, particularly those with serious underlying health conditions, are at higher risk for severe COVID-19-associated illness and death than are younger persons (3). Although the majority of reported COVID-19 cases in China were mild (81%), approximately 80% of deaths occurred among adults aged ≥60 years; only one (0.1%) death occurred in a person aged ≤19 years (3). In this report, COVID-19 cases in the United States that occurred during February 12-March 16, 2020 and severity of disease (hospitalization, admission to intensive care unit [ICU], and death) were analyzed by age group. As of March 16, a total of 4,226 COVID-19 cases in the United States had been reported to CDC, with multiple cases reported among older adults living in long-term care facilities (4). Overall, 31% of cases, 45% of hospitalizations, 53% of ICU admissions, and 80% of deaths associated with COVID-19 were among adults aged ≥65 years with the highest percentage of severe outcomes among persons aged ≥85 years. In contrast, no ICU admissions or deaths were reported among persons aged ≤19 years. Similar to reports from other countries, this finding suggests that the risk for serious disease and death from COVID-19 is higher in older age groups.

PMID 32214079
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, Yan Zhao, Yirong Li, Xinghuan Wang, Zhiyong Peng
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
JAMA. 2020 Feb 7;. doi: 10.1001/jama.2020.1585. Epub 2020 Feb 7.
Abstract/Text Importance: In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
Objective: To describe the epidemiological and clinical characteristics of NCIP.
Design, Setting, and Participants: Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020.
Exposures: Documented NCIP.
Main Outcomes and Measures: Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked.
Results: Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0).
Conclusions and Relevance: In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.

PMID 32031570
Qun Li, Xuhua Guan, Peng Wu, Xiaoye Wang, Lei Zhou, Yeqing Tong, Ruiqi Ren, Kathy S M Leung, Eric H Y Lau, Jessica Y Wong, Xuesen Xing, Nijuan Xiang, Yang Wu, Chao Li, Qi Chen, Dan Li, Tian Liu, Jing Zhao, Man Liu, Wenxiao Tu, Chuding Chen, Lianmei Jin, Rui Yang, Qi Wang, Suhua Zhou, Rui Wang, Hui Liu, Yinbo Luo, Yuan Liu, Ge Shao, Huan Li, Zhongfa Tao, Yang Yang, Zhiqiang Deng, Boxi Liu, Zhitao Ma, Yanping Zhang, Guoqing Shi, Tommy T Y Lam, Joseph T Wu, George F Gao, Benjamin J Cowling, Bo Yang, Gabriel M Leung, Zijian Feng
Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.
N Engl J Med. 2020 Mar 26;382(13):1199-1207. doi: 10.1056/NEJMoa2001316. Epub 2020 Jan 29.
Abstract/Text BACKGROUND: The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP.
METHODS: We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number.
RESULTS: Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).
CONCLUSIONS: On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).

Copyright © 2020 Massachusetts Medical Society.
PMID 31995857
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, Zhenshun Cheng, Ting Yu, Jiaan Xia, Yuan Wei, Wenjuan Wu, Xuelei Xie, Wen Yin, Hui Li, Min Liu, Yan Xiao, Hong Gao, Li Guo, Jungang Xie, Guangfa Wang, Rongmeng Jiang, Zhancheng Gao, Qi Jin, Jianwei Wang, Bin Cao
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
Abstract/Text BACKGROUND: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients.
METHODS: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.
FINDINGS: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
INTERPRETATION: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies.
FUNDING: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 31986264
Xiaobo Yang, Yuan Yu, Jiqian Xu, Huaqing Shu, Jia'an Xia, Hong Liu, Yongran Wu, Lu Zhang, Zhui Yu, Minghao Fang, Ting Yu, Yaxin Wang, Shangwen Pan, Xiaojing Zou, Shiying Yuan, You Shang
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
Lancet Respir Med. 2020 Feb 24;. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24.
Abstract/Text BACKGROUND: An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia.
METHODS: In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation.
FINDINGS: Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3-11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients.
INTERPRETATION: The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1-2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced.
FUNDING: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32105632
Ryan P Barbaro, Graeme MacLaren, Philip S Boonstra, Theodore J Iwashyna, Arthur S Slutsky, Eddy Fan, Robert H Bartlett, Joseph E Tonna, Robert Hyslop, Jeffrey J Fanning, Peter T Rycus, Steve J Hyer, Marc M Anders, Cara L Agerstrand, Katarzyna Hryniewicz, Rodrigo Diaz, Roberto Lorusso, Alain Combes, Daniel Brodie, Extracorporeal Life Support Organization
Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry.
Lancet. 2020 Oct 10;396(10257):1071-1078. doi: 10.1016/S0140-6736(20)32008-0. Epub 2020 Sep 25.
Abstract/Text BACKGROUND: Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. However, initial reports of ECMO use in patients with COVID-19 described very high mortality and there have been no large, international cohort studies of ECMO for COVID-19 reported to date.
METHODS: We used data from the Extracorporeal Life Support Organization (ELSO) Registry to characterise the epidemiology, hospital course, and outcomes of patients aged 16 years or older with confirmed COVID-19 who had ECMO support initiated between Jan 16 and May 1, 2020, at 213 hospitals in 36 countries. The primary outcome was in-hospital death in a time-to-event analysis assessed at 90 days after ECMO initiation. We applied a multivariable Cox model to examine whether patient and hospital factors were associated with in-hospital mortality.
FINDINGS: Data for 1035 patients with COVID-19 who received ECMO support were included in this study. Of these, 67 (6%) remained hospitalised, 311 (30%) were discharged home or to an acute rehabilitation centre, 101 (10%) were discharged to a long-term acute care centre or unspecified location, 176 (17%) were discharged to another hospital, and 380 (37%) died. The estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4% (95% CI 34·4-40·4). Mortality was 39% (380 of 968) in patients with a final disposition of death or hospital discharge. The use of ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20-2·97). In the subset of patients with COVID-19 receiving respiratory (venovenous) ECMO and characterised as having acute respiratory distress syndrome, the estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6-41·5).
INTERPRETATION: In patients with COVID-19 who received ECMO, both estimated mortality 90 days after ECMO and mortality in those with a final disposition of death or discharge were less than 40%. These data from 213 hospitals worldwide provide a generalisable estimate of ECMO mortality in the setting of COVID-19.
FUNDING: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32987008
Matthieu Schmidt, David Hajage, Guillaume Lebreton, Antoine Monsel, Guillaume Voiriot, David Levy, Elodie Baron, Alexandra Beurton, Juliette Chommeloux, Paris Meng, Safaa Nemlaghi, Pierre Bay, Pascal Leprince, Alexandre Demoule, Bertrand Guidet, Jean Michel Constantin, Muriel Fartoukh, Martin Dres, Alain Combes, Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Université, Paris-Sorbonne ECMO-COVID investigators
Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.
Lancet Respir Med. 2020 Nov;8(11):1121-1131. doi: 10.1016/S2213-2600(20)30328-3. Epub 2020 Aug 13.
Abstract/Text BACKGROUND: Patients with COVID-19 who develop severe acute respiratory distress syndrome (ARDS) can have symptoms that rapidly evolve to profound hypoxaemia and death. The efficacy of extracorporeal membrane oxygenation (ECMO) for patients with severe ARDS in the context of COVID-19 is unclear. We aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and COVID-19 treated with ECMO.
METHODS: This retrospective cohort study was done in the Paris-Sorbonne University Hospital Network, comprising five intensive care units (ICUs) and included patients who received ECMO for COVID-19 associated ARDS. Patient demographics and daily pre-ECMO and on-ECMO data and outcomes were collected. Possible outcomes over time were categorised into four different states (states 1-4): on ECMO, in the ICU and weaned off ECMO, alive and out of ICU, or death. Daily probabilities of occupation in each state and of transitions between these states until day 90 post-ECMO onset were estimated with use of a multi-state Cox model stratified for each possible transition. Follow-up was right-censored on July 10, 2020.
FINDINGS: From March 8 to May 2, 2020, 492 patients with COVID-19 were treated in our ICUs. Complete day-60 follow-up was available for 83 patients (median age 49 [IQR 41-56] years and 61 [73%] men) who received ECMO. Pre-ECMO, 78 (94%) patients had been prone-positioned; their median driving pressure was 18 (IQR 16-21) cm H2O and PaO2/FiO2 was 60 (54-68) mm Hg. At 60 days post-ECMO initiation, the estimated probabilities of occupation in each state were 6% (95% CI 3-14) for state 1, 18% (11-28) for state 2, 45% (35-56) for state 3, and 31% (22-42) for state 4. 35 (42%) patients had major bleeding and four (5%) had a haemorrhagic stroke. 30 patients died.
INTERPRETATION: The estimated 60-day survival of ECMO-rescued patients with COVID-19 was similar to that of studies published in the past 2 years on ECMO for severe ARDS. If another COVID-19 outbreak occurs, ECMO should be considered for patients developing refractory respiratory failure despite optimised care.
FUNDING: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32798468
Ryan P Barbaro, Folafoluwa O Odetola, Kelley M Kidwell, Matthew L Paden, Robert H Bartlett, Matthew M Davis, Gail M Annich
Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry.
Am J Respir Crit Care Med. 2015 Apr 15;191(8):894-901. doi: 10.1164/rccm.201409-1634OC.
Abstract/Text RATIONALE: Recent pediatric studies suggest a survival benefit exists for higher-volume extracorporeal membrane oxygenation (ECMO) centers.
OBJECTIVES: To determine if higher annual ECMO patient volume is associated with lower case-mix-adjusted hospital mortality rate.
METHODS: We retrospectively analyzed an international registry of ECMO support from 1989 to 2013. Patients were separated into three age groups: neonatal (0-28 d), pediatric (29 d to <18 yr), and adult (≥18 yr). The measure of hospital ECMO volume was age group-specific and adjusted for patient-level case-mix and hospital-level variance using multivariable hierarchical logistic regression modeling. The primary outcome was death before hospital discharge. A subgroup analysis was conducted for 2008-2013.
MEASUREMENTS AND MAIN RESULTS: From 1989 to 2013, a total of 290 centers provided ECMO support to 56,222 patients (30,909 neonates, 14,725 children, and 10,588 adults). Annual ECMO mortality rates varied widely across ECMO centers: the interquartile range was 18-50% for neonates, 25-66% for pediatrics, and 33-92% for adults. For 1989-2013, higher age group-specific ECMO volume was associated with lower odds of ECMO mortality for neonates and adults but not for pediatric cases. In 2008-2013, the volume-outcome association remained statistically significant only among adults. Patients receiving ECMO at hospitals with more than 30 adult annual ECMO cases had significantly lower odds of mortality (adjusted odds ratio, 0.61; 95% confidence interval, 0.46-0.80) compared with adults receiving ECMO at hospitals with less than six annual cases.
CONCLUSIONS: In this international, case-mix-adjusted analysis, higher annual hospital ECMO volume was associated with lower mortality in 1989-2013 for neonates and adults; the association among adults persisted in 2008-2013.

PMID 25695688
Chaomin Wu, Xiaoyan Chen, Yanping Cai, Jia'an Xia, Xing Zhou, Sha Xu, Hanping Huang, Li Zhang, Xia Zhou, Chunling Du, Yuye Zhang, Juan Song, Sijiao Wang, Yencheng Chao, Zeyong Yang, Jie Xu, Xin Zhou, Dechang Chen, Weining Xiong, Lei Xu, Feng Zhou, Jinjun Jiang, Chunxue Bai, Junhua Zheng, Yuanlin Song
Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.
JAMA Intern Med. 2020 Mar 13;. doi: 10.1001/jamainternmed.2020.0994. Epub 2020 Mar 13.
Abstract/Text Importance: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.
Objective: To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.
Design, Setting, and Participants: Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020.
Exposures: Confirmed COVID-19 pneumonia.
Main Outcomes and Measures: The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.
Results: Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).
Conclusions and Relevance: Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.

PMID 32167524
Saskia Middeldorp, Michiel Coppens, Thijs F van Haaps, Merijn Foppen, Alexander P Vlaar, Marcella C A Müller, Catherine C S Bouman, Ludo F M Beenen, Ruud S Kootte, Jarom Heijmans, Loek P Smits, Peter I Bonta, Nick van Es
Incidence of venous thromboembolism in hospitalized patients with COVID-19.
J Thromb Haemost. 2020 Aug;18(8):1995-2002. doi: 10.1111/jth.14888. Epub 2020 Jul 27.
Abstract/Text BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications.
OBJECTIVES: To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID-19.
METHODS: Single-center cohort study of 198 hospitalized patients with COVID-19.
RESULTS: Seventy-five patients (38%) were admitted to the intensive care unit (ICU). At time of data collection, 16 (8%) were still hospitalized and 19% had died. During a median follow-up of 7 days (IQR, 3-13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10-22), 33% (95% CI, 23-43) and 42% (95% CI 30-54) respectively. For symptomatic VTE, these were 10% (95% CI, 5.8-16), 21% (95% CI, 14-30) and 25% (95% CI 16-36). VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02-5.5). The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17-37), 47% (95% CI, 34-58), and 59% (95% CI, 42-72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4-15), 9.2% (95% CI, 2.6-21), and 9.2% (2.6-21) at 7, 14, and 21 days).
CONCLUSIONS: The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.

© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.
PMID 32369666
F A Klok, M J H A Kruip, N J M van der Meer, M S Arbous, D Gommers, K M Kant, F H J Kaptein, J van Paassen, M A M Stals, M V Huisman, H Endeman
Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.
Thromb Res. 2020 Jul;191:148-150. doi: 10.1016/j.thromres.2020.04.041. Epub 2020 Apr 30.
Abstract/Text INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses.
METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.
RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8).
CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.

Copyright © 2020. Published by Elsevier Ltd.
PMID 32381264
David Kim, James Quinn, Benjamin Pinsky, Nigam H Shah, Ian Brown
Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens.
JAMA. 2020 Apr 15;. doi: 10.1001/jama.2020.6266. Epub 2020 Apr 15.
Abstract/Text
PMID 32293646
Daniel A Solomon, Amy C Sherman, Sanjat Kanjilal
Influenza in the COVID-19 Era.
JAMA. 2020 Aug 14;. doi: 10.1001/jama.2020.14661. Epub 2020 Aug 14.
Abstract/Text
PMID 32797145
Lirong Zou, Feng Ruan, Mingxing Huang, Lijun Liang, Huitao Huang, Zhongsi Hong, Jianxiang Yu, Min Kang, Yingchao Song, Jinyu Xia, Qianfang Guo, Tie Song, Jianfeng He, Hui-Ling Yen, Malik Peiris, Jie Wu
SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients.
N Engl J Med. 2020 Mar 19;382(12):1177-1179. doi: 10.1056/NEJMc2001737. Epub 2020 Feb 19.
Abstract/Text
PMID 32074444
Wenling Wang, Yanli Xu, Ruqin Gao, Roujian Lu, Kai Han, Guizhen Wu, Wenjie Tan
Detection of SARS-CoV-2 in Different Types of Clinical Specimens.
JAMA. 2020 Mar 11;. doi: 10.1001/jama.2020.3786. Epub 2020 Mar 11.
Abstract/Text
PMID 32159775
Yang Pan, Daitao Zhang, Peng Yang, Leo L M Poon, Quanyi Wang
Viral load of SARS-CoV-2 in clinical samples.
Lancet Infect Dis. 2020 Apr;20(4):411-412. doi: 10.1016/S1473-3099(20)30113-4. Epub 2020 Feb 24.
Abstract/Text
PMID 32105638
E Pasomsub, S P Watcharananan, K Boonyawat, P Janchompoo, G Wongtabtim, W Suksuwan, S Sungkanuparph, A Phuphuakrat
Saliva sample as a non-invasive specimen for the diagnosis of coronavirus disease 2019: a cross-sectional study.
Clin Microbiol Infect. 2020 May 15;. doi: 10.1016/j.cmi.2020.05.001. Epub 2020 May 15.
Abstract/Text OBJECTIVES: Amid the increasing number of pandemic coronavirus disease 2019 (COVID-19) cases, there is a need for a quick and easy method to obtain a non-invasive sample for the detection of this novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2). We aimed to investigate the potential use of saliva samples as a non-invasive tool for the diagnosis of COVID-19.
METHODS: From 27 March to 4 April 2020, we prospectively collected saliva samples and a standard nasopharyngeal and throat swab in persons seeking care at an acute respiratory infection clinic in a university hospital during the outbreak of COVID-19. Real-time polymerase chain reaction (RT-PCR) was performed, and the results of the two specimens were compared.
RESULTS: Two-hundred pairs of samples were collected. Sixty-nine (34.5%) individuals were male, and the median (interquartile) age was 36 (28-48) years. Using nasopharyngeal and throat swab RT-PCR as the reference standard, the prevalence of COVID-19 diagnosed by nasopharyngeal and throat swab RT-PCR was 9.5%. The sensitivity and specificity of the saliva sample RT-PCR were 84.2% (95% CI 60.4%-96.6%), and 98.9% (95% CI 96.1%-99.9%), respectively. An analysis of the agreement between the two specimens demonstrated 97.5% observed agreement (κ coefficient 0.851, 95% CI 0.723-0.979; p < 0.001).
CONCLUSIONS: Saliva might be an alternative specimen for the diagnosis of COVID-19. The collection is non-invasive, and non-aerosol generating. This method could facilitate the diagnosis of the disease, given the simplicity of specimen collection and good diagnostic performance.

Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
PMID 32422408
Eloise Williams, Katherine Bond, Bowen Zhang, Mark Putland, Deborah A Williamson
Saliva as a Noninvasive Specimen for Detection of SARS-CoV-2.
J Clin Microbiol. 2020 Jul 23;58(8). doi: 10.1128/JCM.00776-20. Epub 2020 Jul 23.
Abstract/Text
PMID 32317257
厚生労働省:唾液を用いたPCR検査に係る厚生労働科学研究の結果について「新型コロナウイルス感染症の診断における鼻かみ鼻汁及び唾液の有用性の検討」.
厚生労働省:第47回厚生科学審議会感染症部会 資料(2020年9月25日)「新型コロナウイルス感染症の鼻腔拭い液を用いた検査について」 (厚生労働科学研究 研究者代表:りんくう総合医療センター感染症センター長 倭 正也).
Nanshan Chen, Min Zhou, Xuan Dong, Jieming Qu, Fengyun Gong, Yang Han, Yang Qiu, Jingli Wang, Ying Liu, Yuan Wei, Jia'an Xia, Ting Yu, Xinxin Zhang, Li Zhang
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.
Abstract/Text BACKGROUND: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia.
METHODS: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.
FINDINGS: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure.
INTERPRETATION: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection.
FUNDING: National Key R&D Program of China.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32007143
Stephen R Knight, Antonia Ho, Riinu Pius, Iain Buchan, Gail Carson, Thomas M Drake, Jake Dunning, Cameron J Fairfield, Carrol Gamble, Christopher A Green, Rishi Gupta, Sophie Halpin, Hayley E Hardwick, Karl A Holden, Peter W Horby, Clare Jackson, Kenneth A Mclean, Laura Merson, Jonathan S Nguyen-Van-Tam, Lisa Norman, Mahdad Noursadeghi, Piero L Olliaro, Mark G Pritchard, Clark D Russell, Catherine A Shaw, Aziz Sheikh, Tom Solomon, Cathie Sudlow, Olivia V Swann, Lance Cw Turtle, Peter Jm Openshaw, J Kenneth Baillie, Malcolm G Semple, Annemarie B Docherty, Ewen M Harrison, ISARIC4C investigators
Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.
BMJ. 2020 Sep 9;370:m3339. doi: 10.1136/bmj.m3339. Epub 2020 Sep 9.
Abstract/Text OBJECTIVE: To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19).
DESIGN: Prospective observational cohort study.
SETTING: International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020. PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction.
MAIN OUTCOME MEASURE: In-hospital mortality.
RESULTS: 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73).
CONCLUSIONS: An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations.
STUDY REGISTRATION: ISRCTN66726260.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 32907855
Heshui Shi, Xiaoyu Han, Nanchuan Jiang, Yukun Cao, Osamah Alwalid, Jin Gu, Yanqing Fan, Chuansheng Zheng
Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.
Lancet Infect Dis. 2020 Apr;20(4):425-434. doi: 10.1016/S1473-3099(20)30086-4. Epub 2020 Feb 24.
Abstract/Text BACKGROUND: A cluster of patients with coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were successively reported in Wuhan, China. We aimed to describe the CT findings across different timepoints throughout the disease course.
METHODS: Patients with COVID-19 pneumonia (confirmed by next-generation sequencing or RT-PCR) who were admitted to one of two hospitals in Wuhan and who underwent serial chest CT scans were retrospectively enrolled. Patients were grouped on the basis of the interval between symptom onset and the first CT scan: group 1 (subclinical patients; scans done before symptom onset), group 2 (scans done ≤1 week after symptom onset), group 3 (>1 week to 2 weeks), and group 4 (>2 weeks to 3 weeks). Imaging features and their distribution were analysed and compared across the four groups.
FINDINGS: 81 patients admitted to hospital between Dec 20, 2019, and Jan 23, 2020, were retrospectively enrolled. The cohort included 42 (52%) men and 39 (48%) women, and the mean age was 49·5 years (SD 11·0). The mean number of involved lung segments was 10·5 (SD 6·4) overall, 2·8 (3·3) in group 1, 11·1 (5·4) in group 2, 13·0 (5·7) in group 3, and 12·1 (5·9) in group 4. The predominant pattern of abnormality observed was bilateral (64 [79%] patients), peripheral (44 [54%]), ill-defined (66 [81%]), and ground-glass opacification (53 [65%]), mainly involving the right lower lobes (225 [27%] of 849 affected segments). In group 1 (n=15), the predominant pattern was unilateral (nine [60%]) and multifocal (eight [53%]) ground-glass opacities (14 [93%]). Lesions quickly evolved to bilateral (19 [90%]), diffuse (11 [52%]) ground-glass opacity predominance (17 [81%]) in group 2 (n=21). Thereafter, the prevalence of ground-glass opacities continued to decrease (17 [57%] of 30 patients in group 3, and five [33%] of 15 in group 4), and consolidation and mixed patterns became more frequent (12 [40%] in group 3, eight [53%] in group 4).
INTERPRETATION: COVID-19 pneumonia manifests with chest CT imaging abnormalities, even in asymptomatic patients, with rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities that progressed to or co-existed with consolidations within 1-3 weeks. Combining assessment of imaging features with clinical and laboratory findings could facilitate early diagnosis of COVID-19 pneumonia.
FUNDING: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32105637
Xingzhi Xie, Zheng Zhong, Wei Zhao, Chao Zheng, Fei Wang, Jun Liu
Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing.
Radiology. 2020 Feb 12;:200343. doi: 10.1148/radiol.2020200343. Epub 2020 Feb 12.
Abstract/Text Some patients with positive chest CT findings may present with negative results of real time reverse-transcription-polymerase chain- reaction (RT-PCR) for 2019 novel coronavirus (2019-nCoV). In this report, we present chest CT findings from five patients with 2019-nCoV infection who had initial negative RT-PCR results. All five patients had typical imaging findings, including ground-glass opacity (GGO) (5 patients) and/or mixed GGO and mixed consolidation (2 patients). After isolation for presumed 2019-nCoV pneumonia, all patients were eventually confirmed with 2019-nCoV infection by repeated swab tests. A combination of repeated swab tests and CT scanning may be helpful when for individuals with high clinical suspicion of nCoV infection but negative RT-PCR screening.

PMID 32049601
Tao Ai, Zhenlu Yang, Hongyan Hou, Chenao Zhan, Chong Chen, Wenzhi Lv, Qian Tao, Ziyong Sun, Liming Xia
Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases.
Radiology. 2020 Feb 26;:200642. doi: 10.1148/radiol.2020200642. Epub 2020 Feb 26.
Abstract/Text Background Chest CT is used for diagnosis of 2019 novel coronavirus disease (COVID-19), as an important complement to the reverse-transcription polymerase chain reaction (RT-PCR) tests. Purpose To investigate the diagnostic value and consistency of chest CT as compared with comparison to RT-PCR assay in COVID-19. Methods From January 6 to February 6, 2020, 1014 patients in Wuhan, China who underwent both chest CT and RT-PCR tests were included. With RT-PCR as reference standard, the performance of chest CT in diagnosing COVID-19 was assessed. Besides, for patients with multiple RT-PCR assays, the dynamic conversion of RT-PCR results (negative to positive, positive to negative, respectively) was analyzed as compared with serial chest CT scans for those with time-interval of 4 days or more. Results Of 1014 patients, 59% (601/1014) had positive RT-PCR results, and 88% (888/1014) had positive chest CT scans. The sensitivity of chest CT in suggesting COVID-19 was 97% (95%CI, 95-98%, 580/601 patients) based on positive RT-PCR results. In patients with negative RT-PCR results, 75% (308/413) had positive chest CT findings; of 308, 48% were considered as highly likely cases, with 33% as probable cases. By analysis of serial RT-PCR assays and CT scans, the mean interval time between the initial negative to positive RT-PCR results was 5.1 ± 1.5 days; the initial positive to subsequent negative RT-PCR result was 6.9 ± 2.3 days). 60% to 93% of cases had initial positive CT consistent with COVID-19 prior (or parallel) to the initial positive RT-PCR results. 42% (24/57) cases showed improvement in follow-up chest CT scans before the RT-PCR results turning negative. Conclusion Chest CT has a high sensitivity for diagnosis of COVID-19. Chest CT may be considered as a primary tool for the current COVID-19 detection in epidemic areas.

PMID 32101510
Harrison X Bai, Ben Hsieh, Zeng Xiong, Kasey Halsey, Ji Whae Choi, Thi My Linh Tran, Ian Pan, Lin-Bo Shi, Dong-Cui Wang, Ji Mei, Xiao-Long Jiang, Qiu-Hua Zeng, Thomas K Egglin, Ping-Feng Hu, Saurabh Agarwal, Fangfang Xie, Sha Li, Terrance Healey, Michael K Atalay, Wei-Hua Liao
Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT.
Radiology. 2020 Mar 10;:200823. doi: 10.1148/radiol.2020200823. Epub 2020 Mar 10.
Abstract/Text Background Despite its high sensitivity in diagnosing COVID-19 in a screening population, chest CT appearances of COVID 19 pneumonia are thought to be non-specific. Purpose To assess the performance of United States (U.S.) and Chinese radiologists in differentiating COVID-19 from viral pneumonia on chest CT. Methods A total of 219 patients with both positive COVID-19 by RT-PCR and abnormal chest CT findings were retrospectively identified from 7 Chinese hospitals in Hunan Providence, China from January 6 to February 20, 2020. A total of 205 patients with positive Respiratory Pathogen Panel for viral pneumonia and CT findings consistent with or highly suspicious for pneumonia by original radiology interpretation within 7 days of each other were identified from Rhode Island Hospital in Providence, RI. Three Chinese radiologists blindly reviewed all chest CTs (n=424) to differentiate COVID-19 from viral pneumonia. A sample of 58 age-matched cases was randomly selected and evaluated by 4 U.S. radiologists in a similar fashion. Different CT features were recorded and compared between the two groups. Results For all chest CTs, three Chinese radiologists correctly differentiated COVID-19 from non-COVID-19 pneumonia 83% (350/424), 80% (338/424), and 60% (255/424) of the time, respectively. The seven radiologists had sensitivities of 80%, 67%, 97%, 93%, 83%, 73% and 70% and specificities of 100%, 93%, 7%, 100%, 93%, 93%, 100%. Compared to non-COVID-19 pneumonia, COVID-19 pneumonia was more likely to have a peripheral distribution (80% vs. 57%, p<0.001), ground-glass opacity (91% vs. 68%, p<0.001), fine reticular opacity (56% vs. 22%, p<0.001), and vascular thickening (59% vs. 22%, p<0.001), but less likely to have a central+peripheral distribution (14.% vs. 35%, p<0.001), pleural effusion (4.1 vs. 39%, p<0.001) and lymphadenopathy (2.7% vs. 10.2%, p<0.001). Conclusion Radiologists in China and the United States distinguished COVID-19 from viral pneumonia on chest CT with high specificity but moderate sensitivity. A translation of this abstract in Farsi is available in the supplement. - ترجمه چکیده این مقاله به فارسی، در ضمیمه موجود است.

PMID 32155105
James M Sanders, Marguerite L Monogue, Tomasz Z Jodlowski, James B Cutrell
Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review.
JAMA. 2020 Apr 13;. doi: 10.1001/jama.2020.6019. Epub 2020 Apr 13.
Abstract/Text Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.
Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19.
Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

PMID 32282022
Manli Wang, Ruiyuan Cao, Leike Zhang, Xinglou Yang, Jia Liu, Mingyue Xu, Zhengli Shi, Zhihong Hu, Wu Zhong, Gengfu Xiao
Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4.
Abstract/Text
PMID 32020029
WHO Solidarity Trial Consortium, Hongchao Pan, Richard Peto, Ana-Maria Henao-Restrepo, Marie-Pierre Preziosi, Vasee Sathiyamoorthy, Quarraisha Abdool Karim, Marissa M Alejandria, César Hernández García, Marie-Paule Kieny, Reza Malekzadeh, Srinivas Murthy, K Srinath Reddy, Mirta Roses Periago, Pierre Abi Hanna, Florence Ader, Abdullah M Al-Bader, Almonther Alhasawi, Emma Allum, Athari Alotaibi, Carlos A Alvarez-Moreno, Sheila Appadoo, Abdullah Asiri, Pål Aukrust, Andreas Barratt-Due, Samir Bellani, Mattia Branca, Heike B C Cappel-Porter, Nery Cerrato, Ting S Chow, Najada Como, Joe Eustace, Patricia J García, Sheela Godbole, Eduardo Gotuzzo, Laimonas Griskevicius, Rasha Hamra, Mariam Hassan, Mohamed Hassany, David Hutton, Irmansyah Irmansyah, Ligita Jancoriene, Jana Kirwan, Suresh Kumar, Peter Lennon, Gustavo Lopardo, Patrick Lydon, Nicola Magrini, Teresa Maguire, Suzana Manevska, Oriol Manuel, Sibylle McGinty, Marco T Medina, María L Mesa Rubio, Maria C Miranda-Montoya, Jeremy Nel, Estevao P Nunes, Markus Perola, Antonio Portolés, Menaldi R Rasmin, Aun Raza, Helen Rees, Paula P S Reges, Chris A Rogers, Kolawole Salami, Marina I Salvadori, Narvina Sinani, Jonathan A C Sterne, Milena Stevanovikj, Evelina Tacconelli, Kari A O Tikkinen, Sven Trelle, Hala Zaid, John-Arne Røttingen, Soumya Swaminathan
Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.
N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2.
Abstract/Text BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).
METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.
RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Copyright © 2020 Massachusetts Medical Society.
PMID 33264556
John H Beigel, Kay M Tomashek, Lori E Dodd, Aneesh K Mehta, Barry S Zingman, Andre C Kalil, Elizabeth Hohmann, Helen Y Chu, Annie Luetkemeyer, Susan Kline, Diego Lopez de Castilla, Robert W Finberg, Kerry Dierberg, Victor Tapson, Lanny Hsieh, Thomas F Patterson, Roger Paredes, Daniel A Sweeney, William R Short, Giota Touloumi, David Chien Lye, Norio Ohmagari, Myoung-Don Oh, Guillermo M Ruiz-Palacios, Thomas Benfield, Gerd Fätkenheuer, Mark G Kortepeter, Robert L Atmar, C Buddy Creech, Jens Lundgren, Abdel G Babiker, Sarah Pett, James D Neaton, Timothy H Burgess, Tyler Bonnett, Michelle Green, Mat Makowski, Anu Osinusi, Seema Nayak, H Clifford Lane, ACTT-1 Study Group Members
Remdesivir for the Treatment of Covid-19 - Preliminary Report.
N Engl J Med. 2020 May 22;. doi: 10.1056/NEJMoa2007764. Epub 2020 May 22.
Abstract/Text BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.
METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
RESULTS: A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).
CONCLUSIONS: Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32445440
Christoph D Spinner, Robert L Gottlieb, Gerard J Criner, José Ramón Arribas López, Anna Maria Cattelan, Alex Soriano Viladomiu, Onyema Ogbuagu, Prashant Malhotra, Kathleen M Mullane, Antonella Castagna, Louis Yi Ann Chai, Meta Roestenberg, Owen Tak Yin Tsang, Enos Bernasconi, Paul Le Turnier, Shan-Chwen Chang, Devi SenGupta, Robert H Hyland, Anu O Osinusi, Huyen Cao, Christiana Blair, Hongyuan Wang, Anuj Gaggar, Diana M Brainard, Mark J McPhail, Sanjay Bhagani, Mi Young Ahn, Arun J Sanyal, Gregory Huhn, Francisco M Marty, GS-US-540-5774 Investigators
Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.
JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349.
Abstract/Text Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.
Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.
Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.
Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.
Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.
Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.
Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

PMID 32821939
Brian T Garibaldi, Kunbo Wang, Matthew L Robinson, Joshua Betz, G Caleb Alexander, Kathleen M Andersen, Corey S Joseph, Hemalkumar B Mehta, Kimberly Korwek, Kenneth E Sands, Arielle M Fisher, Robert C Bollinger, Yanxun Xu
Real-World Effectiveness Of Remdesivir In Adults Hospitalized With Covid-19: A Retrospective, Multicenter Comparative Effectiveness Study.
Clin Infect Dis. 2021 Dec 15;. doi: 10.1093/cid/ciab1035. Epub 2021 Dec 15.
Abstract/Text BACKGROUND: There is an urgent need to understand the real-world effectiveness of remdesivir in the treatment of SARS-CoV-2.
METHODS: This was a retrospective comparative effectiveness study. Individuals hospitalized in a large private healthcare network in the US from February 23, 2020 through February 11, 2021 with a positive test for SARS-CoV-2 and ICD-10 diagnosis codes consistent with symptomatic COVID-19 were included. Remdesivir recipients were matched to controls using time-dependent propensity scores. The primary outcome was time to improvement with a secondary outcome of time to death.
RESULTS: Of 96,859 COVID-19 patients, 42,473 (43.9%) received at least one remdesivir dose. The median age of remdesivir recipients was 65 years, 23,701 (55.8%) were male and 22,819 (53.7%) were non-white. Matches were found for 18,328 patients (43.2%). Remdesivir recipients were significantly more likely to achieve clinical improvement by 28 days (adjusted hazard ratio [1.19, 95% confidence interval (CI), 1.16-1.22]). Remdesivir patients on no oxygen (aHR 1.30, 95% CI 1.22-1.38) or low-flow oxygen (aHR 1.23, 95% CI 1.19-1.27) were significantly more likely to achieve clinical improvement by 28 days. There was no significant impact on the likelihood of mortality overall (aHR 1.02, 95% CI 0.97-1.08). Remdesivir recipients on low-flow oxygen were significantly less likely to die than controls (aHR 0.85, 95% CI 0.77-0.92; 28-day mortality 8.4% [865 deaths] for remdesivir patients, 12.5% [1,334 deaths] for controls).
CONCLUSIONS: These results support the use of remdesivir for hospitalized COVID-19 patients on no or low-flow oxygen. Routine initiation of remdesivir in more severely ill patients is unlikely to be beneficial.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 34910128
Jason D Goldman, David C B Lye, David S Hui, Kristen M Marks, Raffaele Bruno, Rocio Montejano, Christoph D Spinner, Massimo Galli, Mi-Young Ahn, Ronald G Nahass, Yao-Shen Chen, Devi SenGupta, Robert H Hyland, Anu O Osinusi, Huyen Cao, Christiana Blair, Xuelian Wei, Anuj Gaggar, Diana M Brainard, William J Towner, Jose Muñoz, Kathleen M Mullane, Francisco M Marty, Karen T Tashima, George Diaz, Aruna Subramanian, GS-US-540-5773 Investigators
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.
N Engl J Med. 2020 Nov 5;383(19):1827-1837. doi: 10.1056/NEJMoa2015301. Epub 2020 May 27.
Abstract/Text BACKGROUND: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
METHODS: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
RESULTS: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
CONCLUSIONS: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32459919
Robert L Gottlieb, Carlos E Vaca, Roger Paredes, Jorge Mera, Brandon J Webb, Gilberto Perez, Godson Oguchi, Pablo Ryan, Bibi U Nielsen, Michael Brown, Ausberto Hidalgo, Yessica Sachdeva, Shilpi Mittal, Olayemi Osiyemi, Jacek Skarbinski, Kavita Juneja, Robert H Hyland, Anu Osinusi, Shuguang Chen, Gregory Camus, Mazin Abdelghany, Santosh Davies, Nicole Behenna-Renton, Frank Duff, Francisco M Marty, Morgan J Katz, Adit A Ginde, Samuel M Brown, Joshua T Schiffer, Joshua A Hill, GS-US-540-9012 (PINETREE) Investigators
Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.
N Engl J Med. 2022 Jan 27;386(4):305-315. doi: 10.1056/NEJMoa2116846. Epub 2021 Dec 22.
Abstract/Text BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28.
RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.
CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34937145
Nelson Lee, K C Allen Chan, David S Hui, Enders K O Ng, Alan Wu, Rossa W K Chiu, Vincent W S Wong, Paul K S Chan, K T Wong, Eric Wong, C S Cockram, John S Tam, Joseph J Y Sung, Y M Dennis Lo
Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.
J Clin Virol. 2004 Dec;31(4):304-9. doi: 10.1016/j.jcv.2004.07.006.
Abstract/Text BACKGROUND: The effect of corticosteroid treatment on the viral load of Severe Acute Respiratory Syndrome (SARS) patients is unknown.
OBJECTIVE: To compare the plasma SARS-CoV RNA concentrations in ribavirin-treated patients who received early hydrocortisone therapy with those who received placebo.
STUDY DESIGN: Serial plasma SARS-CoV RNA concentrations measured in the setting of a prospective, randomized double-blinded, placebo-controlled trial designed to assess the efficacy of "early" (<7 days of illness) hydrocortisone use in previously healthy SARS patients were analyzed. SARS-CoV RNA was quantified using a one-step real-time RT-PCR assay targeting the nucleocapsid gene.
RESULTS: Among 16 non-ICU cases, SARS-CoV RNA was detected in plasma since day 3-4 after fever onset; viral concentration peaked in the first week, which then rapidly declined in the second week of illness. On days 8, 12, 16, and 20, the cumulative proportion of patients with undetectable virus in plasma was 31%, 69%, 92%, and 100%, respectively. Plasma SARS-CoV RNA concentrations in the second and third week of illness were significantly higher in patients who received initial hydrocortisone treatment (n = 9), as compared to those who received placebo (n = 7)(AUC; Mann-Whitney, P = 0.023). The median time for SARS-CoV to become undetectable in plasma was 12 days (11-20 days) versus 8 days (8-15 days), respectively.
CONCLUSION: Our findings suggested "early" corticosteroid treatment was associated with a higher subsequent plasma viral load.

PMID 15494274
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Jonathan A C Sterne, Srinivas Murthy, Janet V Diaz, Arthur S Slutsky, Jesús Villar, Derek C Angus, Djillali Annane, Luciano Cesar Pontes Azevedo, Otavio Berwanger, Alexandre B Cavalcanti, Pierre-Francois Dequin, Bin Du, Jonathan Emberson, David Fisher, Bruno Giraudeau, Anthony C Gordon, Anders Granholm, Cameron Green, Richard Haynes, Nicholas Heming, Julian P T Higgins, Peter Horby, Peter Jüni, Martin J Landray, Amelie Le Gouge, Marie Leclerc, Wei Shen Lim, Flávia R Machado, Colin McArthur, Ferhat Meziani, Morten Hylander Møller, Anders Perner, Marie Warrer Petersen, Jelena Savovic, Bruno Tomazini, Viviane C Veiga, Steve Webb, John C Marshall
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.
JAMA. 2020 Oct 6;324(13):1330-1341. doi: 10.1001/jama.2020.17023.
Abstract/Text Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.
Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.
Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios.
Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).
Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.
Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.
Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

PMID 32876694
Andre C Kalil, Thomas F Patterson, Aneesh K Mehta, Kay M Tomashek, Cameron R Wolfe, Varduhi Ghazaryan, Vincent C Marconi, Guillermo M Ruiz-Palacios, Lanny Hsieh, Susan Kline, Victor Tapson, Nicole M Iovine, Mamta K Jain, Daniel A Sweeney, Hana M El Sahly, Angela R Branche, Justino Regalado Pineda, David C Lye, Uriel Sandkovsky, Anne F Luetkemeyer, Stuart H Cohen, Robert W Finberg, Patrick E H Jackson, Babafemi Taiwo, Catharine I Paules, Henry Arguinchona, Nathaniel Erdmann, Neera Ahuja, Maria Frank, Myoung-Don Oh, Eu-Suk Kim, Seow Y Tan, Richard A Mularski, Henrik Nielsen, Philip O Ponce, Barbara S Taylor, LuAnn Larson, Nadine G Rouphael, Youssef Saklawi, Valeria D Cantos, Emily R Ko, John J Engemann, Alpesh N Amin, Miki Watanabe, Joanne Billings, Marie-Carmelle Elie, Richard T Davey, Timothy H Burgess, Jennifer Ferreira, Michelle Green, Mat Makowski, Anabela Cardoso, Stephanie de Bono, Tyler Bonnett, Michael Proschan, Gregory A Deye, Walla Dempsey, Seema U Nayak, Lori E Dodd, John H Beigel, ACTT-2 Study Group Members
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.
N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. Epub 2020 Dec 11.
Abstract/Text BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.
METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.
RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003).
CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

Copyright © 2020 Massachusetts Medical Society.
PMID 33306283
Vincent C Marconi, Athimalaipet V Ramanan, Stephanie de Bono, Cynthia E Kartman, Venkatesh Krishnan, Ran Liao, Maria Lucia B Piruzeli, Jason D Goldman, Jorge Alatorre-Alexander, Rita de Cassia Pellegrini, Vicente Estrada, Mousumi Som, Anabela Cardoso, Sujatro Chakladar, Brenda Crowe, Paulo Reis, Xin Zhang, David H Adams, E Wesley Ely, COV-BARRIER Study Group
Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
Lancet Respir Med. 2021 Dec;9(12):1407-1418. doi: 10.1016/S2213-2600(21)00331-3. Epub 2021 Sep 1.
Abstract/Text BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19.
METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027.
FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups.
INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19.
FUNDING: Eli Lilly and Company.
TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 34480861
REMAP-CAP Investigators, Anthony C Gordon, Paul R Mouncey, Farah Al-Beidh, Kathryn M Rowan, Alistair D Nichol, Yaseen M Arabi, Djillali Annane, Abi Beane, Wilma van Bentum-Puijk, Lindsay R Berry, Zahra Bhimani, Marc J M Bonten, Charlotte A Bradbury, Frank M Brunkhorst, Adrian Buzgau, Allen C Cheng, Michelle A Detry, Eamon J Duffy, Lise J Estcourt, Mark Fitzgerald, Herman Goossens, Rashan Haniffa, Alisa M Higgins, Thomas E Hills, Christopher M Horvat, Francois Lamontagne, Patrick R Lawler, Helen L Leavis, Kelsey M Linstrum, Edward Litton, Elizabeth Lorenzi, John C Marshall, Florian B Mayr, Daniel F McAuley, Anna McGlothlin, Shay P McGuinness, Bryan J McVerry, Stephanie K Montgomery, Susan C Morpeth, Srinivas Murthy, Katrina Orr, Rachael L Parke, Jane C Parker, Asad E Patanwala, Ville Pettilä, Emma Rademaker, Marlene S Santos, Christina T Saunders, Christopher W Seymour, Manu Shankar-Hari, Wendy I Sligl, Alexis F Turgeon, Anne M Turner, Frank L van de Veerdonk, Ryan Zarychanski, Cameron Green, Roger J Lewis, Derek C Angus, Colin J McArthur, Scott Berry, Steve A Webb, Lennie P G Derde
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.
N Engl J Med. 2021 Apr 22;384(16):1491-1502. doi: 10.1056/NEJMoa2100433. Epub 2021 Feb 25.
Abstract/Text BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.
METHODS: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.
RESULTS: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.
CONCLUSIONS: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Copyright © 2021 Massachusetts Medical Society.
PMID 33631065
RECOVERY Collaborative Group
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0.
Abstract/Text BACKGROUND: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.
METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg-800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
FINDINGS: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77-0·92; p<0·0001).
INTERPRETATION: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Copyright © 2021 Published by Elsevier Ltd. All rights reserved. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
PMID 33933206
Meagan P O'Brien, Eduardo Forleo-Neto, Bret J Musser, Flonza Isa, Kuo-Chen Chan, Neena Sarkar, Katharine J Bar, Ruanne V Barnabas, Dan H Barouch, Myron S Cohen, Christopher B Hurt, Dale R Burwen, Mary A Marovich, Peijie Hou, Ingeborg Heirman, John D Davis, Kenneth C Turner, Divya Ramesh, Adnan Mahmood, Andrea T Hooper, Jennifer D Hamilton, Yunji Kim, Lisa A Purcell, Alina Baum, Christos A Kyratsous, James Krainson, Richard Perez-Perez, Rizwana Mohseni, Bari Kowal, A Thomas DiCioccio, Neil Stahl, Leah Lipsich, Ned Braunstein, Gary Herman, George D Yancopoulos, David M Weinreich, Covid-19 Phase 3 Prevention Trial Team
Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19.
N Engl J Med. 2021 Sep 23;385(13):1184-1195. doi: 10.1056/NEJMoa2109682. Epub 2021 Aug 4.
Abstract/Text BACKGROUND: REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.
METHODS: We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).
RESULTS: Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.
CONCLUSIONS: Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34347950
Yuani M Roman, Paula Alejandra Burela, Vinay Pasupuleti, Alejandro Piscoya, Jose E Vidal, Adrian V Hernandez
Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials.
Clin Infect Dis. 2021 Jun 28;. doi: 10.1093/cid/ciab591. Epub 2021 Jun 28.
Abstract/Text BACKGROUND: We systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients.
METHODS: Published and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 22, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. Risk of bias (RoB) was evaluated using Cochrane RoB 2·0 tool. Inverse variance random effect meta-analyses were performed. with quality of evidence (QoE) evaluated using GRADE methodology.
RESULTS: Ten RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. COVID-19 disease severity was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 0.37, 95%CI 0.12 to 1.13, very low QoE) or LOS vs. controls (MD 0.72 days, 95%CI -0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (all outcomes: low QoE). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality in three RCTs at high RoB was reduced with IVM.
CONCLUSIONS: In comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have an effect on AEs or severe AEs. IVM is not a viable option to treat COVID-19 patients.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
PMID 34181716
Andrew Bryant, Theresa A Lawrie, Therese Dowswell, Edmund J Fordham, Scott Mitchell, Sarah R Hill, Tony C Tham
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines.
Am J Ther. 2021 Jun 21;28(4):e434-e460. doi: 10.1097/MJT.0000000000001402. Epub 2021 Jun 21.
Abstract/Text BACKGROUND: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials.
AREAS OF UNCERTAINTY: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection.
DATA SOURCES: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion.
THERAPEUTIC ADVANCES: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.
CONCLUSIONS: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
PMID 34145166
Martin Neil, Norman Fenton
Bayesian Hypothesis Testing and Hierarchical Modeling of Ivermectin Effectiveness.
Am J Ther. 2021 Sep-Oct 01;28(5):e576-e579. doi: 10.1097/MJT.0000000000001450.
Abstract/Text
PMID 34469917
Thomas M Drake, Cameron J Fairfield, Riinu Pius, Stephen R Knight, Lisa Norman, Michelle Girvan, Hayley E Hardwick, Annemarie B Docherty, Ryan S Thwaites, Peter J M Openshaw, J Kenneth Baillie, Ewen M Harrison, Malcolm G Semple, ISARIC4C Investigators
Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study.
Lancet Rheumatol. 2021 Jul;3(7):e498-e506. doi: 10.1016/S2665-9913(21)00104-1. Epub 2021 May 7.
Abstract/Text Background: Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease.
Methods: This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations.
Results: Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84-1·07; p=0·35), critical care admission (1·01, 0·87-1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80-1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96-1·32; p=0·14), requirement for oxygen (1·00, 0·89-1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92-1·26; p=0·33).
Interpretation: NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity.
Funding: National Institute for Health Research and Medical Research Council.

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
PMID 33997800
Angélica Jayk Bernal, Monica M Gomes da Silva, Dany B Musungaie, Evgeniy Kovalchuk, Antonio Gonzalez, Virginia Delos Reyes, Alejandro Martín-Quirós, Yoseph Caraco, Angela Williams-Diaz, Michelle L Brown, Jiejun Du, Alison Pedley, Christopher Assaid, Julie Strizki, Jay A Grobler, Hala H Shamsuddin, Robert Tipping, Hong Wan, Amanda Paschke, Joan R Butterton, Matthew G Johnson, Carisa De Anda, MOVe-OUT Study Group
Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.
N Engl J Med. 2021 Dec 16;. doi: 10.1056/NEJMoa2116044. Epub 2021 Dec 16.
Abstract/Text BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.
RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval, -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% confidence interval, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.
CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34914868
F A Klok, M J H A Kruip, N J M van der Meer, M S Arbous, D A M P J Gommers, K M Kant, F H J Kaptein, J van Paassen, M A M Stals, M V Huisman, H Endeman
Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
Thromb Res. 2020 Apr 10;. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10.
Abstract/Text INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available.
METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.
RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.
CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.

Copyright © 2020. Published by Elsevier Ltd.
PMID 32291094
R J Smith, R G Bryant
Metal substitutions incarbonic anhydrase: a halide ion probe study.
Biochem Biophys Res Commun. 1975 Oct 27;66(4):1281-6.
Abstract/Text
PMID 3
Jamie Lopez Bernal, Nick Andrews, Charlotte Gower, Eileen Gallagher, Ruth Simmons, Simon Thelwall, Julia Stowe, Elise Tessier, Natalie Groves, Gavin Dabrera, Richard Myers, Colin N J Campbell, Gayatri Amirthalingam, Matt Edmunds, Maria Zambon, Kevin E Brown, Susan Hopkins, Meera Chand, Mary Ramsay
Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.
N Engl J Med. 2021 Aug 12;385(7):585-594. doi: 10.1056/NEJMoa2108891. Epub 2021 Jul 21.
Abstract/Text BACKGROUND: The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.
METHODS: We used a test-negative case-control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients' vaccination status.
RESULTS: Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.
CONCLUSIONS: Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34289274
Paul T Heath, Eva P Galiza, David N Baxter, Marta Boffito, Duncan Browne, Fiona Burns, David R Chadwick, Rebecca Clark, Catherine Cosgrove, James Galloway, Anna L Goodman, Amardeep Heer, Andrew Higham, Shalini Iyengar, Arham Jamal, Christopher Jeanes, Philip A Kalra, Christina Kyriakidou, Daniel F McAuley, Agnieszka Meyrick, Angela M Minassian, Jane Minton, Patrick Moore, Imrozia Munsoor, Helen Nicholls, Orod Osanlou, Jonathan Packham, Carol H Pretswell, Alberto San Francisco Ramos, Dinesh Saralaya, Ray P Sheridan, Richard Smith, Roy L Soiza, Pauline A Swift, Emma C Thomson, Jeremy Turner, Marianne E Viljoen, Gary Albert, Iksung Cho, Filip Dubovsky, Greg Glenn, Joy Rivers, Andreana Robertson, Kathy Smith, Seth Toback, 2019nCoV-302 Study Group
Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.
N Engl J Med. 2021 Sep 23;385(13):1172-1183. doi: 10.1056/NEJMoa2107659. Epub 2021 Jun 30.
Abstract/Text BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.
METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.
RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.
CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

Copyright © 2021 Massachusetts Medical Society.
PMID 34192426
Yinon M Bar-On, Yair Goldberg, Micha Mandel, Omri Bodenheimer, Laurence Freedman, Nir Kalkstein, Barak Mizrahi, Sharon Alroy-Preis, Nachman Ash, Ron Milo, Amit Huppert
Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel.
N Engl J Med. 2021 Oct 7;385(15):1393-1400. doi: 10.1056/NEJMoa2114255. Epub 2021 Sep 15.
Abstract/Text BACKGROUND: On July 30, 2021, the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) was approved in Israel for persons who were 60 years of age or older and who had received a second dose of vaccine at least 5 months earlier. Data are needed regarding the effect of the booster dose on the rate of confirmed coronavirus 2019 disease (Covid-19) and the rate of severe illness.
METHODS: We extracted data for the period from July 30 through August 31, 2021, from the Israeli Ministry of Health database regarding 1,137,804 persons who were 60 years of age or older and had been fully vaccinated (i.e., had received two doses of BNT162b2) at least 5 months earlier. In the primary analysis, we compared the rate of confirmed Covid-19 and the rate of severe illness between those who had received a booster injection at least 12 days earlier (booster group) and those who had not received a booster injection (nonbooster group). In a secondary analysis, we evaluated the rate of infection 4 to 6 days after the booster dose as compared with the rate at least 12 days after the booster. In all the analyses, we used Poisson regression after adjusting for possible confounding factors.
RESULTS: At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of 11.3 (95% confidence interval [CI], 10.4 to 12.3); the rate of severe illness was lower by a factor of 19.5 (95% CI, 12.9 to 29.5). In a secondary analysis, the rate of confirmed infection at least 12 days after vaccination was lower than the rate after 4 to 6 days by a factor of 5.4 (95% CI, 4.8 to 6.1).
CONCLUSIONS: In this study involving participants who were 60 years of age or older and had received two doses of the BNT162b2 vaccine at least 5 months earlier, we found that the rates of confirmed Covid-19 and severe illness were substantially lower among those who received a booster (third) dose of the BNT162b2 vaccine.

Copyright © 2021 Massachusetts Medical Society.
PMID 34525275
Robert L Atmar, Kirsten E Lyke, Meagan E Deming, Lisa A Jackson, Angela R Branche, Hana M El Sahly, Christina A Rostad, Judith M Martin, Christine Johnston, Richard E Rupp, Mark J Mulligan, Rebecca C Brady, Robert W Frenck, Martín Bäcker, Angelica C Kottkamp, Tara M Babu, Kumaravel Rajakumar, Srilatha Edupuganti, David Dobryzynski, Christine M Posavad, Janet I Archer, Sonja Crandon, Seema U Nayak, Daniel Szydlo, Jillian Zemanek, Clara P Dominguez Islas, Elizabeth R Brown, Mehul S Suthar, M Juliana McElrath, Adrian B McDermott, Sarah E O'Connell, David C Montefiori, Amanda Eaton, Kathleen M Neuzil, David S Stephens, Paul C Roberts, John H Beigel, DMID 21-0012 Study Group
Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report.
medRxiv. 2021 Oct 15;. doi: 10.1101/2021.10.10.21264827. Epub 2021 Oct 15.
Abstract/Text Background: While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen.
Methods: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-μg, Janssen Ad26.COV2.S 5×10 10 virus particles, or Pfizer-BioNTech BNT162b2 30-μg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29.
Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations.
Conclusion: Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by National Institute of Allergy and Infectious Diseases; Clinical Trials.gov number, NCT04889209 ).

PMID 34671773
SeyedAhmad SeyedAlinaghi, Amir Masoud Afsahi, Mehrzad MohsseniPour, Farzane Behnezhad, Mohammad Amin Salehi, Alireza Barzegary, Pegah Mirzapour, Esmaeil Mehraeen, Omid Dadras
Late Complications of COVID-19; a Systematic Review of Current Evidence.
Arch Acad Emerg Med. 2021;9(1):e14. Epub 2021 Jan 20.
Abstract/Text
PMID 33681819
Angelo Carfì, Roberto Bernabei, Francesco Landi, Gemelli Against COVID-19 Post-Acute Care Study Group
Persistent Symptoms in Patients After Acute COVID-19.
JAMA. 2020 Aug 11;324(6):603-605. doi: 10.1001/jama.2020.12603.
Abstract/Text
PMID 32644129
Yusuke Miyazato, Shinichiro Morioka, Shinya Tsuzuki, Masako Akashi, Yasuyo Osanai, Keiko Tanaka, Mari Terada, Michiyo Suzuki, Satoshi Kutsuna, Sho Saito, Kayoko Hayakawa, Norio Ohmagari
Prolonged and Late-Onset Symptoms of Coronavirus Disease 2019.
Open Forum Infect Dis. 2020 Nov;7(11):ofaa507. doi: 10.1093/ofid/ofaa507. Epub 2020 Oct 21.
Abstract/Text Some patients who recover from coronavirus disease 2019 (COVID-19) have prolonged symptoms such as dyspnea, fatigue, cough, and dysosmia for longer than 120 days after symptom onset. In addition, some patients who recovered from COVID-19 reported hair loss a few months after the onset of the disease. Alopecia is a late-onset symptom of COVID-19. The cause of alopecia is unknown; however, androgenic alopecia and telogen effluvium are possible causes.

© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
PMID 33230486
Grant Waterer
Recovery from community acquired pneumonia: the view from the top of the iceberg.
Eur Respir J. 2017 Jun;49(6). doi: 10.1183/13993003.00571-2017. Epub 2017 Jun 15.
Abstract/Text
PMID 28619961
Yuhui Wang, Chengjun Dong, Yue Hu, Chungao Li, Qianqian Ren, Xin Zhang, Heshui Shi, Min Zhou
Temporal Changes of CT Findings in 90 Patients with COVID-19 Pneumonia: A Longitudinal Study.
Radiology. 2020 Aug;296(2):E55-E64. doi: 10.1148/radiol.2020200843. Epub 2020 Mar 19.
Abstract/Text Background CT may play a central role in the diagnosis and management of coronavirus disease 2019 (COVID-19) pneumonia. Purpose To perform a longitudinal study to analyze the serial CT findings over time in patients with COVID-19 pneumonia. Materials and Methods During January 16 to February 17, 2020, 90 patients (33 men, 57 women; mean age, 45 years) with COVID-19 pneumonia were prospectively enrolled and followed up until being discharged, death, or the end of the study. A total of 366 CT scans were acquired and reviewed by two groups of radiologists for the patterns and distribution of lung abnormalities, total CT scores, and number of zones involved. Those features were analyzed for temporal change. Results CT scores and number of zones involved progressed rapidly, peaked during illness days 6-11 (median CT score, 5; median number of zones involved, five), and were followed by persistence of high levels. The predominant pattern of abnormalities after symptom onset was ground-glass opacity (35 of 78 scans [45%] to 49 of 79 scans [62%] in different periods). The percentage of mixed pattern peaked on illness days 12-17 (30 of 78 scans [38%]) and became the second most predominant pattern thereafter. Pure ground-glass opacity was the most prevalent subtype of ground-glass opacity after symptom onset (20 of 50 scans [40%] to 20 of 28 scans [71%]). The percentage of ground-glass opacity with irregular linear opacity peaked on illness days 6-11 (14 of 50 scans [28%]) and became the second most prevalent subtype thereafter. The distribution of lesions was predominantly bilateral and subpleural. Sixty-six of the 70 patients discharged (94%) had residual disease on final CT scans (median CT score, 4; median number of zones involved, four), with ground-glass opacity (42 of 70 patients [60%]) and pure ground-glass opacity (31 of 42 patients [74%]) the most common pattern and subtype. Conclusion The extent of lung abnormalities at CT peaked during illness days 6-11. The temporal changes of the diverse CT manifestations followed a specific pattern, which might indicate the progression and recovery of the illness. © RSNA, 2020 Online supplemental material is available for this article.

PMID 32191587
Samir Nusair
Abnormal carbon monoxide diffusion capacity in COVID-19 patients at time of hospital discharge.
Eur Respir J. 2020 Jul;56(1). doi: 10.1183/13993003.01832-2020. Epub 2020 Jul 23.
Abstract/Text
PMID 32703822
Chaolin Huang, Lixue Huang, Yeming Wang, Xia Li, Lili Ren, Xiaoying Gu, Liang Kang, Li Guo, Min Liu, Xing Zhou, Jianfeng Luo, Zhenghui Huang, Shengjin Tu, Yue Zhao, Li Chen, Decui Xu, Yanping Li, Caihong Li, Lu Peng, Yong Li, Wuxiang Xie, Dan Cui, Lianhan Shang, Guohui Fan, Jiuyang Xu, Geng Wang, Ying Wang, Jingchuan Zhong, Chen Wang, Jianwei Wang, Dingyu Zhang, Bin Cao
6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
Lancet. 2021 Jan 16;397(10270):220-232. doi: 10.1016/S0140-6736(20)32656-8. Epub 2021 Jan 8.
Abstract/Text BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity.
METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences.
FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0-65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0-199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up.
INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery.
FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

Copyright © 2021 Elsevier Ltd. All rights reserved.
PMID 33428867
Martijn A Spruit, Anne E Holland, Sally J Singh, Thomy Tonia, Kevin C Wilson, Thierry Troosters
COVID-19: Interim Guidance on Rehabilitation in the Hospital and Post-Hospital Phase from a European Respiratory Society and American Thoracic Society-coordinated International Task Force.
Eur Respir J. 2020 Aug 13;. doi: 10.1183/13993003.02197-2020. Epub 2020 Aug 13.
Abstract/Text BACKGROUND: Patients with COVID-19 or post-COVID-19 will most probably have a need for rehabilitation during and directly after the hospitalisation. Data on safety and efficacy are lacking. Healthcare professionals cannot wait for published randomised controlled trials before they can start these rehabilitative interventions in daily clinical practice, as the number of post-COVID-19 patients increases rapidly. The Convergence of Opinion on Recommendations and Evidence process was used to make interim recommendation for the rehabilitation in the hospital and post-hospital phase in COVID-19 and post-COVID-19 patients, respectively.
METHODS: 93 experts were asked to fill out 13 multiple choice questions. Agreement of directionality was tabulated for each question. At least 70% agreement on directionality was necessary to make consensus suggestions.
RESULTS: 76 experts (82%) reached consensus on all questions based upon indirect evidence and clinical experience on the need for early rehabilitation during the hospital admission, the screening for treatable traits with rehabilitation in all patients at discharge and 6-8 weeks after discharge, and around the content of rehabilitation for these patients. It advocates for assessment of oxygen needs at discharge and more comprehensive assessment of rehabilitation needs including physical as well as mental aspects 6-8 weeks after discharge. Based on the deficits identified multidisciplinary rehabilitation should be offered with attention for skeletal muscle and functional as well as mental restoration.
CONCLUSIONS: This multinational task force recommends early, bedside rehabilitation for patients affected by severe COVID-19. The model of pulmonary rehabilitation may suit as a framework, particularly in a subset of patients with long term respiratory consequences.

Copyright ©ERS 2020.
PMID 32817258
Laura D Zambrano, Sascha Ellington, Penelope Strid, Romeo R Galang, Titilope Oduyebo, Van T Tong, Kate R Woodworth, John F Nahabedian, Eduardo Azziz-Baumgartner, Suzanne M Gilboa, Dana Meaney-Delman, CDC COVID-19 Response Pregnancy and Infant Linked Outcomes Team
Update: Characteristics of Symptomatic Women of Reproductive Age with Laboratory-Confirmed SARS-CoV-2 Infection by Pregnancy Status - United States, January 22-October 3, 2020.
MMWR Morb Mortal Wkly Rep. 2020 Nov 6;69(44):1641-1647. doi: 10.15585/mmwr.mm6944e3. Epub 2020 Nov 6.
Abstract/Text Studies suggest that pregnant women might be at increased risk for severe illness associated with coronavirus disease 2019 (COVID-19) (1,2). This report provides updated information about symptomatic women of reproductive age (15-44 years) with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19. During January 22-October 3, CDC received reports through national COVID-19 case surveillance or through the National Notifiable Diseases Surveillance System (NNDSS) of 1,300,938 women aged 15-44 years with laboratory results indicative of acute infection with SARS-CoV-2. Data on pregnancy status were available for 461,825 (35.5%) women with laboratory-confirmed infection, 409,462 (88.7%) of whom were symptomatic. Among symptomatic women, 23,434 (5.7%) were reported to be pregnant. After adjusting for age, race/ethnicity, and underlying medical conditions, pregnant women were significantly more likely than were nonpregnant women to be admitted to an intensive care unit (ICU) (10.5 versus 3.9 per 1,000 cases; adjusted risk ratio [aRR] = 3.0; 95% confidence interval [CI] = 2.6-3.4), receive invasive ventilation (2.9 versus 1.1 per 1,000 cases; aRR = 2.9; 95% CI = 2.2-3.8), receive extracorporeal membrane oxygenation (ECMO) (0.7 versus 0.3 per 1,000 cases; aRR = 2.4; 95% CI = 1.5-4.0), and die (1.5 versus 1.2 per 1,000 cases; aRR = 1.7; 95% CI = 1.2-2.4). Stratifying these analyses by age and race/ethnicity highlighted disparities in risk by subgroup. Although the absolute risks for severe outcomes for women were low, pregnant women were at increased risk for severe COVID-19-associated illness. To reduce the risk for severe illness and death from COVID-19, pregnant women should be counseled about the importance of seeking prompt medical care if they have symptoms and measures to prevent SARS-CoV-2 infection should be strongly emphasized for pregnant women and their families during all medical encounters, including prenatal care visits. Understanding COVID-19-associated risks among pregnant women is important for prevention counseling and clinical care and treatment.

PMID 33151921
John Allotey, Elena Stallings, Mercedes Bonet, Magnus Yap, Shaunak Chatterjee, Tania Kew, Luke Debenham, Anna Clavé Llavall, Anushka Dixit, Dengyi Zhou, Rishab Balaji, Siang Ing Lee, Xiu Qiu, Mingyang Yuan, Dyuti Coomar, Jameela Sheikh, Heidi Lawson, Kehkashan Ansari, Madelon van Wely, Elizabeth van Leeuwen, Elena Kostova, Heinke Kunst, Asma Khalil, Simon Tiberi, Vanessa Brizuela, Nathalie Broutet, Edna Kara, Caron Rahn Kim, Anna Thorson, Olufemi T Oladapo, Lynne Mofenson, Javier Zamora, Shakila Thangaratinam, for PregCOV-19 Living Systematic Review Consortium
Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis.
BMJ. 2020 Sep 1;370:m3320. doi: 10.1136/bmj.m3320. Epub 2020 Sep 1.
Abstract/Text OBJECTIVE: To determine the clinical manifestations, risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed coronavirus disease 2019 (covid-19).
DESIGN: Living systematic review and meta-analysis.
DATA SOURCES: Medline, Embase, Cochrane database, WHO COVID-19 database, China National Knowledge Infrastructure (CNKI), and Wanfang databases from 1 December 2019 to 6 October 2020, along with preprint servers, social media, and reference lists.
STUDY SELECTION: Cohort studies reporting the rates, clinical manifestations (symptoms, laboratory and radiological findings), risk factors, and maternal and perinatal outcomes in pregnant and recently pregnant women with suspected or confirmed covid-19.
DATA EXTRACTION: At least two researchers independently extracted the data and assessed study quality. Random effects meta-analysis was performed, with estimates pooled as odds ratios and proportions with 95% confidence intervals. All analyses will be updated regularly.
RESULTS: 192 studies were included. Overall, 10% (95% confidence interval 7% to 12%; 73 studies, 67 271 women) of pregnant and recently pregnant women attending or admitted to hospital for any reason were diagnosed as having suspected or confirmed covid-19. The most common clinical manifestations of covid-19 in pregnancy were fever (40%) and cough (41%). Compared with non-pregnant women of reproductive age, pregnant and recently pregnant women with covid-19 were less likely to have symptoms (odds ratio 0.28, 95% confidence interval 0.13 to 0.62; I2=42.9%) or report symptoms of fever (0.49, 0.38 to 0.63; I2=40.8%), dyspnoea (0.76, 0.67 to 0.85; I2=4.4%) and myalgia (0.53, 0.36 to 0.78; I2=59.4%). The odds of admission to an intensive care unit (odds ratio 2.13, 1.53 to 2.95; I2=71.2%), invasive ventilation (2.59, 2.28 to 2.94; I2=0%) and need for extra corporeal membrane oxygenation (2.02, 1.22 to 3.34; I2=0%) were higher in pregnant and recently pregnant than non-pregnant reproductive aged women. Overall, 339 pregnant women (0.02%, 59 studies, 41 664 women) with confirmed covid-19 died from any cause. Increased maternal age (odds ratio 1.83, 1.27 to 2.63; I2=43.4%), high body mass index (2.37, 1.83 to 3.07; I2=0%), any pre-existing maternal comorbidity (1.81, 1.49 to 2.20; I2=0%), chronic hypertension (2.0, 1.14 to 3.48; I2=0%), pre-existing diabetes (2.12, 1.62 to 2.78; I2=0%), and pre-eclampsia (4.21, 1.27 to 14.0; I2=0%) were associated with severe covid-19 in pregnancy. In pregnant women with covid-19, increased maternal age, high body mass index, non-white ethnicity, any pre-existing maternal comorbidity including chronic hypertension and diabetes, and pre-eclampsia were associated with serious complications such as admission to an intensive care unit, invasive ventilation and maternal death. Compared to pregnant women without covid-19, those with the disease had increased odds of maternal death (odds ratio 2.85, 1.08 to 7.52; I2=0%), of needing admission to the intensive care unit (18.58, 7.53 to 45.82; I2=0%), and of preterm birth (1.47, 1.14 to 1.91; I2=18.6%). The odds of admission to the neonatal intensive care unit (4.89, 1.87 to 12.81, I2=96.2%) were higher in babies born to mothers with covid-19 versus those without covid-19.
CONCLUSION: Pregnant and recently pregnant women with covid-19 attending or admitted to the hospitals for any reason are less likely to manifest symptoms such as fever, dyspnoea, and myalgia, and are more likely to be admitted to the intensive care unit or needing invasive ventilation than non-pregnant women of reproductive age. Pre-existing comorbidities, non-white ethnicity, chronic hypertension, pre-existing diabetes, high maternal age, and high body mass index are risk factors for severe covid-19 in pregnancy. Pregnant women with covid-19 versus without covid-19 are more likely to deliver preterm and could have an increased risk of maternal death and of being admitted to the intensive care unit. Their babies are more likely to be admitted to the neonatal unit.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178076.
READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 1 of the original article published on 1 September 2020 (BMJ 2020;370:m3320), and previous updates can be found as data supplements (https://www.bmj.com/content/370/bmj.m3320/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 32873575
Leila Karimi, Somayeh Makvandi, Amir Vahedian-Azimi, Thozhukat Sathyapalan, Amirhossein Sahebkar
Effect of COVID-19 on Mortality of Pregnant and Postpartum Women: A Systematic Review and Meta-Analysis.
J Pregnancy. 2021;2021:8870129. doi: 10.1155/2021/8870129. Epub 2021 Mar 5.
Abstract/Text Background: Based on what is known at this time, pregnant women are at an increased risk of severe illness from COVID-19 compared to nonpregnant women. Additionally, pregnant women with COVID-19 might have an increased risk of adverse pregnancy outcomes. To investigate the effects of coronavirus disease 2019 (COVID-19) on mortality of pregnant and postpartum women, we performed a systematic review of available published literature on pregnancies affected by COVID-19.
Methods: Web of Science, SCOPUS, and MEDLINE- databases were searched for original studies concerning the effect of COVID-19 on mortality of pregnant and postpartum women published by July 10, 2020. Meta-analyses of proportions were used to combine data and report pooled proportions.
Results: 117 studies with a total of 11758 pregnant women were included. The age ranged between 15 and 48 years. Most subjects were infected with SARS-CoV-2 in the third trimester. Disease severity was not reported in 1125 subjects. Maternal mortality was 1.3%. In 100% of fatal cases with adequate data, fever alone or with cough was one of the presenting symptoms. Also, dyspnea (58.3%) and myalgia (50%) were the most common symptoms. Sore throat (8.3%) and gastrointestinal symptoms (anorexia, nausea) (8.3%) were rare. The rate of comorbidities was 20% among COVID-19 deaths. The majority of COVID-19-infected women who died had cesarean section (58.3%), 25% had a vaginal delivery, and 16.7% of patients were not full term.
Conclusion: COVID-19 infection in pregnant women was associated with higher rates (and pooled proportions) of cesarean section and mortality. Because new data are continuously being generated and published, the findings of this study can be complete and updated with new researches. The results of this study can guide and improve prenatal counseling of COVID-19-infected pregnant women.

Copyright © 2021 Leila Karimi et al.
PMID 33728066
Wenhua Liang, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li, Qing Ai, Weixiang Lu, Hengrui Liang, Shiyue Li, Jianxing He
Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
Lancet Oncol. 2020 Mar;21(3):335-337. doi: 10.1016/S1470-2045(20)30096-6. Epub 2020 Feb 14.
Abstract/Text
PMID 32066541
Yang Xia, Rui Jin, Jing Zhao, Wen Li, Huahao Shen
Risk of COVID-19 for patients with cancer.
Lancet Oncol. 2020 Apr;21(4):e180. doi: 10.1016/S1470-2045(20)30150-9. Epub 2020 Mar 3.
Abstract/Text
PMID 32142622
Vikas Mehta, Sanjay Goel, Rafi Kabarriti, Daniel Cole, Mendel Goldfinger, Ana Acuna-Villaorduna, Kith Pradhan, Raja Thota, Stan Reissman, Joseph A Sparano, Benjamin A Gartrell, Richard V Smith, Nitin Ohri, Madhur Garg, Andrew D Racine, Shalom Kalnicki, Roman Perez-Soler, Balazs Halmos, Amit Verma
Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System.
Cancer Discov. 2020 Jul;10(7):935-941. doi: 10.1158/2159-8290.CD-20-0516. Epub 2020 May 1.
Abstract/Text Patients with cancer are presumed to be at increased risk from COVID-19 infection-related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19-positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. SIGNIFICANCE: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.This article is highlighted in the In This Issue feature, p. 890.

©2020 American Association for Cancer Research.
PMID 32357994
Masumi Ueda, Renato Martins, Paul C Hendrie, Terry McDonnell, Jennie R Crews, Tracy L Wong, Brittany McCreery, Barbara Jagels, Aaron Crane, David R Byrd, Steven A Pergam, Nancy E Davidson, Catherine Liu, F Marc Stewart
Managing Cancer Care During the COVID-19 Pandemic: Agility and Collaboration Toward a Common Goal.
J Natl Compr Canc Netw. 2020 Mar 20;:1-4. doi: 10.6004/jnccn.2020.7560. Epub 2020 Mar 20.
Abstract/Text The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

PMID 32197238
Anna S Berghoff, Margaretha Gansterer, Arne C Bathke, Wolfgang Trutschnig, Philipp Hungerländer, Julia M Berger, Judith Kreminger, Angelika M Starzer, Robert Strassl, Ralf Schmidt, Harald Willschke, Wolfgang Lamm, Markus Raderer, Alex D Gottlieb, Norbert J Mauser, Matthias Preusser
SARS-CoV-2 Testing in Patients With Cancer Treated at a Tertiary Care Hospital During the COVID-19 Pandemic.
J Clin Oncol. 2020 Aug 14;:JCO2001442. doi: 10.1200/JCO.20.01442. Epub 2020 Aug 14.
Abstract/Text PURPOSE: To analyze the prevalence of SARS-CoV-2 infection in patients with cancer in hospital care after implementation of institutional and governmental safety measurements.
METHODS: Patients with cancer routinely tested for SARS-CoV-2 RNA by nasal swab and real-time polymerase chain reaction between March 21 and May 4, 2020, were included. The results of this cancer cohort were statistically compared with the SARS-CoV-2 prevalence in the Austrian population as determined by a representative nationwide random sample study (control cohort 1) and a cohort of patients without cancer presenting to our hospital (control cohort 2).
RESULTS: A total of 1,688 SARS-CoV-2 tests in 1,016 consecutive patients with cancer were performed. A total of 270 of 1,016 (26.6%) of the patients were undergoing active anticancer treatment in a neoadjuvant/adjuvant and 560 of 1,016 (55.1%) in a palliative setting. A total of 53 of 1,016 (5.2%) patients self-reported symptoms potentially associated with COVID-19. In 4 of 1,016 (0.4%) patients, SARS-CoV-2 was detected. At the time of testing at our department, all four SARS-CoV-2-positive patients were asymptomatic, and two of them had recovered from symptomatic COVID-19. Viral clearance was achieved in three of the four patients 14-56 days after testing positive. The estimated odds ratio of SARS-CoV-2 prevalence between the cancer cohort and control cohort 1 was 1.013 (95% CI, 0.209 to 4.272; P = 1), and between control cohort 2 and the cancer cohort it was 18.333 (95% CI, 6.056 to 74.157).
CONCLUSION: Our data indicate that continuation of active anticancer therapy and follow-up visits in a large tertiary care hospital are feasible and safe after implementation of strict population-wide and institutional safety measures during the current COVID-19 pandemic. Routine SARS-CoV-2 testing of patients with cancer seems advisable to detect asymptomatic virus carriers and avoid uncontrolled viral spread.

PMID 32795227
Savannah Karmen-Tuohy, Philip M Carlucci, Fainareti N Zervou, Ioannis M Zacharioudakis, Gabriel Rebick, Elizabeth Klein, Jenna Reich, Simon Jones, Joseph Rahimian
Outcomes Among HIV-Positive Patients Hospitalized With COVID-19.
J Acquir Immune Defic Syndr. 2020 Sep 1;85(1):6-10. doi: 10.1097/QAI.0000000000002423.
Abstract/Text BACKGROUND: SARS-CoV-2 infection continues to cause significant morbidity and mortality worldwide. Preliminary data on SARS-CoV-2 infection suggest that some immunocompromised hosts experience worse outcomes. We performed a retrospective matched cohort study to characterize outcomes in HIV-positive patients with SARS-CoV-2 infection.
METHODS: Leveraging data collected from electronic medical records for all patients hospitalized at NYU Langone Health with COVID-19 between March 2, 2020, and April 23, 2020, we matched 21 HIV-positive patients with 42 non-HIV patients using a greedy nearest-neighbor algorithm. Admission characteristics, laboratory test results, and hospital outcomes were recorded and compared between the 2 groups.
RESULTS: Although there was a trend toward increased rates of intensive care unit admission, mechanical ventilation, and mortality in HIV-positive patients, these differences were not statistically significant. Rates for these outcomes in our cohort are similar to those previously published for all patients hospitalized with COVID-19. HIV-positive patients had significantly higher admission and peak C-reactive protein values. Other inflammatory markers did not differ significantly between groups, although HIV-positive patients tended to have higher peak values during their clinical course. Three HIV-positive patients had superimposed bacterial pneumonia with positive sputum cultures, and all 3 patients died during hospitalization. There was no difference in frequency of thrombotic events or myocardial infarction between these groups.
CONCLUSIONS: This study provides evidence that HIV coinfection does not significantly impact presentation, hospital course, or outcomes of patients infected with SARS-CoV-2, when compared with matched non-HIV patients. A larger study is required to determine whether the trends we observed apply to all HIV-positive patients.

PMID 32568770
Joni Gilissen, Lara Pivodic, Kathleen T Unroe, Lieve Van den Block
International COVID-19 Palliative Care Guidance for Nursing Homes Leaves Key Themes Unaddressed.
J Pain Symptom Manage. 2020 Aug;60(2):e56-e69. doi: 10.1016/j.jpainsymman.2020.04.151. Epub 2020 May 11.
Abstract/Text COVID-19 mortality disproportionally affects nursing homes, creating enormous pressures to deliver high-quality end-of-life care. Comprehensive palliative care should be an explicit part of both national and global COVID-19 response plans. Therefore, we aimed to identify, review, and compare national and international COVID-19 guidance for nursing homes concerning palliative care, issued by government bodies and professional associations. We performed a directed documentary and content analysis of newly developed or adapted COVID-19 guidance documents from across the world. Documents were collected via expert consultation and independently screened against prespecified eligibility criteria. We applied thematic analysis and narrative synthesis techniques. We identified 21 eligible documents covering both nursing homes and palliative care, from the World Health Organization (n = 3), and eight individual countries: U.S. (n = 7), The Netherlands (n = 2), Ireland (n = 1), U.K. (n = 3), Switzerland (n = 3), New Zealand (n = 1), and Belgium (n = 1). International documents focused primarily on infection prevention and control, including only a few sentences on palliative care-related topics. Palliative care themes most frequently mentioned across documents were end-of-life visits, advance care planning documentation, and clinical decision making toward the end of life (focusing on hospital transfers). There is a dearth of comprehensive international COVID-19 guidance on palliative care for nursing homes. Most have a limited focus both regarding breadth of topics and recommendations made. Key aspects of palliative care, that is, symptom management, staff education and support, referral to specialist services or hospice, and family support, need greater attention in future guidelines.

Copyright © 2020 American Academy of Hospice and Palliative Medicine. All rights reserved.
PMID 32437942

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