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ROCHESTER ACADEMY OF MEDICINE
COVID-19 ARCHIVE
Since emerging in Wuhan, China, in December,2019, the COVID-19 epidemic caused by the novel coronavirus SARS-CoV-2 has progressed rapidly into a true global pandemic. Scientists and doctors are working furiously to address all aspects of this new virus: more than 7,000 papers on the pandemic -- covering everything from virology to pharmacology -- have appeared in the past three months. To assist health care professionals in all disciplines working under these continuously evolving conditions to bring this outbreak to a close, the RAOM has created a curated archive of the most critical publications to emerge from the COVID-19 pandemic to this time. The goal of this resource is to bring together vital COVID-19 content for care providers in a user-friendly, accessible format. To this end, we have assembled the most significant publications, organized by content. To access any publication, copy the DOI and enter it into your browser. The RAOM Archive will be continuously updated with new publications added each week.
For suggestions, questions, please contact: Rae-Ellen W. Kavey, MD, MPH; rekavey@gmail.com.
BRIEF DISEASE OUTBREAK NARRATIVE
On Dec. 1st when the first reported case appeared in Wuhan, China, it might have seemed inconsequential, just one patient with a community-acquired pneumonia of unknown etiology. But Wuhan in Hubei province is a major Chinese commerce and transportation hub with a population of more than 11 million people: disease spread of any contagion was inevitable. By Dec. 31st, there were 26 more hospitalized cases with a similar clinical picture with 6 deaths; two-thirds of the patients had direct contact with a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus. On Dec. 31st, the Wuhan Municipal Health Commission publicly announced the outbreak and alerted the W.H.O.
In the 3 weeks that followed, Wuhan health authorities reported no new information despite identification of the pathogen as a new coronavirus very similar to SARS-CoV by Chinese scientists on January 7th. A Ministry of Health team reported there was no person-to-person transmission and that the outbreak was well controlled after closure of the Huanan market; the outbreak was represented as "preventable and controllable." It was not until definite person-to-person transmission was confirmed with 2019-nCoV cases reported in Thailand and Japan, as well as in Chinese patients with no exposure to the Huanan market that the Ministry of Health confirmed person-to-person transmission -- including multiple cases in local doctors and nurses -- and a national response was finally triggered on January 20. Three days later, on January 23rd, national authorities abruptly placed a complete lockdown on Wuhan, eliminating all forms of transportation and effectively sealing off the city. But by then, an estimated 5 million people had already left the city. By January 25th, confirmed cases in mainland China stood at 2,016 and there were already reported cases, all linked to Wuhan by travel or contact, throughout Asia and in Australia, France, the United States and Sweden.
The W.H.O. convened an advisory Emergency Committee and on January 30, they concluded the outbreak had become a Public Health Emergency of International Concern. On February 5, W.H.O. announced a $675 million 2019-nCoV preparedness plan to coordinate the international response. At a “Global Research and Innovation Forum” to mobilize international action on Feb. 11-12, the W.H.O. Director-General announced that the illness caused by 2019-nCoV now had an official name: COVID-19; and the International Committee on Taxonomy of Viruses proposed SARS-CoV-2 as the official name for 2019-nCoV.
National and international efforts to slow spread of the epidemic proved fruitless. By Feb. 28, COVID-19 had been reported in 47 countries, with >84,124 cases and 2,862 deaths. On that day, China reported 327 new cases but South Korea with a total of 2337 cases -- the largest number outside of China -- reported 511 new cases. There were increasing numbers of cases in northern Italy, in Iran and in Japan. And there were cases in three different countries in Africa. At this stage, it was obvious that early Chinese suppression of knowledge about the outbreak had squandered a critical window of opportunity to limit spread of the virus: a true global pandemic was underway.
Home.Tan W, Zhao X, Ma X, et al. A novel coronavirus genome identified in a cluster of pneumonia cases—Wuhan, China 2019−2020. China CDC Weekly 2020; 2: 61–62.
Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382:727-33. Published online Jan 24. DOI:10.1056/NEJMoa2001017
· Researchers at the China Center for Disease Control investigating the cause of infection in 3 adults with pneumonia of unknown etiology definitively identified a novel coronavirus from broncho-alveolar lavage specimens using whole-genome sequencing, direct polymerase chain reaction (PCR), and culture on January 7,2020.
· The 2019-nCoV virus -- now officially known as SARS-CoV-2 -- is physically large among viruses, measuring 125 nanometers in diameter, covered with spiky projections -- the surface spike glycoprotein is critical for binding to host cell receptors and is believed to represent a key determinant of host range restriction.
· By phylogenetic analysis, the previously unknown virus fell into the betacoronavirus genus, which includes SARS-CoV, MERS-CoV, and a bat SARS-like coronavirus.
· Novel coronavirus was named 2019-nCoV and formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily.
(Coronaviruses are enveloped non-segmented positive-sense RNA viruses belonging to the family Coronaviridae and the order Nidovirales and are broadly distributed in humans and other mammals. Coronaviruses are ecologically diverse with the greatest variety seen in bats, the suggested reservoir for these viruses. An important CoV factor is their ability to expand their genetic diversity through ongoing recombination and mutation events. Four CoVs are endemic globally and cause 10% to 30% of mild upper respiratory tract infections in adults. Although most human coronavirus infections are mild, SARS-CoV and MERS-CoV have caused more than 10 000 cumulative cases of severe respiratory disease in the past two decades, with mortality rates of 10% for SARS and 37% for MERS.
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Roujian Lu, Xiang Zhao, Juan Li et al. Genomic characterization & epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395: 565–74. DOI: https://doi.org/10.1016/S0140-6736(20)30251-8
· Next-generation sequencing of samples from bronchoalveolar lavage fluid from 9 pts with SARS-CoV-2 infection; 8/9 had visited the Huanan seafood market in Wuhan
· Genome sequences were extremely similar, exhibiting >99·98% sequence identity.
· By phylogenetic analysis, 2019-nCoV was most closely related (88% identity) to 2 bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 & bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China; virus is more distant from SARS-CoV (~79%) and MERS-CoV (~ 50%).
· Homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.
· Bats might be the original host of this virus with an animal from the seafood market representing an intermediate host facilitating the emergence of the virus in humans.
· Structural analysis suggests that 2019-nCoV may bind to the angiotensin converting enzyme 2 receptor in humans.
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South China Agricultural University finds pangolin as a potential intermediate host for new coronavirus. Published Jan. 20,2020. Available at: flutrackers.com › -2019-ncov-new-coronavirus › china-2019-ncov.
· The chief suspect for intermediate host between bats and humans for SARS-C0V-2 is the pangolin, a small ant-eating creature.
· Pangolins are prized in Asia as food and medicine and were being sold in the Wuhan Huanan seafood and wild animal market, linked to early cases of 2019-nCoV
· The genome sequence of the novel coronavirus strain derived from pangolins is 99% identical to SARS-CoV-2.
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Paraskevisa D, Kostakia G, Magiorkinisa G et al. Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event. Infection, Genetics and Evolution 2020; 79. April 20, 2020. https://doi.org/10.1016/j.meegid.2020.104212
· Full-genomic sequence analysis of the novel corona virus (2019-nCoV).
· Phylogenetic and recombination analysis within the subgenus of sarbecovirus.
· Evidence that the 2019-nCoV shows discordant clustering with the BatSARS-like coronavirus sequences.
· No evidence that 2019-CoV 2 emerged as a result of a recent recombination event.
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vanDorp L, Acman M, Richard D et al. Emergence of genomic diversity and recurrent mutations in SARS-CoV-2. Infection, Genetics and Evolution (2019). https://doi.org/10.1016/j.meegid.2020.
· Curating a dataset of 7666 public genome SARS-CoV-2 assemblies allowed analysis of the emergence of genomic diversity over time.
· Results point to all sequences sharing a common ancestor towards the end of 2019, supporting this as the period when SARS-CoV-2 jumped to its human host.
· Due to extensive transmission, the genetic diversity of the virus in several countries recapitulates a large fraction of its worldwide genetic diversity.
· By focusing on mutations which have emerged independently multiple times,198 filtered recurrent mutations in the SARS-CoV-2 genome were identified.
· Nearly 80% of recurrent mutations produced non-synonymous changes at the protein level, suggesting possible ongoing adaptation of SARS-CoV-2.
Zheng S, Fan J, Yu F et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020 Apr 21;369:m1443. doi: 10.1136/bmj.m1443.
Wölfel R, Corman VM, Guggemos W et al. Virologic assessment of hospitalized patients with COVID-2019. Nature. 2020 Apr 1. doi: 10.1038/s41586-020-2196-x
CHINA
Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. Published online on Jan. 24, 2020. doi:10.1016/S0140-6736(20)30183-5.
Case series of the first 41 hospitalized pts infected with 2019-nCoV by Jan 2, 2020:
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Chan JF-W, Yuan S, Kok K-H et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020 Jan 24; [e-pub]. https://doi.org/10.1016/S0140-6736(20)30154-9.
Confirmation of person-to-person transmission.
WHO. Daily media briefing on #2019-nCoV. Feb. 7, 2020. Available at: www.who.int/ Coronavirus disease 2019 › Media resources.
In clinical series of culture (+) pts from China, 82% have had mild symptoms, 15% severe, 3% critical.
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Li Q, Guan X, Wu P et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N Engl J Med. Published January 29, 2020.https://www.nejm.org/doi/full/10.1056/NEJMoa2001316
Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020. Published January 30,2020. https://doi.org/10.1016/S0140-6736(20)30211-7.
Wang D, Hu B, Hu C et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. Published online February 7, 2020. http://doi:10.1001/jama.2020.1585.
3 early published series of laboratory-confirmed, hospitalized cases from Wuhan à
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To KK, Tsang OT, Leung WS et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23. pii: S1473-3099(20)30196-1. doi: 10.1016/S1473-3099(20)30196-1.
Serial respiratory viral load of SARS-CoV-2 in posterior oropharynx saliva samples and serum antibody responses from 23 patients with COVID-19 showed highest viral load at presentation and during the first week of illness with subsequent decline over time.
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Zheng S, Fan J, Yu F et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020 Apr 21;369:m1443. doi:10.1136/bmj.m1443.
USA
Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382; 10: 929-936. DOI: 10.1056/NEJMoa2001191
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Wölfel R, Corman VM, Guggemos W et al. Virologic assessment of hospitalized patients with COVID-2019. Nature. 2020 Apr 1. doi: 10.1038/s41586-020-2196-x
Detailed virologic analysis of nine cases of COVID-19 showed active replication of the SARS-CoV-2 virus in tissues of the throat /upper respiratory tract à Confirmation of early contagious state due to active pharyngeal viral shedding.
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Sutton D, Fuchs K, D’Alton M, Goffman D. Universal screening for SARS-CoV-2 in women admitted for delivery. N Engl J Med April 13, 2020. DOI: 10.1056/NEJMc2009316
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Eliezer M, Hautefort C, Hamel A-L et al. Sudden and Complete Olfactory Loss Function as a Possible Symptom of COVID-19. JAMA Otolaryngol Head Neck Surg. Published online April 8, 2020. doi:10.1001/jamaoto.2020.0832
Case report of sudden loss of olfactory function due to COVID-19 infection with bilateral obstructive inflammation of olfactory clefts on imaging, which severely impaired the olfactory function by preventing odorant molecules from reaching the olfactory epithelium.
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Oxley TJ, Mocco J, Majidi S et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. Correspondence. N Engl J Med: April 28, 2020 DOI: 10.1056/NEJMc2009787
Case series of 5 COVID-19 pts < 60 yrs whose initial disease presentation was a large vessel ischemic stroke. All presented in NYC in March and early April. Mixed picture of coagulopathy in the group. 5% of Wuhan pts experienced stroke as part of their illness. Further knowledge pending.
FRANCE
Poissy J, Goutay J, Caplan M et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation 2020. Originally published 24 Apr 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.047430
Case-series of 107 consecutive COVID-19 ICU pts with pneumonia admitted to a tertiary care center in northern France. 22/107(20.6%) developed a pulmonary embolus (PE) within a median of 6 days (range 1 to 18 days) from ICU admission. Frequency of PE in COVID-19 series was twice as high as comparison group of ICU pts with pneumonia (20.6% vs 6.1%; absolute increase risk of 14.4%, 95%CI 6.1 to 22.8%). At PE diagnosis, 20/22 patients were receiving prophylactic antithrombotic treatment. Of note, median BMI of PE pts was 30 (range:22-53). No additional information provided.
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USA – NYC
Richardson S, Hirsch JS, Narasimhan M et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775
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Petrelli CM, Jones SA, Yang J et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. medRxiv 2020. doi: https://doi.org/10.1101/2020.04.08.20057794
ITALY
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Grasselli G, Zangrillo A, Zanella A et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394
Retrospective case series of all 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the COVID-19 Lombardy ICU Network and treated at one of the 72 ICUs in this network between 2/2/2020 3/18/2020. and March 18, 2020. Median (IQR) age was 63 (56-70) years, 82% male. 68% had > comorbidity & 49% had hypertension. 99% (1287/1300 patients) required respiratory support, including endotracheal intubation in 88% and noninvasive ventilation in 11%; ICU mortality was 26%.
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To KK, Tsang OT, Leung WS et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23. pii: S1473-3099(20)30196-1. doi: 10.1016/S1473-3099(20)30196-1.
Serial respiratory viral load of SARS-CoV-2 in posterior oropharynx saliva samples and serum antibody responses from 23 patients with COVID-19 showed highest viral load at presentation and during the first week of illness with subsequent decline over time.
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Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med.2020. DOI: 10.1056/NEJMoa2008457.
à Infection-control strategies focused solely on symptomatic individuals are not sufficient to prevent transmission of this very highly contagious virus after SARS-CoV-2 introduction into this kind of facility.
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Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. Published online on Jan. 24, 2020. doi:10.1016/S0140-6736(20)30183-5.
Case series of the first 41 hospitalized pts infected with 2019-nCoV by Jan 2, 2020
àTwo-thirds of patients had worked or shopped at a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus.
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Progress continues in coronavirus trace: Wuhan Market Cultures. By Wang Xiaodong | chinadaily.com.cn Updated: 2020-01-26 14:26.
China Center for Disease Control reported on January 26th that of 585 collected samples from the Huanan market, 33 tested positive for the virus. The 33 samples came from 22 stalls and a garbage vehicle in the market, most in the area where wild animals were traded. Further public results of this investigation are still pending.
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Chan JF-W, Yuan S, Kok K-H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020 January 24 (Epub ahead of print ) DOI: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa077/5739751
First formal report of person-to-person transmissibility in China.
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Zhao S, Lin Q, Ran J et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Inter J Inf Dis 2020. Published online 30 January 2020. https://doi.org/10.1016/j.ijid.2020.01.050.
Early estimates of the basic reproduction number or R0 for SARS-CoV-2 ranged from 2.2 to 3.6.
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Li Q, Guan X, Wu P et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N Engl J Med. Published January 29, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2001316
Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020. Published January 30,2020. https://doi.org/10.1016/S0140-6736(20)30211-7
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Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382; 10: 929-936. DOI: 10.1056/NEJMoa2001191
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Gonzalez-Reiche AS, Hernandez MM, Sullivan M et al. Introductions and early spread of SARS-CoV-2 in the New York City area. medRxiv 2020. doi: https://doi.org/10.1101/2020.04.08.20056929
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Millett GA, Jones AT, Benkeser D et al. Assessing Differential Impacts of COVID-19 on Black Communities. Manuscript under review - JAMA.
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Sadoughi S, Saltz R. Pediatric multisystem inflammatory syndrome. NEJM Journal Watch. May 5, 2020.
At least 64 children in New York state, primarily in NYC and on Long Island, New York, have developed a multisystem inflammatory syndrome related to COVID-19, the New York Times reports. The cases first emerged about a month after a surge in COVID-19 in the region, suggesting "it's a post-infectious immune response," one pediatrician said. Most cases have tested positive either for SARS-CoV-2 or for antibodies to the virus. The syndrome includes persistent fever and features of Kawasaki disease or toxic shock but it is definitively not KD. Many of the children have been admitted to intensive care, where they've received cardiac or respiratory support. None have died. U.K. health officials last week warned clinicians to be on the lookout for this syndrome. The Times notes that cases have also been reported elsewhere in the U.S.
Shen C, Wang Z, Zhao F et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma: Preliminary Communication. JAMA 2020;323(16): 1582-1589. doi:10.1001/jama.2020.4783.
Uncontrolled case series of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS) with multiple indicators of disease severity received donor convalescent plasma containing neutralizing antibody. Clinical status and all measures of disease severity improved beginning within 3 days and 3 pats were extubated between 2 and 9 days post infusion.
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News Release. NIH – NIAID. April 29, 2020. NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.
Hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to preliminary data analysis from a RCT involving 1063 pts, which began on 2/21/20. Pts who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for pts treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059). More detailed trial results are forthcoming. The trial known as the Adaptive COVID-19 Treatment Trial, or ACTT involved 68 sites, 47 in the U.S. and 21 in countries in Europe and Asia. Remdesivir, developed by Gilead Sciences Inc., is an investigational broad-spectrum antiviral treatment administered via daily infusion for 10 days. Published report pending.
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Magagnoli J, Narendran S, Pereira F et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv 2020. https://doi.org/10.1101/2020.04.16.20065920
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Chloroquine, Hydroxychloroquine Likely Ineffective For COVID-19. CONTAGION Review: Rachel Lutz. April 30, 2020. (Publication pending)
Chloroquine and hydroxychloroquine likely are not effective against the novel coronavirus, according to a paper published in the May issue of The FASEB Journal. Investigators from Harvard Medical School and Mass General conducted a comprehensive literature review of clinical experiences with chloroquine and hydroxychloroquine. Data through April 22 showed that these drugs reduced viral uptake by cells cultured in a lab but not in patients. The drugs prevent the immune system from completing its vital response to viruses, investigators wrote. The drugs also disrupt the cell-mediated immunity that is critical to controlling a viral outbreak such as the one the world is currently facing. There is a need for caution if using these therapies to treat the coronavirus based solely on the results of lab studies and not human trials. “Current trial results involving chloroquine and hydroxychloroquine are leading to a rapidly diminishing view of their utility for COVID-19.”
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Borba MGS, Almeida-Val FF, Sampaio VS et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Network Open 2020;3(4):e208857. April 24, 2020. doi:10.1001/jamanetworkopen.2020.8857
In this phase IIb randomized clinical trial of 81 pts with COVID-19, an unplanned interim analysis by an independent data safety and monitoring board found that the higher dosage of chloroquine diphosphate was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation. The limited sample size did not show any benefit regarding treatment efficacy. The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloroquine should not be used for treatment of severe COVID-19 because of safety concerns regarding QTc interval prolongation and increased lethality.
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Richardson P, Griffin I Tucker C et al. Baracitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020; 395:e30-e31. February 3, 2020. https://doi.org/10.1016/S0140-6736(20)30304-4.
Application of a proprietary, AI-derived knowledge graph queried by a suite of 2019-CoV derived algorithms enabled identification of a potential therapeutic agent. Baracitinib is an already approved anti-arthritic drug with known antiviral and anti-inflammatory properties which has the potential to inhibit the cellular processes used by the virus in cell infection and to inhibit potential cytokine storm. Investigator-led studies have been underway since March with a large randomized trial beginning on April 14 in conjunction with Eli Lilly and NIH-USAID. Results anticipated within 2 months.
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Paranjpe I, Fuster V, Lala A et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. J Amer Coll Cardiol 2020. May 2020. DOI: 10.1016/j.jacc.2020.05.001
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Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; E-published ahead of print, April 30, 2020. https://doi.org/10.1038/s41586-020-2286-9.
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AHJ Danser, M Epstein, D Batlle. Renin-angiotensin system blockers and the COVID-19 pandemic: At present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020 Mar 25;[EPub Ahead of Print], DOI: 10.1161/HYPERTENSIONAHA.120.15082
The angiotensin-converting enzyme 2 (ACE2) protein facilitates the entry of coronavirus-2 into cells. ACE inhibitors do not impact ACE2 as ACE and ACE2 are distinct enzymes. There are no data to support the hypothesis that ACE inhibitors or angiotensin II type 1 receptor blockers increase ACE2 expression and hence increase coronavirus entry. Current evidence does not support the discontinuation of ACE inhibitor treatment due to concerns regarding coronavirus infection.
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PREPREVENTION: VACCINE DEVELOPMENT (There are at least 108 vaccines in development as of 5/8/2020, 8 in clinical trials)
Lane R. Carving a path towards a COVID-19 vaccine. Lancet April 18, 2020; 395:1247. DOI: https://doi.org/10.1016/S0140-6736(20)30796-0
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Gao Q, Bao L, Mao H et al.Rapid development of an inactivated vaccine for SARS-CoV-2. bioRxiv 2020. https://doi.org/10.1101/2020.04.17.046375
[To quickly obtain phase 2 & 3 data, investigators may ask regulatory agencies in multiple countries for emergency authorization to give the vaccine to high risk individuals. The DRC in 2018 began to widely use an experimental Ebola vaccine under that status and evidence suggests it significantly helped curb that epidemic.]
Kissler SM, Tedijanto C, Goldstein E, et al. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 2020 Apr 14. doi: 10.1126/science.abb5793. [Epub ahead of print.]
Theoretical transmission dynamics based on modelling including possible contributions of seasonality, duration of immunity, and cross-protection from prior infection with other beta-coronaviruses in common circulation (HKU1 and OC43). Scenarios assess the effects of the length (short=4 weeks to indefinite) & strength (0–60% reductions in Ro) of social distancing.
Baseline seasonality and immunity info:
Modeling results: Social distancing without seasonality:
Social distancing + seasonality:
(There are many reported theoretical models of disease transmission dynamics going forward – these will be added as they are published.)
COVID-19 UPDATE May/June/July/August 2020
THE VIRUS
Wajnberg A, Mansour M, Leven E et al. Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. region. medRxiv 2020. May 5, 2020. doi: https://doi.org/10.1101/2020.04.30.20085613
· Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of 21 anti SARS-CoV-2 spike antibodies.
· Of the 1,343 total participants, almost all were outpatients who had experienced mild to moderate symptoms; only 3% were seen in the ED or hospital
Zhang L, Jackson CB, Mou H et al. The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. BioRxiv: Posted 6/12/2020. doi: https://doi.org/10.1101/2020.06.12.148726
· In SARS-C0V-2, the spike (S) protein mediates receptor binding and fusion of the viral and host cellular membrane via 2 domains: S1 which mediates receptor binding & S2 which mediates downstream membrane fusion.
· Over time, SARS-CoV-2 isolates encoding a D614G mutation in the viral spike (S) protein were found to predominate, implying that this change enhanced viral transmission. The G614 genotype was not detected in February and observed at low frequency in March (26%) but increased rapidly by April (65%) and May (70%).
· Researchers studying both versions of the gene using a proxy virus in a petri dish of human cells showed that G variant viruses had more & more stable spike proteins.
· Retroviruses pseudo-typed with SG614 infected ACE2-expressing cells 9X more efficiently than those with SD614 & this greater infectivity was correlated with less S1 shedding and greater incorporation of the S protein into the pseudo-virion.
· àSG614 is more stable than SD614, consistent with epidemiological data suggesting that viruses with SG614 transmit more efficiently.
· The pseudo-viruses containing these S proteins were neutralized with comparable efficiencies by convalescent plasma suggesting that vaccines based on the original version of the virus will be effective against the new strain.
Ibarrondo FJ, Fulcher JA, Goodman-Meza D et al. Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19. N Engl J Med 2020; Published July 21, 2020. DOI: 10.1056/NEJMc2025179
· Antibody evaluation of 34 persons who had recovered from Covid-19 infection confirmed by PCR assay in 30/34; typical symptoms of Covid-19 + cohabitation with Covid-19 (+) individuals in remaining 4.
· Most had mild illness; 2 received low flow O2 + leronlimab (a CCR5 antagonist).
· Mean age: 43 years (range, 21 to 68); 20 women/14 men.
· Samples were analyzed by ELISA to detect anti–SARS-CoV-2 spike receptor-binding domain IgG + modified ELISA to quantify serum anti–receptor-binding domain activity relative to control anti–receptor-binding domain monoclonal IgG.
· 31/34 participants had 2 serial measurements of IgG levels, 3 participants had 3.
· The first measurement was obtained a mean of 37 days after the onset of symptoms (range, 18 to 65), and the last measurement was obtained at a mean of 86 days after the onset of symptoms (range, 44 to 119).
· On the basis of a linear regression model, the antibody half-life averaged 36 days.
· Antibody loss was faster than that reported for SARS-CoV-1
· Findings raise concern that humoral immunity against SARS-CoV-2 may not be long lasting in persons with mild illness.
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Griffoni A, Weiskopf D, Ramirez SI et al. Targets of T cell responses to SARS-CoV-2 in humans wth COVID-19 and unexposed individuals. Cell 2020; 181(7). June 25,2020. DOI:https://doi.org/10.1016/j.cell.2020.05.015D
· Measuring immunity to SARS-CoV-2 is key for understanding COVID-19 and vaccine development
· Epitope pools detect CD4+ and CD8+ T cells in 100% and 70% of convalescent COVID patients
· T cell responses are focused not only on spike but also on M, N, and other proteins.
· T cell reactivity to SARS-CoV-2 epitopes is also detected in non-exposed individuals suggesting prior, unrecognized exposure to other CoVs.
**********
Braun, J., Loyal, L., Frentsch, M. et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature (2020). https://doi.org/10.1038/s41586-020-2598-9and patients with COVID-19. Nature (2020)
· SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells assessed in peripheral blood of COVID-19 pts & SARS-CoV-2-unexposed healthy blood donors (HD).
· SARS-CoV-2 S-reactive CD4+ T cells were detected in 83% of pts with COVID-19 but also in 35% of HD.
· S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and to SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses.
· The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts. However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.
· CONCLUSION: 83% of pts with COVID-19 were found to have CD4+ T cells reactive against SARS-CoV-2; 35% of unexposed healthy donors were also found to possess these immune cells.
**********
Chen M, Shen W, Rowan NR, et al. Elevated ACE2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.01948-2020).
· SARS-CoV-2 infection often presents with olfactory loss without nasal inflammatory symptoms, suggesting direct targeting of the olfactory system.
· The cellular location of ACE2 protein in the olfactory epithelium has not been previously demonstrated.
· In this study, we performed immunohistological analyses to determine the location of ACE2 protein in human nasal and tracheal specimens in 23 pts undergoing biopsy for non-SARS-C0V-2 problems.
· Results: ACE2 protein is expressed at high levels in the human olfactory epithelium relative to upper airway epithelial cells, evidence that the upper, rather than the lower, airway is the initial site of SARS-CoV-2 infection.
· Findings may explain COVID-19-associated olfactory dysfunction, while suggesting a SARS-CoV-2 reservoir site and potential intranasal therapy.
**********
Lemieux J, Siddle KJ, Shaw BM et al. Phylogenetic analysis of SARS-CoV-2 in the Boston area highlights the role of recurrent importation and superspreading events. medRxiv 2020.08.23.20178236; doi: https://doi.org/10.1101/2020.08.23.20178236
· Detailed viral genome sequencing & phylogenetic analysis of a Boston area SARS-CoV-2 epidemic using NP samples collected from 1/29/2020 – 5/9/2020.
· Phylogenetic tree constructed from this dataset in the context of a global set of 4,011 genomes from the Global Initiative on Sharing All Influenza Data (GISAID).
· Root-to-tip regression showed a clear, temporal signal in our dataset, with the fitted regression model accounting for 17% of the variance in the root-to-tip distance. The presence of a temporal signal means that a molecular clock can be fitted to infer the timing of ancestral branching based on SARS-CoV-2 genomes.
· First large cluster of cases was recognized in the context of an international business conference held in Boston from 2/26 – 27 with >90 cases diagnosed in conference attendees or their contacts, raising suspicion of a superspreading event.
· Dataset containing SARS-CoV-2 genomes from 28 of these cases, allowed search for genetic evidence of superspreading in the form of phylogenetic clustering of identical/highly similar viruses in a narrow time window àall 28 genomes formed a well-supported monophyletic cluster marked by the presence of the SNP C2416T, first seen in the GISAID database in 2 French pts on 2/29/2020 àall 27 US C2416T-containing viruses collected before 3/10 were from conference exposures.
· This strongly suggests there was low-level community transmission of C2416T in Europe in 2/2020 before the allele was introduced to Boston via a single introduction and amplified by superspreading at the conference.
· SARS-CoV-2 containing C2416T allele subsequently spread extensively in the Boston area, representing 35.1% of our dataset. Beginning in early March, C2416T appeared in multiple other US states & other countries & increased steeply in frequency, comprising 2.7% of domestic & 1.7% of global SARS-CoV-2 genomes in GISAID through 6/28 à ultimately, >20,000 cases spread from this 1 conference.
· Single introduction had an outsize effect because it was amplified by superspreading in a highly mobile population very early in the outbreak, before precautions were in place & when its effects were amplified by exponential growth.
· This is direct evidence that superspreading events may profoundly alter the course of an epidemic & implies that prevention, detection & mitigation of such events should be a public health priority.
**********
THE DISEASE
Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med.2020. 5/28/2020. DOI: 10.1056/NEJMoa2008457.
à Infection-control strategies focused solely on symptomatic individuals are not sufficient to prevent transmission of this very highly contagious virus after SARS-CoV-2 introduction into this kind of facility.
**********
Ackermann M, Verleden SE, Kuehnel M. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. New Engl J Med 2020; May 21, 2020 DOI: 10.1056/NEJMoa2015432
**********
Toubiana J, Poirault C, Corsia A et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ 2020;369:m2094. Published online, 6/2/2020. http://dx.doi.org/10.1136 bmj.m2094
**********
McGuinness G, Zhan C, Rosenberg N et al. High Incidence of Barotrauma in Patients with COVID-19 Infection on Invasive Mechanical Ventilation. Radiology 2020; Published Online: Jul 2 2020. https://doi.org/10.1148/radiol.2020202352
***********
Davies, N.G., Klepac, P., Liu, Y et al. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat Med (2020). Published 6/16/2020. https://doi.org/10.1038/s41591-020-0962-9
**********
Nicolai L, Leunig A, Brambs S, et al. Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy. Circulation. 2020 Jul 28. doi: 10.1161/CIRCULATIONAHA.120.048488. Online ahead of print. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048488
**********
Yonker LM, Neilan AM, Bartsch Y et al. Pediatric SARS-CoV-2: Clinical Presentation, Infectivity, and Immune Responses. The Journal of Pediatrics (2020). doi: https://doi.org/10.1016/j.jpeds.2020.08.037.
**********
Del Valle, D.M., Kim-Schulze, S., Huang, H. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med (2020). Aug. 24,2020. https://doi.org/10.1038/s41591-020-1051-9
· A hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death.
· A rapid multiplex cytokine assay was used to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in 1484 hospitalized patients with COVID-19 on admission to the Mount Sinai Health System in New York from 3/21-4/28/2020.
· Pts (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected.
· Cutoffs chosen for further statistical analyses were >70 pg ml−1 for IL-6, >50 pg ml−1 for IL-8, >35 pg ml−1 for TNF-α and >0.5 pg ml−1 for IL-1β.
· Men had significantly higher levels of IL-6 than women (P < 0.0001), but no sex differences were observed for the other three cytokines.
· With increasing age brackets (<50, 50–70 and >70 years old), levels of IL-6, IL-8 and TNF-α increased.
· CKD was the only other comorbidity significantly associated with elevated cytokine levels
· RESULTS: High serum IL-6, IL-8 and TNF-α levels at hospitalization were strong and independent negative predictors of patient survival by Cox regression analysis. (P < 0.0001, P = 0.0205 and P = 0.0140, respectively).
· After adjustment for demographics and comorbidities, only age (50–70 versus <70 years, hazard ratio (HR) = 2.09 (1.25–3.49); >70 versus <50 years, HR = 3.76 (2.24–6.33)), IL-6 (HR = 2.23 (1.61–3.09)), IL-8 (HR = 1.41 (1.05–1.89)) and TNF-α (HR = 1.50 (1.09–2.07)) remained significantly associated with decreased survival (P = 0.0049, P < 0.0001, P = 0.0205 and P = 0.0140, respectively).
· CONCLUSION: After adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death.
PREVENTION/ TRANSMISSION
Chan JF-W, Yuan DS, Zhang AJ et al. Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19). Clinical Infectious Diseases: Published: 30 May 2020 https://doi.org/10.1093/cid/ciaa644
**********
Shen y, Li C, Dong H et al. Community Outbreak Investigation of SARS-CoV-2 Transmission Among Bus Riders in Eastern China. JAMA Intern Med. Published online September 1, 2020. doi:10.1001/jamainternmed.2020.5225
TREATMENT
Gharbharan A, Jordans CCE, Geurtsvan-Kessel C et al. Convalescent Plasma for COVID-19. A randomized clinical trial. medRxiv 2020.07.01.20139857. doi: https://doi.org/10.1101/2020.07.01.20139857
**********
Mather JF, et al. Impact of famotidine use on clinical outcomes of hospitalized COVID-19 patients. Am J Gastroenterol; August 14, 2020.
The Writing Committee for the REMAP-CAP Investigators. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17022
Tomazini BM , Maia IS , Cavalcanti AB , et al; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17021
Dequin PF , Heming N , Meziani F , et al; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16761
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17023
COVID-19 UPDATE May- October/ 2020
THE VIRUS
Wajnberg A, Mansour M, Leven E et al. Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. region. medRxiv 2020. May 5, 2020.
doi: https://doi.org/10.1101/2020.04.30.20085613
· Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of 21 anti SARS-CoV-2 spike antibodies.
· Of the 1,343 total participants, almost all were outpatients who had experienced mild to moderate symptoms; only 3% were seen in the ED or hospital
Zhang L, Jackson CB, Mou H et al. The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. BioRxiv: Posted 6/12/2020. doi: https://doi.org/10.1101/2020.06.12.148726
· In SARS-C0V-2, the spike (S) protein mediates receptor binding and fusion of the viral and host cellular membrane via 2 domains: S1 which mediates receptor binding & S2 which mediates downstream membrane fusion.
· Over time, SARS-CoV-2 isolates encoding a D614G mutation in the viral spike (S) protein were found to predominate, implying that this change enhanced viral transmission. The G614 genotype was not detected in February and observed at low frequency in March (26%) but increased rapidly by April (65%) and May (70%).
· Researchers studying both versions of the gene using a proxy virus in a petri dish of human cells showed that G variant viruses had more & more stable spike proteins.
· Retroviruses pseudo-typed with SG614 infected ACE2-expressing cells 9X more efficiently than those with SD614 & this greater infectivity was correlated with less S1 shedding and greater incorporation of the S protein into the pseudo-virion.
· àSG614 is more stable than SD614, consistent with epidemiological data suggesting that viruses with SG614 transmit more efficiently.
· The pseudo-viruses containing these S proteins were neutralized with comparable efficiencies by convalescent plasma suggesting that vaccines based on the original version of the virus will be effective against the new strain.
Ibarrondo FJ, Fulcher JA, Goodman-Meza D et al. Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19. N Engl J Med 2020; Published July 21, 2020. DOI: 10.1056/NEJMc2025179
· Antibody evaluation of 34 persons who had recovered from Covid-19 infection confirmed by PCR assay in 30/34; typical symptoms of Covid-19 + cohabitation with Covid-19 (+) individuals in remaining 4.
· Most had mild illness; 2 received low flow O2 + leronlimab (a CCR5 antagonist).
· Mean age: 43 years (range, 21 to 68); 20 women/14 men.
· Samples were analyzed by ELISA to detect anti–SARS-CoV-2 spike receptor-binding domain IgG + modified ELISA to quantify serum anti–receptor-binding domain activity relative to control anti–receptor-binding domain monoclonal IgG.
· 31/34 participants had 2 serial measurements of IgG levels, 3 participants had 3.
· The first measurement was obtained a mean of 37 days after the onset of symptoms (range, 18 to 65), and the last measurement was obtained at a mean of 86 days after the onset of symptoms (range, 44 to 119).
· On the basis of a linear regression model, the antibody half-life averaged 36 days.
· Antibody loss was faster than that reported for SARS-CoV-1
· Findings raise concern that humoral immunity against SARS-CoV-2 may not be long lasting in persons with mild illness.
**********
Griffoni A, Weiskopf D, Ramirez SI et al. Targets of T cell responses to SARS-CoV-2 in humans wth COVID-19 and unexposed individuals. Cell 2020; 181(7). June 25,2020. DOI:https://doi.org/10.1016/j.cell.2020.05.015D
· Measuring immunity to SARS-CoV-2 is key for understanding COVID-19 and vaccine development
· Epitope pools detect CD4+ and CD8+ T cells in 100% and 70% of convalescent COVID patients
· T cell responses are focused not only on spike but also on M, N, and other proteins.
· T cell reactivity to SARS-CoV-2 epitopes is also detected in non-exposed individuals suggesting prior, unrecognized exposure to other CoVs.
**********
Braun, J., Loyal, L., Frentsch, M. et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature (2020). https://doi.org/10.1038/s41586-020-2598-9and patients with COVID-19. Nature (2020)
· SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells assessed in peripheral blood of COVID-19 pts & SARS-CoV-2-unexposed healthy blood donors (HD).
· SARS-CoV-2 S-reactive CD4+ T cells were detected in 83% of pts with COVID-19 but also in 35% of HD.
· S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and to SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses.
· The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts. However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.
· CONCLUSION: 83% of pts with COVID-19 were found to have CD4+ T cells reactive against SARS-CoV-2; 35% of unexposed healthy donors were also found to possess these immune cells.
**********
Chen M, Shen W, Rowan NR, et al. Elevated ACE2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.01948-2020).
· SARS-CoV-2 infection often presents with olfactory loss without nasal inflammatory symptoms, suggesting direct targeting of the olfactory system.
· The cellular location of ACE2 protein in the olfactory epithelium has not been previously demonstrated.
· In this study, we performed immunohistological analyses to determine the location of ACE2 protein in human nasal and tracheal specimens in 23 pts undergoing biopsy for non-SARS-C0V-2 problems.
· Results: ACE2 protein is expressed at high levels in the human olfactory epithelium relative to upper airway epithelial cells, evidence that the upper, rather than the lower, airway is the initial site of SARS-CoV-2 infection.
· Findings may explain COVID-19-associated olfactory dysfunction, while suggesting a SARS-CoV-2 reservoir site and potential intranasal therapy.
**********
Lemieux J, Siddle KJ, Shaw BM et al. Phylogenetic analysis of SARS-CoV-2 in the Boston area highlights the role of recurrent importation and superspreading events. medRxiv 2020.08.23.20178236; doi: https://doi.org/10.1101/2020.08.23.20178236
· Detailed viral genome sequencing & phylogenetic analysis of a Boston area SARS-CoV-2 epidemic using NP samples collected from 1/29/2020 – 5/9/2020.
· Phylogenetic tree constructed from this dataset in the context of a global set of 4,011 genomes from the Global Initiative on Sharing All Influenza Data (GISAID).
· Root-to-tip regression showed a clear, temporal signal in our dataset, with the fitted regression model accounting for 17% of the variance in the root-to-tip distance. The presence of a temporal signal means that a molecular clock can be fitted to infer the timing of ancestral branching based on SARS-CoV-2 genomes.
· First large cluster of cases was recognized in the context of an international business conference held in Boston from 2/26 – 27 with >90 cases diagnosed in conference attendees or their contacts, raising suspicion of a superspreading event.
· Dataset containing SARS-CoV-2 genomes from 28 of these cases, allowed search for genetic evidence of superspreading in the form of phylogenetic clustering of identical/highly similar viruses in a narrow time window àall 28 genomes formed a well-supported monophyletic cluster marked by the presence of the SNP C2416T, first seen in the GISAID database in 2 French pts on 2/29/2020 àall 27 US C2416T-containing viruses collected before 3/10 were from conference exposures.
· This strongly suggests there was low-level community transmission of C2416T in Europe in 2/2020 before the allele was introduced to Boston via a single introduction and amplified by superspreading at the conference.
· SARS-CoV-2 containing C2416T allele subsequently spread extensively in the Boston area, representing 35.1% of our dataset. Beginning in early March, C2416T appeared in multiple other US states & other countries & increased steeply in frequency, comprising 2.7% of domestic & 1.7% of global SARS-CoV-2 genomes in GISAID through 6/28 à ultimately, >20,000 cases spread from this 1 conference.
· Single introduction had an outsize effect because it was amplified by superspreading in a highly mobile population very early in the outbreak, before precautions were in place & when its effects were amplified by exponential growth.
· This is direct evidence that superspreading events may profoundly alter the course of an epidemic & implies that prevention, detection & mitigation of such events should be a public health priority.
**********
Bunyavanich S, Grant C, Vicencio A. Racial/Ethnic Variation in Nasal Gene Expression of Transmembrane Serine Protease 2 (TMPRSS2). JAMA. Published online September 10, 2020. doi:10.1001/jama.2020.17386
· SARS-CoV-2) is spread by airway contact & uses TMPRSS2 to facilitate viral entry and spread. Host-expressed TMPRSS2 on nasal and bronchial epithelium activates the SARS-CoV-2 spike protein & cleaves the ACE-2 receptor to which the virus binds, enabling SARS-CoV-2 to enter the body
· Nasal epithelium collected by nasal brushing from healthy individuals & individuals with asthma aged 4-60 yrs from 2015-2018 were analyzed for TMPRSS2 by self-identified race/ethnicity.
· RNA isolation of brushings followed by RNA sequencing, sequence alignment, and normalization were performed.
· The cohort (n = 305) was 8.2% Asian, 15.4% Black, 26.6% Latino, 9.5% mixed race/ethnicity, & 40.3% White. 48.9% were male and 49.8% had asthma.
· Nasal gene expression of TMPRSS2 in log2 counts per million was highest in Blacks (n = 47; mean, 8.64 [95% CI, 8.41-8.86]) compared with Asians (n = 25; mean, 8.07 [95% CI, 7.74-8.40]), Latinos (n = 81; mean, 8.02 [95% CI, 7.90-8.14]), individuals of mixed race/ethnicity (n = 29; mean, 7.97 [95% CI, 7.77-8.16]), and Whites (n = 123; mean, 8.04 [95% CI, 7.94-8.15]) .
· CONCLUSION: By linear regression, TMPRSS2 expression was significantly higher in Black individuals compared with Asian, Latino, mixed race/ethnicity & Whites (all P < .001). There were no significant associations between TMPRSS2 expression & sex, age, or asthma.
**********
Zhang T, Wu Q, Zhang Z. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Current Biology 2020; 30:1346-1351.e2. https://doi.org/10.1016/j.cub.2020.03.022
· Genomic and evolutionary evidence of the occurrence of a SARS-CoV-2-like CoV (named Pangolin-CoV) was identified in dead Malayan pangolins.
· Pangolin-CoV is 91.02% identical to SARS-CoV-2 at the whole-genome level
· Pangolin-CoV is the second closest relative of SARS-CoV-2 behind RaTG13 – the bat coronavirus thought to be the origin of SARS-CoV-2
· The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13.
· Five key amino acids involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but 4 amino acid mutations are present in RaTG13.
· Only SARS-CoV-2 contains a potential cleavage site for furin proteases – this is lost in both Pangolin-CoV and bat RaTG13.
· Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.
**********
Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open. 2020;3(9):e2019722. doi:10.1001/jamanetworkopen.2020.19722
· Vitamin D treatment has been found to decrease the incidence of viral respiratory tract infection, especially in pts with vitamin D deficiency. This study examines whether the last vitamin D status before COVID-19 testing is associated with COVID-19 test results.
· This retrospective cohort study at an urban academic medical center included all pts with a 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol level measured within 1 year before being tested for COVID-19 from March 3 to April 10, 2020.
· Vitamin D deficiency was defined by the last measurement of 25-hydroxychole- calciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before COVID-19 testing. Treatment changes were defined by changes in vitamin D type and dose between the date of the last vitamin D level measurement and the date of COVID-19 testing. Vitamin D deficiency and treatment changes were combined to categorize the most recent vitamin D status before COVID-19 testing as likely deficient (last level deficient and treatment not increased), likely sufficient (last level not deficient and treatment not decreased), and 2 groups with uncertain deficiency (last level deficient and treatment increased, and last level not deficient and treatment decreased).
· RESULTS A total of 489 patients (mean [SD] age, 49.2 [18.4] years; 366 [75%] women; and 331 [68%] race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status before COVID-19 testing was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%).
· Overall, 71 participants (15%) tested positive for COVID-19. In multivariate analysis, testing positive for COVID-19 was associated with increasing age up to age 50 years (relative risk, 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (relative risk, 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (relative risk, 1.77; 95% CI, 1.12-2.81; P = .02) compared with likely sufficient vitamin D status.
· Predicted COVID-19 rates in the deficient group were 21.6% (95% CI, 14.0%-29.2%) vs 12.2%(95% CI, 8.9%-15.4%) in the sufficient group.
· In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk.
**********
Popkin BM, Du S, Green WD et al. Individuals with obesity and COVID‐19: A global perspective on the epidemiology and biological relationships.Obesity Review. First published: 26 August 2020. https://doi.org/10.1111/obr.13128
· A systematic search of the Chinese & English language literature on COVID‐19 identified 75 studies used to conduct a series of meta‐analyses on the relationship of individuals with obesity–COVID‐19 over the full spectrum from risk to mortality.
· Pooled analysis shows that individuals with obesity were more at risk for COVID‐19 infection, >46.0% higher (OR = 1.46; 95% CI, 1.30–1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74–2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46–2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22–1.80; p < 0.001).
· Mechanistic pathways for COVID-19 infection and increased disease severity in individuals with obesity include associated metabolic dysfunction, impaired immune function & chronic inflammation.
· CONCLUSION: Individuals with obesity are linked to large significant increases in morbidity and mortality from COVID‐19.
THE DISEASE
Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med.2020. 5/28/2020. DOI: 10.1056/NEJMoa2008457.
à Infection-control strategies focused solely on symptomatic individuals are not sufficient to prevent transmission of this very highly contagious virus after SARS-CoV-2 introduction into this kind of facility.
**********
Ackermann M, Verleden SE, Kuehnel M. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. New Engl J Med 2020; May 21, 2020 DOI: 10.1056/NEJMoa2015432
**********
Toubiana J, Poirault C, Corsia A et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ 2020;369:m2094. Published online, 6/2/2020. http://dx.doi.org/10.1136 bmj.m2094
**********
McGuinness G, Zhan C, Rosenberg N et al. High Incidence of Barotrauma in Patients with COVID-19 Infection on Invasive Mechanical Ventilation. Radiology 2020; Published Online: Jul 2 2020. https://doi.org/10.1148/radiol.2020202352
***********
Davies, N.G., Klepac, P., Liu, Y et al. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat Med (2020). Published 6/16/2020. https://doi.org/10.1038/s41591-020-0962-9
**********
Nicolai L, Leunig A, Brambs S, et al. Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy. Circulation. 2020 Jul 28. doi: 10.1161/CIRCULATIONAHA.120.048488. Online ahead of print. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048488
**********
Yonker LM, Neilan AM, Bartsch Y et al. Pediatric SARS-CoV-2: Clinical Presentation, Infectivity, and Immune Responses. The Journal of Pediatrics (2020). doi: https://doi.org/10.1016/j.jpeds.2020.08.037.
**********
Del Valle, D.M., Kim-Schulze, S., Huang, H. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med (2020). Aug. 24,2020. https://doi.org/10.1038/s41591-020-1051-9
· A hyper-inflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death.
· A rapid multiplex cytokine assay was used to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β in 1484 hospitalized patients with COVID-19 on admission to the Mount Sinai Health System in New York from 3/21-4/28/2020.
· Pts (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected.
· Cutoffs chosen for further statistical analyses were >70 pg ml−1 for IL-6, >50 pg ml−1 for IL-8, >35 pg ml−1 for TNF-α and >0.5 pg ml−1 for IL-1β.
· Men had significantly higher levels of IL-6 than women (P < 0.0001), but no sex differences were observed for the other three cytokines.
· With increasing age brackets (<50, 50–70 and >70 years old), levels of IL-6, IL-8 and TNF-α increased.
· CKD was the only other comorbidity significantly associated with elevated cytokine levels
· RESULTS: High serum IL-6, IL-8 and TNF-α levels at hospitalization were strong and independent negative predictors of patient survival by Cox regression analysis. (P < 0.0001, P = 0.0205 and P = 0.0140, respectively).
· After adjustment for demographics and comorbidities, only age (50–70 versus <70 years, hazard ratio (HR) = 2.09 (1.25–3.49); >70 versus <50 years, HR = 3.76 (2.24–6.33)), IL-6 (HR = 2.23 (1.61–3.09)), IL-8 (HR = 1.41 (1.05–1.89)) and TNF-α (HR = 1.50 (1.09–2.07)) remained significantly associated with decreased survival (P = 0.0049, P < 0.0001, P = 0.0205 and P = 0.0140, respectively).
· CONCLUSION: After adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death.
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Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2-Associated Deaths Among Persons Aged <21 Years - United States, February 12-July 31, 2020. MMWR. Morb Mortal Wkly Rep. ePub: 15 September 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6937e4external icon.
· This report describes characteristics of 121 U.S. persons <21 yrs who died in association with SARS-CoV-2 infection between 2/12-7/31/2020, as reported to the CDC. Persons aged <21 yrs constitute 26% of the U.S. population
· 63% of deaths occurred in males, 10% were aged <1 year, 20% were aged 1–9 years, 70% were aged 10–20 years; 50 deaths (41%) occurred in 18-20 yr olds.
· 45% were Hispanic, 29% were non-Hispanic Black (Black) persons, and 4% were non-Hispanic American Indian or Alaska Native (AI/AN) persons.
· Among these 121 decedents, 91 (75%) had an underlying medical condition,*
· 120 (99.2) had COVID-19; 15 (12.4) had MIS-C.
· 79 (65%) died after admission to a hospital, 39 (32%) died at home or in the ED.
· CONCLUSION: Nearly three quarters of SARS-CoV-2–associated deaths among infants, children, adolescents, & young adults have occurred in persons aged 10–20 yrs, with a disproportionate percentage among young adults aged 18–20 yrs and among Hispanics, Blacks, AI/ANs, and persons with underlying medical conditions.
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Dennis J, McGovern A, Vollmer S et al. Improving COVID-19 critical care mortality over time in England: A national cohort study, March to June 2020. MedRxiv 2020; Preprint, 10/20/2020. doi: https://doi.org/10.1101/2020.07.30.20165134
· To determine mortality trend in pts with severe COVID-19 requiring critical care (high intensive unit [HDU] or intensive care unit [ICU]management), national English data on all 14,958 adult COVID-19 specific critical care admissions from 3/1/2020-5/30/2020 was accessed from a national surveillance system.
· Primary outcome was in-hospital 30-day all-cause mortality. Cox proportional hazards model adjusted for age, sex, ethnicity, comorbidities & geographical region.
· Results: 30-day mortality peaked for people admitted to critical care in early April (peak 29.1% for HDU, 41.5% for ICU). There was subsequently a sustained decrease in mortality risk until the end of the study period.
· Adjusted mortality risk decreased by 11.2% (adjusted HR 0.89 [95% CI 0.87 - 0.91]) per week in HDU, and 9.0% (adjusted HR 0.91 [95% CI 0.88 - 0.94]) in ICU.
· Conclusions: There has been a substantial mortality improvement in COVID-19 pts admitted to critical care in England, with markedly lower mortality in people admitted in mid-April and May compared to earlier in the pandemic.
· Trend remains after adjustment for patient demographics and comorbidities, suggesting this improvement is not due to changing patient characteristics.
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Horwitz L, Jones SA, Cerfolio RJ et al. Trends in Covid-19 risk-adjusted mortality rates in a single health system. medRxiv 2020.08.11.20172775. October, 2020. doi: https://doi.org/10.1101/2020.08.11.20172775
· COVID-19 outcomes over time were assessed in a single health system, accounting for changes in demographics and clinical factors.
· METHOD: Biweekly mortality rates for admissions between March 1 and June 20, 2020 were analyzed in a single health system in New York City. Outcomes were obtained as of July 14, 2020. All hospitalizations with laboratory-confirmed Covid-19 disease were included. Mortality was defined as in-hospital death or discharge to hospice care.
· A multivariable logistic regression model was created to generate expected risk of death, adjusting for age; sex; self-reported race and ethnicity; body mass index; smoking history; presence of hypertension, heart failure, hyperlipidemia, coronary artery disease, diabetes, cancer, chronic kidney disease, or pulmonary disease individually as dummy variables; and admission oxygen saturation, D-dimer, C reactive protein, ferritin, and cycle threshold for RNA detection. All data were obtained from the electronic health record.
· Observed and expected deaths in each two-week period were added and multiplied by each period's observed/expected (O/E) risk by the overall average crude mortality to generate biweekly adjusted rates.
· RESULTS; We included 4,689 hospitalizations, of which 4,661 (99.4%) had died or been discharged. The median age decreased from 67 years in the first two weeks to 49 in the last two; the proportion male or with any comorbidity decreased over time.
· Unadjusted mortality dropped each period, from 30.2% in the first two weeks to 3% in the last two weeks, with the last eight weeks being lower than the 95% control limits.
· Risk adjustment partially attenuated the mortality decline, but adjusted mortality rates in the second-to-last two weeks remained outside the control limits. The O/E risk of mortality decreased from 1.07 (0.64-1.67) in the first two weeks to 0.39 (0.08-1.12) in the last two weeks.
· In this 16-week study of Covid-19 mortality at a single health system, we found a significant decrease in unadjusted mortality; changes in demographics and severity of illness at presentation accounted for some, but not all, of the decrease in unadjusted mortality. Even after risk adjustment for multiple clinical and demographic factors, mortality was significantly lower at the end of the study period.
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Nadkarni GN, Lala A, Bagiella E et al. Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020 Aug, 76 (16) 1815–1826.
· To evaluate the association of thromboembolic disease and anticoagulation in pts with COVID-19 with outcomes and postmortem findings, cases were evaluated retrospectively for therapeutic versus prophylactic AC initiated ≤48 h from admission and mortality, intubation and major bleeding.
· Thromboembolic disease was contextualized by premortem AC among consecutive autopsies..
· RESULTS: Among 4,389 patients, median age was 65 yrs, 44% women. Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53( CI: 0.45 to 0.62); aHR: 0.50 (CI: 0.45 to 0.57), and intubation (aHR: 0.69 (CI: 0.51 to 0.94); aHR: 0.72 (CI: 0.58 to 0.89).
· Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC.
· Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC.
· CONCLUSIONS: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant. Autopsies revealed frequent thromboembolic disease.
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Anup A, Aparna M, Kumar Gunjan K et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) BMJ 2020; 371 :m3939
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Giustino G, Croft LB, Stefanini GG et al. Characterization of Myocardial Injury in Patients With COVID-19. J Am Coll Cardiol. 2020 October; 76 (18) 2043–2055.
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Gold JA, Rossen LM, Ahmad FB et al. Race, Ethnicity, and Age Trends in Persons Who Died from COVID-19 — United States, May–August 2020. MMWR; October 23, 2020; 69:1517–1521. DOI: http://dx.doi.org/10.15585/mmwr.mm6942e1
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Perry RJ, Smith CJ, Roffe C et al. Characteristics and outcomes of COVID-19-associated stroke: a UK multicentre case-control study. J Neurol Neurosurg Psychiatry 2020. October, 2020. http://dx.doi.org/10.1136/jnnp-2020-324927
PREVENTION/ TRANSMISSION
Chan JF-W, Yuan DS, Zhang AJ et al. Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19). Clinical Infectious Diseases: Published: 30 May 2020 https://doi.org/10.1093/cid/ciaa644
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Shen y, Li C, Dong H et al. Community Outbreak Investigation of SARS-CoV-2 Transmission Among Bus Riders in Eastern China. JAMA Intern Med. Published online September 1, 2020. doi:10.1001/jamainternmed.2020.5225
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Anand S, Montez-Rath M, Han J et al. Prevalence of SARS-CoV-2 antibodies in a large nationwide sample of patients on dialysis in the USA: a cross-sectional study. Lancet 2020. Published online September 25, 2020 https://doi.org/10.1016/S0140-6736(20)32009-2
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Meltzer DO, Best TJ, Zhang H et al. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Network Open 2020; 3(9): e2019722. Online 9/3/2020. doi:10.1001/jamanetworkopen.2020.19722
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Hoiland RL, Fergusson NA, Mitra AR et al. The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19. Blood Adv 2020; 4 (20): 4981–4989. https://doi.org/10.1182/bloodadvances.2020002623
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Viner RM, Mytton OT, Bonell C et al. Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis. JAMA Pediatr. Published online September 25, 2020. doi:10.1001/jamapediatrics.2020.4573
Chang, S., Pierson, E., Koh, P.W. et al. Mobility network models of COVID-19 explain inequities and inform reopening. Nature; November, 2020. https://doi.org/10.1038/s41586-020-2923-3.
TREATMENT
Gharbharan A, Jordans CCE, Geurtsvan-Kessel C et al. Convalescent Plasma for COVID-19. A randomized clinical trial. medRxiv 2020.07.01.20139857. doi: https://doi.org/10.1101/2020.07.01.20139857
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Mather JF, et al. Impact of famotidine use on clinical outcomes of hospitalized COVID-19 patients. Am J Gastroenterol; August 14, 2020.
The Writing Committee for the REMAP-CAP Investigators. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17022
Tomazini BM , Maia IS , Cavalcanti AB , et al; COALITION COVID-19 Brazil III Investigators. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17021
Dequin PF , Heming N , Meziani F , et al; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.16761
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17023
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Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 — Final Report. NEJM 2020; Published online October 8, 2020. DOI: 10.1056/NEJMoa2007764