BRIEF DISEASE OUTBREAK NARRATIVE

On Dec. 1^st 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. 31^st, 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 23^rd, 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.

THE VIRUS

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.

• ·      Serial respiratory, stool, serum, and urine samples for RNA viral load collected from 96 consecutive pts with SARS-CoV-2 during hospital course in Zhejiang, China.
• ·      RNA virus detected in sputum and saliva samples in all pts, 55% in stool, 41% in serum.
• ·      Median virus duration in stool (22 days, IQR:17-31) was significantly longer than in respiratory (18 days, IQR:13-29) & serum samples (16 days, IQR:11-21).
• ·      Viral load was higher in pts with severe disease than in those with mild disease.
• ·      Virus duration was longer in patients older than 60 years and in male patient

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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THE DISEASE

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:

• ·      Prodromal phase included fever, dry cough, and malaise.
• ·      Two-thirds of pts had worked or shopped at a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus.
• ·      Upper respiratory and GI symptoms were notably infrequent.
• ·      Common laboratory findings on admission included lymphopenia and bilateral ground-glass opacity on CXR &/or consolidation in chest CT scans.
• ·      22/41 pts (55%) developed severe dyspnea and 13 (32%) required ICU admission;
• ·      6 pts died à case-fatality rate of 14·6%. (With true number of infections unknown, fatality rate is likely much lower.)  

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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

•       Median age: 55-59 yrs with male predominance; no pt <15 yrs.
• ·      Pts with earlier presentation much more likely had exposure to the Huanan Market.
• ·      Increasing proportion of cases acquired in hospital by pts or hospital personnel over time, to maximum of 40% in one series.

• ·      Mean incubation period: 5.2 days, 95th%ile at 12.5 days è resulted in 14 day standard quarantine period
• ·      Most common clinical symptoms: fever( 80%); dry cough(70%), sob(30% ); myalgias(10%).
• ·      On CXR &/or CT scan, bilateral pneumonia present in 75% of pts with multiple areas of consolidation and ground-glass opacifications.
• ·      Median time from 1^st symptom to sob was 5 days and to hospital admission was 7 days; ~60% developed ARDS at a median of 8 days S/P first symptom.
• ·      Mortality ranged from 4 to 17%, predominantly in older patients, due to progressive respiratory and multi-organ failure.
• ·      Overall, mean mortality estimated at ~2%.

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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.

• ·      Serial respiratory, stool, serum & urine samples for RNA viral load collected from 96 consecutive pts with SARS-CoV-2 during hospital course in Zhejiang province,China
• ·      RNA virus detected in sputum and saliva samples in all pts, in 55% in stool, in 41% in serum.
• ·      Median duration of virus in stool (22 days, IQR:17-31) was significantly longer than in respiratory (18 days, IQR:13-29) and serum samples (16 days, IQR:11-21).
• ·      Viral load was higher in pts with severe disease than in those with mild disease.
• ·      Virus duration was longer in patients >60 years and in males.

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

• ·      41 yr old previously healthy male resident of Snohamish county, Washington who returned from a visit to Wuhan, China on January 14,2020, presented to an urgent care center on Jan. 21, 2020  with 4 d hx of fever, cough
• ·      Because of pt.’s travel and awareness of the new coronavirus, SARS-CoV-2 cultures were obtained and were positive
• ·      Illness was relatively benign with minimal O2 requirement, no critical events
• ·      Pt was normally active in the community before presentation and sat in the waiting room for some time before he was seen
• ·      On Feb.28, the virus in another case in that community was found to be very likely descended from that first case based on  phylogenetic analysis. à These genetic findings suggest that SARS-CoV-2 had been spreading through the community for close to six weeks.
• ·      Snohamish county is close to Everett, Washington where major early COVID-19 outbreak occurred à local disease spread was occurring in the US beginning in the third week of January.

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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

• ·      Case series: 215 pregnant women who delivered infants at NY-Presbyterian MC screened for COVID-19
• ·      4 women had fever, all tested (+) for SARS-CoV-2
• ·      Of 211 women without symptoms, 29(13.7%) tested (+) for SARS-CoV-2 on N/P culture à 87.9% of culture (+) women were asymptomatic
• ·      Overall, 15% of women presenting for delivery were SARS-CoV-2 (+)
• ·      Universal testing in asymptomatic women presenting for delivery allows protection of mothers, babies and hospital staff.

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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

• ·      Case series of 5700 consecutive pts with culture-proven SARS-CoV-2 infection admitted to 12 hospitals in New York City & environs (in the Northwell Health system) from 3/1/2020 through 4/42020.
• ·      Median age, 63 years [{IQR}, 52-75; range, 0-107 years]; 39.7% female.
• ·      At triage, 30.7% of patients were febrile, 17.3% had RR>24 breaths/min, and 27.8% on supplemental oxygen. Rate of respiratory virus co-infection was 2.1%.
• ·      Most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%) & diabetes (1808; 33.8%). Pulmonary diagnoses were not significant co-morbidities.
• ·      Outcomes assessed for pts who were discharged or died by study end point.            è During hospitalization, 373 patients (14.2%) (median age, 68 yrs [IQR, 56-78]; 33.5% female) were treated in ICU, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) received dialysis, and 553 (21%) died.
• ·      For pts requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, & 831 (72.2%) remained in hospital.
• ·      Mortality was 0% (0/20) for male and female patients younger than 20 years.
• ·      Mortality rates were higher for male vs female pts at every 10-yr age interval.
• ·      Mortality rates for those who received mechanical ventilation in the 18-to-65 vs > 65 age groups were 76.4% and 97.2%, respectively.
• ·      Mortality rates for those in the 18-to-65 and older-than-65 age groups who did not receive mechanical ventilation were 19.8% and 26.6%, respectively.

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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

• ·      Cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020.
• ·      Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death).
• ·      Among 4,103 Covid-19 patients, 1,999 (48.7%) were hospitalized, of whom 981/1,999 (49.1%) have been discharged home, and 292/1,999 (14.6%) have died or were discharged to hospice.
• ·      Of 445 patients requiring mechanical ventilation, 162/445 (36.4%) have died.
• ·      Strongest hospitalization risks were age ≥75 years (OR 66.8, 95% CI, 44.7-102.6), age 65-74 (OR 10.9, 95% CI, 8.35-14.34), BMI>40 (OR 6.2, 95% CI, 4.2-9.3), and heart failure (OR 4.3 95% CI, 1.9-11.2).
• ·      Strongest critical illness risks were admission oxygen saturation <88% (OR 6.99, 95% CI 4.5-11.0) and elevated inflammatory markers: d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95% CI, 2.6-13.8).
• ·      In the decision tree for admission, most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200.
• ·      Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.

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.

• ·      After 1 resident in a skilled nursing facility tested (+) for SARS-CoV-2, all residents underwent 2 assessments of symptoms and NP/OP testing including real-time RT-PCR, viral culture, and sequencing.
• ·      Asymptomatic residents who tested positive were reassessed 7 days later.
• ·      23 days after the first (+) test result, 57/89 residents(64%) tested (+) for SARS-CoV2.
• ·      In 76 residents who participated in 2 surveys, 27/48 tested (+) and were asymptomatic at the time of testing; 24/27 developed symptoms within 4 days.  
• ·      Among 64%(+) for SARS-CoV-2, 11 hospitalized &15 died (mortality, 26%).
• ·      Rapid, widespread transmission of SARS-CoV-2 was demonstrated with more than half of culture (+) residents asymptomatic at the time of testing.

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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EPIEPIDEMIOLOGY

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

• ·      Median age: 55-59 yrs with male predominance; no pt <15 yrs.
• ·      Pts with earlier presentation much more likely to report exposure to the Huanan Mkt.
• ·      Increasing proportion of cases acquired in hospital by pts or hospital personnel over time, to maximum of 40% in one series à increasing evidence of importance of person-to-person transmission.

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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

• ·      41 yr old previously healthy male resident of Snohamish county, Washington who returned from a visit to Wuhan, China on January 14, 2020, presented to an urgent care center on Jan. 21, 2020 with 4 d hx of fever, cough
• ·      Because of pt.’s travel and awareness of the new coronavirus, SARS-CoV-2 cultures were obtained and were positive
• ·      Illness was relatively benign with minimal O2 requirement, no critical events
• ·      Pt was normally active in the community before presentation and sat in the waiting room for some time before he was seen
• ·      On Feb.28, the virus in another case in that community was found to be descended from that first case based on phylogenetic analysis. à These genetic findings suggest that SARS-CoV-2 had been spreading through the community for close to six weeks, beginning in mid-January.
• ·      Snohamish county is close to Everett, Washington where the major early COVID-19 outbreak occurred à proof that local disease spread was occurring in the US beginning in the third week of January.

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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

• ·      To identify the early events underlying the rapid spread of the virus in the NYC metropolitan area, investigators sequenced the virus causing COVID19 in 90 patients
• ·      Phylogenetic analysis of 84 distinct SARS-CoV2 genomes indicates multiple, independent but isolated introductions mainly from Europe and other parts of the United States with limited evidence of direct introductions from China.
• ·      As early as February 20 (90%CI: January 29 to February 26) (Table 1), an identified virus was inferred to be of domestic origin based on its close relationship with US isolates, including those from the main community transmission in Washington state
• ·      The earliest sequences include isolates from Italy, Finland, Spain, France, the UK, and other European countries from late February plus a few North American isolates (Canada and US) from the first week of March 2020.
• ·      The sequenced isolates were spatially distributed throughout all NYC boroughs and 21 neighborhoods providing evidence for community transmission of SARS-CoV2 suggested by clusters of related viruses found in patients living in different neighborhoods of the city.

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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.

• ·      Discrete state and city data sources show Black Americans to be at elevated risk for COVID-19 infection and death but the race/ethnicity of 78% of current diagnoses nationally is unknown.
• ·      Investigators compared COVID-19 cases and deaths in above average (i.e. > 13% of the population) black counties versus all other US counties.
• ·      Roughly one in five counties nationally is disproportionately black, representing 22% of all U.S. counties but these counties accounted for 52% of coronavirus cases and 58% of COVID-19 deaths.
• ·      Structural factors including health care access, density of households, unemployment +/- pervasive discrimination and others drive these disparities, not intrinsic characteristics of black communities or individual-level factors.

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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.

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TREATMENT

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.

• è Promising preliminary findings require RCT evaluation.

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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

• ·      Retrospective analysis of data of all pts hospitalized with confirmed SARS-CoV-2 infection in all U.S. VA medical centers until April 11, 2020.
• ·      Patients were categorized based on exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard COVID-19 management. Primary outcomes were death and need for mechanical ventilation.
• ·      RESULTS: 368 patients were evaluated (HC: n=97; HC+AZ: n=113; No HC: n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.
• ·      à Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted HR, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted HR, 1.14; 95% CI, 0.56 to 2.32; P=0.72).
• ·      à No evidence that use of HC, either with or without AZ reduced the risk of mechanical ventilation in patients hospitalized with COVID-19.

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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

• ·      Increased thromboembolic events and anecdotal observations of improved outcomes with systemic anticoagulation(AC) have been reported in hospitalized COVID-19 pts
• ·      àRetrospective analysis of association between administration of in-hospital AC and survival in a cohort of 2773 COVID-19 pts hospitalized in NYC
• ·      786/2773 pts (28%) received AC a median of 2 days post admission; median AC duration was 3 days.
• ·      Pts who received AC had significantly more B/L coagulation abnormalities
• ·      Overall, in-hospital mortality for AC pts was 22.5% with median survival of 21 days vs. mortality of 22.8% and median survival of 14 days for non-AC group.
• ·      In pts who required ventilation, in-hospital mortality for those who received AC was 29.1% with median survival of 21 days vs. 62.7% mortality with 9 day survival for those who did not received AC.
• ·      In a multivariable proportional hazards model, longer duration of AC was associated with reduced mortality risk.
• ·      No increased incidence of bleeding events with AC
• ·      RCT of systemic AC needed.

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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.

• ·      Investigators cloned, tagged & expressed 26 SARS-CoV-2 proteins in human cells & identified physically associated proteins using affinity-purification mass spectrometry
• ·      332 high-confidence SARS-CoV-2-human protein-protein interactions were identified with 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, 28 preclinical compounds).
• ·      Screening these in multiple viral assays identified 2 sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors.
• ·      Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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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  

• ·      Post SARS-CoV-2 genome sequence availability, Oxford University team used recombinant DNA techniques to create a vaccine with SARS-CoV-2 antigen embedded in a primate adenovirus vector.
• ·      The vaccine includes Spike glycoproteins genetic material, a surface protein from SARS-CoV-2 responsible for virus binding to host cell ACE2 inhibitors.
• ·      Investigators hope to engender an immune response to the Spike protein that will prevent SARS-CoV-2 from entering human cells and causing infection.
• ·      ChAdOx1-derived vaccines have already been given to >320 people to date, with consistent reports of safety and tolerability and no major adverse events.
• ·      RCT of the potential vaccine -- ChAdOx1 nCoV-19 -- in 1100 volunteers has begun with results anticipated in 2-6 months. Participants are randomized to the trial vaccine or a control meningitis vaccine.
• ·      Main outcome is assessment of effectiveness, safety, and immune responses to the vaccine. COVID-19 cases in the 2 groups will be compared.
• ·      The Serum Institute of India—the world’s largest producer of vaccines—announced plans to make 40 million doses of hAdOx1 nCov-19 beginning prior to trial results.

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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

• ·      Researchers from Sinovac Biotech, a privately held Beijing-based company, gave two different doses of their COVID-19 vaccine to a total of eight rhesus macaques.
• ·      Three weeks later, the group introduced SARS-CoV-2 directly into the monkeys’ lungs à none developed a full-blown infection.
• ·      The purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) conferred complete protection in these non-human primates against multiple SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology. Phase 1-2 studies underway.

[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.]

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PREDICTION DYNAMICS

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:

• ·      Seasonal coronaviruses circulate from autumn to early spring in temperate regions
• ·      High levels of seasonality àsmaller initial peak, but larger wintertime outbreaks
• ·      Immunity to these viruses (HKU1 and OC43) wanes rapidly, over ~1 year
• ·      Some cross-protection exists between these 2 viruses à ? also SARS-CoV-2
• ·      SARS-CoV-2 can proliferate at any time of the year (as we are seeing now)
• ·      If immunity is not permanent, SARS-CoV-2 will eventually enter regular circulation as a fifth seasonal coronavirus
• ·      If immunity permanent, SARS-CoV-2 will disappear in a few yrs 2^o to herd immunity.

Modeling results:                                                                                                                           Social distancing without seasonality:

• è Short durations of social distancing displace cases into the near future
• è Longer durations of higher-intensity social distancing reduce case burden in the near term, but result in significant outbreaks during autumn and winter
• è Permanent social distancing of moderate to high intensity works well to keep SARS-CoV-2 at bay but difficult & unpleasant to sustain

Social distancing + seasonality:

• è Short durations of social distancing slightly delay peaks of COVID-19, but result in high overall infection rates
• è Longer durations of social distancing push the peaks into the winter months and increase the overall infection rate
• è Intermittent social distancing, based on good surveillance, may be needed to keep case load in check until vaccines are available or a sufficient percentage of the population has been infected & herd immunity is achieved

(There are many reported theoretical models of disease transmission dynamics going forward – these will be added as they are published.)

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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

• ·      57% of participants in the total sample were antibody positive, 5% were weakly positive, 39% were negative.
• ·      47% had confirmed SARS-CoV-2 diagnosis by prior PCR testing. All but three of these confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike
• ·      Only 37.4% of suspected SARS-CoV-2 patients had seroconverted.
• ·      PCR- throat culture positivity was detected up to 28 days from symptom resolution but it is unclear whether this represents infectious virus.

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.  

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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.

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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.

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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.

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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.

• ·      After 1 resident in a skilled nursing facility tested (+) for SARS-CoV-2, all residents underwent 2 assessments of symptoms and NP/OP testing including real-time RT-PCR, viral culture, and sequencing.
• ·      Asymptomatic residents who tested positive were reassessed 7 days later.
• ·      23 days after the first (+) test result, 57/89 residents(64%) tested (+) for SARS-CoV2.
• ·      In 76 residents who participated in 2 surveys, 27/48 tested (+) and were asymptomatic at the time of testing; 24/27 developed symptoms within 4 days.  
• ·      Among 64%(+) for SARS-CoV-2, 11 hospitalized &15 died (mortality, 26%).
• ·      Rapid, widespread transmission of SARS-CoV-2 was demonstrated with more than half of culture (+) residents asymptomatic at the time of testing.

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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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

• ·      7 lungs obtained at autopsy from COVID-19 pts were compared with 7 lungs obtained at autopsy from pts who died from ARDS secondary to influenza A(H1N1) and 10 age-matched, uninfected control lungs.
• ·      Lungs studied with 7-color immunohistochemical analysis, micro-CT imaging, scanning EM, corrosion casting & direct multiplexed measurement of gene expression.
• ·      RESULTS: In both COVID-19 pts and pts who died from influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration.
• ·      Only COVID-19 lungs also showed distinctive vascular features of severe endothelial injury associated with presence of intracellular virus and disrupted cell membranes.
• ·      Histologic analysis of pulmonary vessels in COVID-19 pts showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9X as prevalent in COVID-19 pts as in influenza pts(P<0.001).
• ·      In lungs from COVID-19 pts, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7X as high as that in the lungs from influenza pts (P<0.001).

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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

• ·      Case series of 21 children and adolescents with features suggestive of Kawasaki disease admitted to hospital between 27 April and 11 May 2020
• ·      Median age 7.9 yrs (range 3.7-16.6); 12 (57%) of African ancestry.
• ·      21/21 had GI symptoms; 12 (57%) presented in shock and 16 (76%) had myocarditis; 17 (81%) required intensive care support.
• ·      Moderate coronary artery dilations detected in 5 pts (24%) but none had coronary aneurysms.
• ·      21/21 had high levels of inflammatory markers; 19 (90%) had evidence of recent SARS-CoV-2 infection ([+] RT-PCR result in 8/21, [+] IgG antibody in 19/21).
• ·      All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids.
• ·      The clinical outcome was favorable in all pts.
• ·      Delay between the peak of SARS-CoV-2 infections and presentation of PIMS raises the possibility that this is a post-infectious, immunologically mediated phenomenon.

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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

• ·      Retrospective review of clinical and imaging data of COVID-19 pts seen between 3/1/2020 & 4/6/2020 who experienced barotrauma (extrapulmonary air) during invasive mechanical ventilation were compared to pts without COVID-19 infection ventilated during the same period.
• ·      Historical comparison also made to barotrauma rates of ARDS ptsfrom 02/01/2016 to 02/01/2020 at our institution.
• ·      Of 601 ventilated COVID-19 pts (63 ± 15 years, 71% men), 89/601 (15%) had >/= 1 barotrauma events, 145 total barotrauma events (24% overall events) (95% CI 21-28%). Of 196 ventilated pts without COVID-19 infection (64 ± 19 years, 52% male) only 1 had a single barotrauma event (.5% 95% CI, 0-3%, p<.001).
• ·      Of 285 ventilated ARDS pts over the prior 4 years (68 ± 17 years, 60% men), 28 patients (10%) had 31 barotrauma events, with overall barotrauma rate of 11% (95% CI 8-15%, p<.001 vs. the group with COVID-19 infection).
• ·      Barotrauma was an independent risk factor for death in COVID-19 (OR=2.2, p=.03), and was associated with longer hospital length of stay (OR=.92, p<.001).

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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

• ·      To evaluate age disparities in observed COVID-19 cases, an age-structured mathematical model to data from China, Italy, Japan, Singapore, Canada and South Korea was constructed.
• ·      Results indicate susceptibility to infection in individuals </= 20 yrs of age is half that of adults >20 yrs, and that
• ·      Clinical symptoms were manifest in 21% (95% credible interval: 12–31%) of infections in 10-19-yr-olds, rising to 69% (57–82%) in people > 70 yrs.

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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

• ·      38 pts with RT-PCR confirmed COVID-19 and 24 controls underwent histo-pathological assessment of autopsy specimens, surface-marker based phenotyping of neutrophils & platelets & functional assays for platelet, neutrophil function & coagulation.
• ·      In COVID-19. inflammatory microvascular thrombi are present in the lung, kidney& heart, containing neutrophil extracellular traps associated with platelets and fibrin.
• ·      COVID-19 pts also present with neutrophil-platelet aggregates & a distinct neutrophil/ platelet activation pattern in blood, changing with disease severity: cases of intermediate severity show an exhausted platelet & hyporeactive neutrophil phenotype, severely affected COVID-19 pts are characterized by excessive platelet & neutrophil activation vs healthy controls & non-COVID pneumonia.
• ·      Dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability suggesting that this is a key marker of disease severity in COVID-19.

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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.

• ·      Children ages 0-22 years with suspected SARS-CoV-2 infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) were evaluated.
• ·      A total of 192 children (mean age 10.2 +/- 7 years) were enrolled: 49 (26%) with acute SARS-CoV-2 infection; an additional 18 children (9%) met criteria for MIS-C.
• ·      Only 25 (51%) children with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were non-specific.
• ·      Nasopharyngeal viral load was highest in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002).
• ·      Age did not impact viral load, but younger children had lower ACE2 expression (P=0.004).
• ·      IgM and IgG to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein were increased in severe MIS-C (P<0.001), with dysregulated humoral responses observed.
• ·      Children may be a potential source of contagion in the SARS-CoV-2 pandemic in spite of milder disease or lack of symptoms, and immune dysregulation is implicated in severe post-infectious MIS-C.

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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

• ·      Investigation of SARS-CoV-2-challenged & naïve hamsters in closed system units separated by a polyvinyl chloride air porous partition with unidirectional airflow within the isolator +/- a surgical mask partition placed in between the cages.
• ·      Hamsters tested for viral load, histopathology & viral nucleocapsid Ag expression.
• ·      Non-contact transmission was found in 66.7% (10/15) of exposed naïve hamsters.
• ·      Surgical mask partition for challenged index or naïve hamsters reduced transmission to 25% (6/24, P=0.018). Surgical mask partition for challenged index hamsters reduced transmission to only 16.7% (2/12, P=0.019) of exposed naïve hamsters.
• ·      Unlike the severe COVID-19 manifestations of challenged hamsters, infected naïve hamsters had lower clinical scores, milder histopathological changes, and lower viral nucleocapsid antigen expression in respiratory tract tissues.

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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

• ·      Background: Evidence supporting airborne transmission of SARS-CoV-2 is emerging with an experimental study demonstrating SARS-CoV-2 viability in aerosols for >3 hrs & evidence of SARS-CoV-2 transmission between ferrets via the air established. 
• ·      To investigate airborne transmission between humans in a community setting, an outbreak of COVID-19 among lay Buddhists in Zhejiang province was investigated.
• ·      On January 19, 2020, 128 individuals took 2 buses (60 in bus 1, 68 in bus 2) on a 100-min round trip to attend a 150-min worship event. One passenger on bus 2 was SARS-C0V-2 positive. In both buses, central A/Cs were in indoor recirculation mode.
• ·      Results: 24 of 68 individuals (35.3%) on bus 2, received a diagnosis of COVID-19 after the event vs. none of the 60 individuals in bus 1. Among the other 172 individuals at the event, 7 (4.1%) subsequently received a COVID-19 diagnosis.
• ·      Individuals in bus 2 had a 34.3% (95% CI, 24.1%-46.3%) higher risk of getting COVID-19 vs. those in bus 1 and were 11.4 times (95% CI, 5.1-25.4) more likely to have COVID-19 compared with all other individuals attending the event.
• ·      On bus 2, individuals in high-risk zones had moderately, but not significantly, higher risk for COVID-19 compared with those in low-risk zones. Absence of a significantly increased infection risk in locations closer to the index case suggests that airborne spread at least partially explains the extremely high attack rate.
  

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

• ·      RCT comparing convalescent plasma with standard of care therapy in pts hospitalized for COVID-19 in the Netherlands.
• ·      Pts were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80.
• ·      Primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.
• ·      Results: The trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline.
• ·      A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) pts tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40).
• ·      No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated pts and pts on standard of care.
• ·      Conclusion Most COVID-19 pts already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma.

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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.

• ·      Famotidine, a histamine-2 receptor antagonist used to treat heartburn, is postulated to be effective against SARS-C0V-2 infection since that process is thought to be at least partially mediated by pathological histamine release.
• ·      Retrospective, propensity-matched observational study of consecutive COVID-19 positive pts between 2/24/2020 and 5/13/2020.
• ·      878 pts, 83 received famotidine; FAM pts were slightly younger but did not differ with respect to baseline demographics or pre-existing comorbidities.
• ·      FAM use was associated with a significantly decreased risk of in-hospital mortality (OR 0.37, 95%CI 0.16-0.86; p=.021) as well as combined death or intubation.(OR 0.47. 95% CI 0.23-0.96; p=0.04)
• ·      Adjusting for age difference did not change results.
• ·      FAM pts had lower serum markers for severe disease including CRP & pro-calcitonin.
• ·      By logistic regression, FAM was an independent predictor of lower mortality and death/intubation while older age, BMI>30 kg/m², CKD & higher neutrophil/lymphocyte ratio were all predictors of both adverse outcomes.

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

• ·      On Sept. 2, JAMA published the results of 3 multicenter RCTs that assessed corticosteroid therapy in critically ill patients with COVID-19 and a WHO-sponsored prospective M/A.
• ·      Results show conclusive benefit for steroid treatment best appreciated in the prospective M/A which included the results of these 3 RCTs, the RECOVERY trial of dexamethiasone published in the NEJM in 6/2020 & 3 additional trials, totaling 1703 patients (678 had been randomized to corticosteroids and 1025 to usual care or placebo. 28-day mortality was significantly lower in pts randomized to corticosteroids: 222 deaths among 678 pts vs. 425 deaths among 1025 pts (summary odds ratio, 0.66 [95% CI, 0.53,-0.82]; P < .001).
• ·      The association between administration of corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect; was similar with lower- vs higher-dose steroid regimens; and was similar among pts with fewer vs greater than 7 days of symptoms at randomization.
• ·      Corticosteroids also appear to be associated with benefit among critically ill pts with COVID-19 whether they are receiving mechanical ventilation or O2 alone.
• ·      The launch and conduct of these high-quality trials in the midst of a pandemic is an important accomplishment, as is the agreement to share unpublished data with WHO, exemplifying how science can advance even in the context of numerous underpowered RCTs.
• Ø Corticosteroids are inexpensive, readily available, and based on these data, are associated with reduced mortality in critically ill patients with COVID-19.

Home.

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

• ·      57% of participants in the total sample were antibody positive, 5% were weakly positive, 39% were negative.
• ·      47% had confirmed SARS-CoV-2 diagnosis by prior PCR testing. All but three of these confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike
• ·      Only 37.4% of suspected SARS-CoV-2 patients had seroconverted.
• ·      PCR- throat culture positivity was detected up to 28 days from symptom resolution but it is unclear whether this represents infectious virus.

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.  

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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.

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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.

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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.

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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.

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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.

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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.

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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.

• ·      After 1 resident in a skilled nursing facility tested (+) for SARS-CoV-2, all residents underwent 2 assessments of symptoms and NP/OP testing including real-time RT-PCR, viral culture, and sequencing.
• ·      Asymptomatic residents who tested positive were reassessed 7 days later.
• ·      23 days after the first (+) test result, 57/89 residents(64%) tested (+) for SARS-CoV2.
• ·      In 76 residents who participated in 2 surveys, 27/48 tested (+) and were asymptomatic at the time of testing; 24/27 developed symptoms within 4 days.  
• ·      Among 64%(+) for SARS-CoV-2, 11 hospitalized &15 died (mortality, 26%).
• ·      Rapid, widespread transmission of SARS-CoV-2 was demonstrated with more than half of culture (+) residents asymptomatic at the time of testing.

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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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

• ·      7 lungs obtained at autopsy from COVID-19 pts were compared with 7 lungs obtained at autopsy from pts who died from ARDS secondary to influenza A(H1N1) and 10 age-matched, uninfected control lungs.
• ·      Lungs studied with 7-color immunohistochemical analysis, micro-CT imaging, scanning EM, corrosion casting & direct multiplexed measurement of gene expression.
• ·      RESULTS: In both COVID-19 pts and pts who died from influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration.
• ·      Only COVID-19 lungs also showed distinctive vascular features of severe endothelial injury associated with presence of intracellular virus and disrupted cell membranes.
• ·      Histologic analysis of pulmonary vessels in COVID-19 pts showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9X as prevalent in COVID-19 pts as in influenza pts(P<0.001).
• ·      In lungs from COVID-19 pts, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7X as high as that in the lungs from influenza pts (P<0.001).

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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

• ·      Case series of 21 children and adolescents with features suggestive of Kawasaki disease admitted to hospital between 27 April and 11 May 2020
• ·      Median age 7.9 yrs (range 3.7-16.6); 12 (57%) of African ancestry.
• ·      21/21 had GI symptoms; 12 (57%) presented in shock and 16 (76%) had myocarditis; 17 (81%) required intensive care support.
• ·      Moderate coronary artery dilations detected in 5 pts (24%) but none had coronary aneurysms.
• ·      21/21 had high levels of inflammatory markers; 19 (90%) had evidence of recent SARS-CoV-2 infection ([+] RT-PCR result in 8/21, [+] IgG antibody in 19/21).
• ·      All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids.
• ·      The clinical outcome was favorable in all pts.
• ·      Delay between the peak of SARS-CoV-2 infections and presentation of PIMS raises the possibility that this is a post-infectious, immunologically mediated phenomenon.

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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

• ·      Retrospective review of clinical and imaging data of COVID-19 pts seen between 3/1/2020 & 4/6/2020 who experienced barotrauma (extrapulmonary air) during invasive mechanical ventilation were compared to pts without COVID-19 infection ventilated during the same period.
• ·      Historical comparison also made to barotrauma rates of ARDS ptsfrom 02/01/2016 to 02/01/2020 at our institution.
• ·      Of 601 ventilated COVID-19 pts (63 ± 15 years, 71% men), 89/601 (15%) had >/= 1 barotrauma events, 145 total barotrauma events (24% overall events) (95% CI 21-28%). Of 196 ventilated pts without COVID-19 infection (64 ± 19 years, 52% male) only 1 had a single barotrauma event (.5% 95% CI, 0-3%, p<.001).
• ·      Of 285 ventilated ARDS pts over the prior 4 years (68 ± 17 years, 60% men), 28 patients (10%) had 31 barotrauma events, with overall barotrauma rate of 11% (95% CI 8-15%, p<.001 vs. the group with COVID-19 infection).
• ·      Barotrauma was an independent risk factor for death in COVID-19 (OR=2.2, p=.03), and was associated with longer hospital length of stay (OR=.92, p<.001).

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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

• ·      To evaluate age disparities in observed COVID-19 cases, an age-structured mathematical model to data from China, Italy, Japan, Singapore, Canada and South Korea was constructed.
• ·      Results indicate susceptibility to infection in individuals </= 20 yrs of age is half that of adults >20 yrs, and that
• ·      Clinical symptoms were manifest in 21% (95% credible interval: 12–31%) of infections in 10-19-yr-olds, rising to 69% (57–82%) in people > 70 yrs.

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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

• ·      38 pts with RT-PCR confirmed COVID-19 and 24 controls underwent histo-pathological assessment of autopsy specimens, surface-marker based phenotyping of neutrophils & platelets & functional assays for platelet, neutrophil function & coagulation.
• ·      In COVID-19. inflammatory microvascular thrombi are present in the lung, kidney& heart, containing neutrophil extracellular traps associated with platelets and fibrin.
• ·      COVID-19 pts also present with neutrophil-platelet aggregates & a distinct neutrophil/ platelet activation pattern in blood, changing with disease severity: cases of intermediate severity show an exhausted platelet & hyporeactive neutrophil phenotype, severely affected COVID-19 pts are characterized by excessive platelet & neutrophil activation vs healthy controls & non-COVID pneumonia.
• ·      Dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability suggesting that this is a key marker of disease severity in COVID-19.

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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.

• ·      Children ages 0-22 years with suspected SARS-CoV-2 infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) were evaluated.
• ·      A total of 192 children (mean age 10.2 +/- 7 years) were enrolled: 49 (26%) with acute SARS-CoV-2 infection; an additional 18 children (9%) met criteria for MIS-C.
• ·      Only 25 (51%) children with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were non-specific.
• ·      Nasopharyngeal viral load was highest in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002).
• ·      Age did not impact viral load, but younger children had lower ACE2 expression (P=0.004).
• ·      IgM and IgG to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein were increased in severe MIS-C (P<0.001), with dysregulated humoral responses observed.
• ·      Children may be a potential source of contagion in the SARS-CoV-2 pandemic in spite of milder disease or lack of symptoms, and immune dysregulation is implicated in severe post-infectious MIS-C.

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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  

• ·      To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India, an open label, parallel arm, phase II, multi-centre, randomised controlled trial was performed in 39 public and private hospitals across India.
• ·      464 adults admitted to hospital between 22 April & 14 July 2020 with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm).
• ·      Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study.
• ·      Main outcome measure as a composite of progression to severe disease (PaO2/FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment.
• ·      Results: Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval −0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54).
• ·      Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality.
• ·      This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity.

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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.

• ·      To characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in hospitalized pts with COVID-19, a combined multicenter study evaluated all pts with elevated cardiac troponin at any point during hospitalization plus recorded ECG and trans-thoracic echocardiographic assessment (TTE).
• ·      Of 305 pts, myocardial injury was observed in 190 patients (62.3%). Compared with patients without myocardial injury, those with myocardial injury had more ECG abnormalities, higher inflammatory biomarkers and an increased prevalence of major
• ·      TTE abnormalities. included LV wall motion abnormalities, global LV,dysfunction, LV diastolic dysfunction grade II or III, RV dysfunction and pericardial effusions.
• ·      In-hospital mortality rates were 5.2%, 18.6%, & 31.7% in pts without myocardial injury, with myocardial injury without TTE abnormalities & with myocardial injury and TTE abnormalities.
• ·      With MVA, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities.

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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

• ·      Updated COVID-19 mortality data reported from the CDC for May to August 2020.,
• ·      Of 114,411 deaths across the US during this time, a disproportionate percentage were black (18.7% of overall deaths despite representing 12.5% of the US population) and Hispanic (24.2% of overall deaths despite representing 18.5% of the US population) decedents.
• ·      The Hispanic percentage of overall COVID-19 deaths increased from 14% in May to 25% in August.
• ·      The report highlights geographic trends, including a dramatic increase in the % distribution of COVID-19–associated deaths in the South from 23.4% in May to 62.7% in August.
• ·      àThe COVID-19 pandemic continues to expose and exacerbate pre-existing health disparities in the US. By highlighting racial and geographic trends, this updated report provides sobering evidence to direct ongoing public health efforts.

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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

• ·      To determine characteristics and outcomes of stroke associated with COVID19, this case-control study included all patients admitted with stroke to 13 hospitals in England and Scotland between 9th March and 5th July 2020.
• ·      There were 86 strokes (81 ischaemic strokes & 5 intracerebral hemorrhages) in pts with evidence of COVID-19 at the time of stroke onset; they were compared with 1384 strokes (1193 ischaemic strokes & 191 intracerebral haemorrhages) in pts admitted during the same time period who never had evidence of COVID19 (Controls).
• ·      The whole group of stroke admissions, plus another 37 in pts who appeared to have developed COVID-19 after their stroke, were included in two logistic regression analyses examining which features were independently associated with COVID-19 status and with inpatient mortality.
• ·      RESULTS: Cases with ischaemic stroke were more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%, p<0.0002), were more likely to involve multiple large vessel occlusions (17·9% vs 8.1%,p<0·03), were more severe (median NIHSS 8 vs 5, p<0·002), were associated with higher D-dimer levels (p<0·01) and were associated with more severe disability on discharge (median mRS 4 vs 3,p<0·0001) and inpatient death (19.8% vs9·6%, p<0·0001).
• ·      Data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke.

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

• ·      Investigation of SARS-CoV-2-challenged & naïve hamsters in closed system units separated by a polyvinyl chloride air porous partition with unidirectional airflow within the isolator +/- a surgical mask partition placed in between the cages.
• ·      Hamsters tested for viral load, histopathology & viral nucleocapsid Ag expression.
• ·      Non-contact transmission was found in 66.7% (10/15) of exposed naïve hamsters.
• ·      Surgical mask partition for challenged index or naïve hamsters reduced transmission to 25% (6/24, P=0.018). Surgical mask partition for challenged index hamsters reduced transmission to only 16.7% (2/12, P=0.019) of exposed naïve hamsters.
• ·      Unlike the severe COVID-19 manifestations of challenged hamsters, infected naïve hamsters had lower clinical scores, milder histopathological changes, and lower viral nucleocapsid antigen expression in respiratory tract tissues.

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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

• ·      Background: Evidence supporting airborne transmission of SARS-CoV-2 is emerging with an experimental study demonstrating SARS-CoV-2 viability in aerosols for >3 hrs & evidence of SARS-CoV-2 transmission between ferrets via the air established. 
• ·      To investigate airborne transmission between humans in a community setting, an outbreak of COVID-19 among lay Buddhists in Zhejiang province was investigated.
• ·      On January 19, 2020, 128 individuals took 2 buses (60 in bus 1, 68 in bus 2) on a 100-min round trip to attend a 150-min worship event. One passenger on bus 2 was SARS-C0V-2 positive. In both buses, central A/Cs were in indoor recirculation mode.
• ·      Results: 24 of 68 individuals (35.3%) on bus 2, received a diagnosis of COVID-19 after the event vs. none of the 60 individuals in bus 1. Among the other 172 individuals at the event, 7 (4.1%) subsequently received a COVID-19 diagnosis.
• ·      Individuals in bus 2 had a 34.3% (95% CI, 24.1%-46.3%) higher risk of getting COVID-19 vs. those in bus 1 and were 11.4 times (95% CI, 5.1-25.4) more likely to have COVID-19 compared with all other individuals attending the event.
• ·      On bus 2, individuals in high-risk zones had moderately, but not significantly, higher risk for COVID-19 compared with those in low-risk zones. Absence of a significantly increased infection risk in locations closer to the index case suggests that airborne spread at least partially explains the extremely high attack rate.

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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

• ·      Cross-sectional study of SARS-CoV-2 spike protein receptor binding domain total antibody in 28,503 randomly selected adult pts who received dialysis in 7/2020
• ·      Data on age, sex, race and ethnicity, residence and facility ZIP codes were extracted from EHRs, linking pt-level residence data with cumulative and daily cases, deaths per 100 000 population and with nasal swab test positivity rates.
• ·      Prevalence estimates were standardized according to the overall US dialysis and adult population, and present estimates for 4 strata: age, sex, region, R/E.
• ·      RESULTS:  Seroprevalence was 9·3% (8·8–9·9) when standardised to
• the US adult population.
• ·      When standardised to the US dialysis population, seroprevalence ranged from 3·5%(3·1–3·9) in the west to 27·2% (25·9–28·5) in the northeast.
• ·      Comparing seroprevalent and case counts per 100000 population, 9·2% (8·7–9·8) of seropositive patients were diagnosed.
• ·      Seroprevalence correlated best with deaths per 100 000 population (Spearman’s
• ρ=0·77).
• ·      Residents of non-Hispanic Black and Hispanic neighborhoods experienced higher odds of seropositivity (OR 3·9 [95% CI 3·4–4·6] & 2·3 [1·9–2·6], respectively) vs residents of predominantly non-Hispanic white neighborhoods.
• ·      Residents of neighborhoods in the highest population density quintile experienced
• increased odds of seropositivity (10·3 [8·7–12·2]) vs lowest density quintile residents.
• ·      INTERPRETATION: During the first wave of the COVID-19 pandemic, fewer than 10% of the US adult population formed antibodies against SARS-CoV-2, and fewer than 10% of those with antibodies were diagnosed.

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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

• ·      Retrospective study of all pts at an urban academic medical ctr with vitamin D level (25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol) measured within 1 yr  before COVID-19 testing, from 3/3 to 4/19/2020.
• ·      Vitamin D deficiency defined by the last 25-hydroxycholecalciferol <20 ng/mL. or 1,25-dihydroxycholecalciferol <18 pg/mL before COVID-19 testing.
• ·      Vitamin D deficiency & Rx changes combined to categorize vitamin D status as likely deficient (last level deficient/ Rx not increased); likely sufficient (last level not deficient/ Rx not decreased), and 2 groups with uncertain deficiency.
• ·      RESULTS: 489 pts, mean age 49.2+/-18.4 yrs, 75% women, 68% nonwhite; vit D likely deficient for 25%, sufficient for 59%, uncertain for 16%
• ·      71 pts (15%) tested (+) for COVID-19. In MVA, testing (+) for COVID-19 was associated with increasing age up to age 50 yrs (RR 1.06; CI, 1.01-1.09; P = .02); non-White race (RR 2.54; CI 1.26-5.12; P = .009), likely deficient vitamin D status (RR 1.77; CI, 1.12-2.81; P = .02) vs, 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.
• ·      à In this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased risk of COVID-19 infection.

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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

• ·      Multicenter retrospective analysis and nested prospective observational substudy of 95 critically ill patients with COVID-19.
• ·      ABO blood group distributions did not differ from national standards
• ·      Higher proportion of COVID-19 pts with blood group A or AB required mechanical ventilation (P = .02) and dialysis (P = .004) and had a longer ICU stay (P = .03)
• ·      Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity.
• ·      CONCLUSION: COVID-19 pts with blood group A or AB are at increased risk for requiring mechanical ventilation and exhibit greater disease severity than patients with blood group O or B.

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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

• ·      To systematically review the susceptibility to and transmission of SARS-CoV-2 among children and adolescents compared with adults, PubMed and medRxiv were searched & a total of 13 926 studies were identified..
• ·      Main Outcomes and Measures:  Secondary infection rate (contact-tracing studies) or prevalence or seroprevalence (population screening studies) among children and adolescents compared with adults.
• ·      Results: A total of 32 studies comprising 41 640 children and adolescents and 268 945 adults met inclusion criteria (18 contact-tracing studies;14 population screening studies). Pooled odds ratio of being an infected contact in children compared with adults was 0.56 (95% CI, 0.37-0.85), with substantial heterogeneity.
• ·      Three school-based contact-tracing studies found minimal transmission from child or teacher index cases. Findings from population screening studies were heterogenous and were not suitable for meta-analysis.
• ·      à There is preliminary evidence that children and adolescents have lower susceptibility to SARS-CoV-2, with an odds ratio of 0.56 for being an infected contact compared with adults. There is weak evidence that children and adolescents play a lesser role than adults in transmission of SARS-CoV-2 at a population level.
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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.

• ·      Analysis of mobile-phone records from 3/2 to 5/1, 2020 for 98 million US people provided anonymized location information, comprising more than 5 billion time points.
• ·      Cell phone data allowed creation of acquired mobility networks mapping the hourly movements of all 98 million people from neighborhoods (census blocks[CBGs]) to points of interest (POIs) such as restaurants and religious establishments, connecting 57k CBGs to 553k POIs with 5.4 billion hourly edges.
• ·      For a given venue, the mobile phone data gives detailed estimates of how many people visit/hr, average length of stay and neighborhood of origin.
• ·      Hypothesis is that the rate at which people in a population are likely to become infected depends on which venues they visit and how long they stay. Venues at which people stay longer and that are more densely occupied carry a higher risk than less crowded settings where people stay for less time.
• ·      Cell phone data was used as parameters in a mathematical metapopulation SEIR model to simulate the spread of SARS-CoV-2 in 10 large US cities.
• ·      By capturing information about individual POIs (e.g., hourly number of visitors, median visit duration), the model can estimate the impacts of specific reopening
• strategies, such as only reopening certain POI categories or restricting maximum occupancy at each POI.
• ·      RSULTS: Restaurants, gyms, cafes and other crowded indoor venues accounted for 8 in 10 new coronavirus infections in large cities in the early months of the epidemic.
• ·      Low-income neighborhoods were hardest hit because public venues in those communities were more crowded than in more affluent ones, and residents were more mobile on average, likely because of work demands.
• ·      à Capping the maximum occupancy of venues — a strategy that implicitly reduces the number of person-hours spent in risky, high-occupancy settings — was predicted to result in a decreased number of new infections compared with a strategy of
• less-targeted, overall activity reduction.
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• de Vries RD, Schmitz KS, Bovier FT et al. Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets. Med Rx iv. Nov. 5, 2020. doi: https://doi.org/10.1101/2020.11.04.361154
• ·      SARS-CoV-2 infection is initiated by membrane fusion between the virus and host  nasal membrane cells, mediated by the viral spike protein.
• ·      A nasal spray containing a dimeric lipopeptide fusion inhibitor that blocks this critical first step of infection was developed.
• ·      Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals.
• ·      These lipopeptides are highly stable and non-toxic and could translate into a safe & effective intranasal prophylactic approach to reduce transmission of SARS-CoV-2.
• ·      Studies in humans are underway.

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

• ·      RCT comparing convalescent plasma with standard of care therapy in pts hospitalized for COVID-19 in the Netherlands.
• ·      Pts were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80.
• ·      Primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.
• ·      Results: The trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline.
• ·      A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) pts tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40).
• ·      No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated pts and pts on standard of care.
• ·      Conclusion Most COVID-19 pts already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma.

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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.

• ·      Famotidine, a histamine-2 receptor antagonist used to treat heartburn, is postulated to be effective against SARS-C0V-2 infection since that process is thought to be at least partially mediated by pathological histamine release.
• ·      Retrospective, propensity-matched observational study of consecutive COVID-19 positive pts between 2/24/2020 and 5/13/2020.
• ·      878 pts, 83 received famotidine; FAM pts were slightly younger but did not differ with respect to baseline demographics or pre-existing comorbidities.
• ·      FAM use was associated with a significantly decreased risk of in-hospital mortality (OR 0.37, 95%CI 0.16-0.86; p=.021) as well as combined death or intubation.(OR 0.47. 95% CI 0.23-0.96; p=0.04)
• ·      Adjusting for age difference did not change results.
• ·      FAM pts had lower serum markers for severe disease including CRP & pro-calcitonin.
• ·      By logistic regression, FAM was an independent predictor of lower mortality and death/intubation while older age, BMI>30 kg/m², CKD & higher neutrophil/lymphocyte ratio were all predictors of both adverse outcomes.

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

• ·      On Sept. 2, JAMA published the results of 3 multicenter RCTs that assessed corticosteroid therapy in critically ill patients with COVID-19 and a WHO-sponsored prospective M/A.
• ·      Results show conclusive benefit for steroid treatment best appreciated in the prospective M/A which included the results of these 3 RCTs, the RECOVERY trial of dexamethiasone published in the NEJM in 6/2020 & 3 additional trials, totaling 1703 patients (678 had been randomized to corticosteroids and 1025 to usual care or placebo. 28-day mortality was significantly lower in pts randomized to corticosteroids: 222 deaths among 678 pts vs. 425 deaths among 1025 pts (summary odds ratio, 0.66 [95% CI, 0.53,-0.82]; P < .001).
• ·      The association between administration of corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect; was similar with lower- vs higher-dose steroid regimens; and was similar among pts with fewer vs greater than 7 days of symptoms at randomization.
• ·      Corticosteroids also appear to be associated with benefit among critically ill pts with COVID-19 whether they are receiving mechanical ventilation or O2 alone.
• ·      The launch and conduct of these high-quality trials in the midst of a pandemic is an important accomplishment, as is the agreement to share unpublished data with WHO, exemplifying how science can advance even in the context of numerous underpowered RCTs.
• Ø Corticosteroids are inexpensive, readily available, and based on these data, are associated with reduced mortality in critically ill patients with COVID-19.

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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

• ·      Double-blind RCT of intravenous remdesivir in adults hospitalized with Covid-19 who had evidence of lower respiratory tract infection.
• ·      1062 pts 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.
• ·      RESULTS Remdesivir pts had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11) vs 15 days (95% CI, 13 to 18) (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test).
• ·      Patients who received remdesivir were more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity).
• ·      Kaplan–Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03).
• ·      Serious AEs were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%).
• ·      CONCLUSIONS Remdesivir was superior to placebo in shortening time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.

Home.

RAOM COVID-19 ARCHIVE: NOVEMBER-DECEMBER 2020

THE VIRUS

Y. J. Hou, Chiba S, Halfmann P et al.  et al. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science 10.1126/science.abe 8499 (2020). First release: 12 November 2020 www.sciencemag.org

• ·      Recent reports have identified an emergent D614G substitution in the spike glycoprotein of SARS-CoV-2 strains that is now the most prevalent form globally.
• ·      Patients infected with the D614G variant have higher upper respiratory tract viral loads than seen with the ancestral strain, but not altered disease severity.
• ·      SARS-CoV-2 S pseudotyped viruses encoding the D614G substitution were reported to exhibit increased infectivity in continuous cell lines and increased sensitivity to neutralization
• ·      To examine whether the D614G substitution enhances authentic SARS-CoV-2 entry, four susceptible cell lines were infected with the ancestral wild-type (WT)-nLuc and D614G-nLuc viruses. The D614G-nLuc infection resulted in a 3.7 to 8.2-fold higher transgene expression as compared with WT-nLuc virus in different cell lines.
• ·      Growth curves comparing WT and D614G viruses were performed in those cell lines. Although the D614G variant showed similar or slightly higher titers at 8 hrs, its peak titers were ~0.5 logs lower than the ancestral WT virus.
• ·      With multi-step growth kinetics (MOI = 0.1) of the WT and D614G viruses in ex vivo primary human nasal epithelial (HNE) cells, large proximal airway epithelial cells from SARS-CoV-2 D614G variant exhibited efficient replication ex vivo and transmission in vivo.

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Meinhardt, J., Radke, J., Dittmayer, C. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-00758-5

• ·      Neurological symptoms such as loss of smell and taste, headache, fatigue, nausea and vomiting are present in more than one-third of individuals with COVID-19., investigators performed a systematic analysis of autopsy brains and peripheral tissues aimed at understanding the port of entry and distribution for SARS-CoV-2 within the CNS.
• ·      To investigate SARS-CoV-2 penetrance of the CNS, investigators analyzed the cellular mucosal–nervous micromilieu as a first site of viral infection and replication, followed by thorough regional mapping of the consecutive olfactory nervous tracts and defined CNS regions, in autopsy material from 33 individuals with COVID-19.
• ·      Analysis visualized viral RNA and protein using ISH and immunohistochemical staining techniques and showed SARS-CoV-2 can enter the nervous system by crossing the neural–mucosal interface in olfactory mucosa in the nasopharynx, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings.
• ·      Morphological changes such as thromboembolic ischemic infarction of the CNS & present evidence of SARS-CoV-2 neurotropism were shown to follow neuroanatomical structures in defined neuro- anatomical areas including the primary respiratory & CV control center in the medulla oblongata.
• ·      Presence of intact CoV particles & SARS-CoV-2 RNA in the olfactory mucosa and in neuro-anatomical areas receiving olfactory tract projections suggests SARS-CoV-2 neuro-invasion via axonal transport.

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Çevik M, et al. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe 2020; DOI: 10.1016/S2666-5247(20)30172-5.

• ·      To characterize viral load dynamics, duration of viral RNA shedding, and viable virus shedding of SARS-CoV-2, and to compare SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) viral dynamics, a systematic review and meta-analysis of research articles published between Jan 1, 2003, and June 6, 2020 was performed.
• ·      Findings: 79 studies (5340 individuals) on SARS-CoV-2, 8 studies (1858 individuals) on SARS-CoV, and 11 studies (799 individuals) on MERS-CoV were included.
• ·      Mean duration of SARS-CoV-2 RNA shedding was 17·0 days (95% CI 15·5–18·6) in upper respiratory tract, 14·6 days (9·3–20·0) in lower respiratory tract, 17·2 days (14·4–20·1) in stool, and 16·6 days (3·6–29·7) in serum samples.
• ·      Pooled mean SARS-CoV-2 shedding duration was positively associated with age (slope 0·304 [95% CI 0·115–0·493]; p=0·0016).
• ·      No study detected live virus beyond day 9 of illness, despite persistently high viral loads, which were inferred from cycle threshold values. SARS-CoV-2 viral load in the upper respiratory tract appeared to peak in the first week of illness, whereas that of SARS-CoV peaked at days 10–14 and that of MERS-CoV peaked at days 7–10.

à Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived.

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Mengfei Chen, Wenjuan Shen, Nicholas R. Rowan et al. Elevated ACE2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. European Respiratory Journal, 2020; 2001948 DOI: 10.1183/13993003.01948-2020

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Peckham, H., de Gruijter, N.M., Raine, C. et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun 11, 6317 (2020). https://doi.org/10.1038/s41467-020-19741-6

• ·      To address whether the reported sex-bias is validated by large-scale statistical analysis of global data, we have collected available case data from 90 reports including 46 different countries and 44 US states totalling 3,111,714 infected cases, and present a meta-analysis to investigate sex as a risk factor for SARS-CoV-2 infection, and COVID-19 morbidity and mortality.
• ·      The proportion of male cases with COVID-19 in these reports was exactly half at 0.50 (95% confidence interval (CI) = 0.48,0.51; p = 0.56; n = 3,111,714), demonstrating that males and females have similar numbers of infections.
• ·      Male sex was associated with increased odds of ITU admission (odds ratio (OR) = 2.84; 95% CI = 2.06, 3.92; p = 1.86 × 10−10; n = 341,571), and increased odds of death (OR = 1.39; 95% CI = 1.31,1.47; p = 5.00 × 10−30; n = 2,751,115).

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Emerging SARS-CoV-2 Variants. MMWR Dec. 20, 2020.

• ·        Multiple SARS-CoV-2 variants are circulating globally with several new variants emerging in the fall of 2020.
• ·        In the United Kingdom, a Variant of Concern (VOC) 202012/01, a.k.a. B.1.1.7, has a mutation in the receptor binding domain (RBD) of the spike protein at position 501, where amino acid asparagine (N) has been replaced with tyrosine (Y). The shorthand for this mutation is N501Y. There are several other associated, identified mutations.
• ·        This variant is estimated to have first emerged in the UK during September 2020.
• ·        Since December 20, 2020, 33 countries have reported cases of B.1.1.7 , including the US and Canada.
• ·        Preliminary epidemiologic indicators suggest that this variant is associated with increased transmissibility.
• ·        In South Africa, another variant of SARS-CoV-2 (501Y.V2 or B.1.351) has emerged independently although the 2 variants share some mutations.
• ·        In Nigeria, another distinct variant strain of SARS-CoV-2 also emerged.
• ·        Currently there is no evidence to suggest that these variants have any impact on the severity of disease or vaccine efficacy.

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Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data.  Faculty of Medicine. School of Public Health, Infectious Disease & Epidemiology. MRC Centre for Global Infectious Disease.  Analysis of COVID-19:  Report 42 - Dec. 31,2020. Erik Volz, Ferguson N, Mishra S eta l. e.volz@imperial.ac.uk, neil.ferguson@imperial.ac.uk.

• ·        The SARS-CoV-2 lineage B.1.1.7 originated in the UK in late Summer to early Autumn 2020. British investigators examined epidemiological evidence for a transmission advantage of B.1.1.7.
• ·        Whole genome sequence data collected from community-based diagnostic testing reveals an increased prevalence of the B.1.1.7 variant over time. Phylodynamic modelling additionally indicates that genetic diversity of this lineage has changed consistent with exponential growth.
• ·        Changes in B.1.1.7 frequency inferred from genetic data correspond closely to changes inferred by S-gene target failures (SGTF) in community-based diagnostic PCR testing.
• ·        Growth trends in SGTF and non-SGTF case numbers at local area level across England show that B.1.1.7 has higher transmissibility than non-B.1.1.7 lineages, even if B.1.1.7 has a different latent period or generation time.
• ·        B.1.1.7 has a substantial transmission advantage with its reproduction numbers varying from 1.4 to 1.8. (For context, prior research found seasonal influenza had a median reproduction number of 1.28, while the median reproduction number for the 1918 flu pandemic was 1.80.)
• ·        Available SGTF data indicate a shift in the age composition of reported cases, with a larger share of under 20 yr olds among reported B.1.1.7 than non-B.1.1.7 cases.

THE DISEASE

Dam JM, Mateus J, Kato Y et al. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection  bioRxiv. November 17, 2020. doi: https://doi.org/10.1101/2020.11.15.383323

We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 185 COVID-19 cases, including 41 cases at > 6 months post-infection. Spike IgG was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics. Eight months after infection, most people who have recovered still have enough immune cells to fend off the virus and prevent illness, the new data show. A slow rate of decline in the short term suggests, happily, that these cells may persist in the body for a very, very long time to come.

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Levin AT, Hanage WP, Owasu-Boaitey N et al. Assessing the Age Specificity of Infection Fatality Rates for COVID-19: Systematic Review, Meta-Analysis, and Public Policy Implications. medRxiv. Nov, 2020 doi: https://doi.org/10.1101/2020.07.23.20160895

• ·      To determine age-specific infection fatality rates for COVID-19, studies of COVID-19 prevalence were collected and 17 studies satisfied the inclusion criteria and were included in the meta-analysis.
• ·      Age-specific IFRs were computed using the prevalence data in conjunction with reported fatalities 4 weeks after the midpoint date of the study, reflecting typical lags in fatalities and reporting. Meta-regression procedures in Stata were used to analyze the infection fatality rate (IFR) by age.
• ·      Results: There is an exponential relationship between age and IFR for COVID-19. The estimated age-specific IFR is very low for children (0.002% at age 10) and younger adults (0.01% at age 25) but increases progressively to 0.4% at age 55, 1.4% at age 65, 4.6% at age 75, and 15% at age 85.
• ·      90% of the variation in population IFR across geographical locations reflects differences in the age composition of the population.

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Piazza G, Campia U, Hurwitz S et al. Registry of Arterial and Venous Thromboembolic Complications in Patients With COVID-19. J Amer Coll Cardiol 2020; 76(18):2060-2072. November, 2020.

• ·      To assess the frequency of arterial and venous thromboembolic disease, risk factors, prevention and management patterns, and outcomes in patients with COVID-19, a multicenter, observational cohort study assessed 1114 pts.
• ·      Analysis was by site of acre: ICU (n = 170); hospitalized non-ICU (n = 229); Out Pt (n = 715).  Primary study outcome was a composite of adjudicated major arterial or venous thromboembolic events.
• ·      Patients with COVID-19 were 22.3% Hispanic/Latinx and 44.2% non-White. Hypertension (35.8%), hyperlipidemia (28.6%), and DM (18.0%) were common.
• ·      Prophylactic anticoagulation was prescribed in 89.4% of patients in the ICU cohort and 84.7% of those in the hospitalized non-ICU setting.
• ·      Major arterial or venous thromboembolism, major CV adverse events, and symptomatic venous thromboembolism were highest in the ICU cohort (35.3%, 45.9%, and 27.0 %, respectively) followed by the hospitalized non=ICU cohort (2.6%, 6.1%, and 2.2%, respectively). No outpts had any TE event.
• ·      CONCLUSION: Despite high utilization of thromboprophylaxis, major arterial or venous thrombo- embolism, major CV events, and symptomatic venous thromboembolism occurred with high frequency in patients with COVID-19, especially in the ICU setting.

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Bailey LC, Razzaghi H, Burrows EK, et al. Assessment of 135 794 Pediatric Patients Tested for Severe Acute Respiratory Syndrome Coronavirus 2 Across the United States. JAMA Pediatr. Published online November 23, 2020. doi:10.1001/jamapediatrics.2020.5052

• ·      To describe SARS-CoV-2 testing & the epidemiology of infected pts, a retrospective cohort study was conducted using EHR data from all pts <25 yrs tested for SARS-CoV-2 from 1/1 – 9/8, 2020 in PEDSnet, a network of 7 US pediatric health systems, comprising 6,500,000 pts from 11 states.
• ·      Results:  Of 135 794 pediatric pts, 53% were male; mean [SD] age, 8.8 [6.7] years; 3% Asian, 15% Black, 11% Hispanic, and 59% White.
• ·      290 per 10 000 population were tested for SARS-CoV-2, and 5374 (4%) were infected with the virus (12 per 10 000 population [range, 7-16 per 10 000 population]).
• ·      Compared with White pts, those of Black, Hispanic, and Asian race/ethnicity had lower rates of testing (Black: odds ratio [OR], 0.70 [95% CI, 0.68-0.72]; Hispanic: OR, 0.65 [95% CI, 0.63-0.67]; Asian: OR, 0.60 [95% CI, 0.57-0.63]); however, they were significantly more likely to have (+) test results (Black: OR, 2.66 [95% CI, 2.43-2.90]; Hispanic: OR, 3.75 [95% CI, 3.39-4.15]; Asian: OR, 2.04 [95% CI, 1.69-2.48]).
• ·      Older age (5-11 years: OR, 1.25 [95% CI, 1.13-1.38]; 12-17 years: OR, 1.92 [95% CI, 1.73-2.12]; 18-24 years: OR, 3.51 [95% CI, 3.11-3.97]), public payer (OR, 1.43 [95% CI, 1.31-1.57]), outpatient testing (OR, 2.13 [1.86-2.44]), & ED  testing (OR, 3.16 [95% CI, 2.72-3.67]) were associated with increased risk of infection.
• ·      In univariate analyses, nonmalignant chronic disease was associated with lower likelihood of testing, and preexisting respiratory conditions were associated with lower risk of (+) test results (standardized ratio [SR], 0.78 [95% CI, 0.73-0.84]). Every other diagnosis group was associated with a higher risk of (+) test results.
• ·      Among the 5374 pts with (+) test results, 359 (7%) were hospitalized for respiratory, hypotensive, or COVID-19–specific illness. Of these, 99 (28%) required ICU services, and 33 (9%) required mechanical ventilation.  The case fatality rate was 0.2% (8 of 5374).
• ·      Conclusions/ Relevance:  In this large cohort study of US pediatric patients, SARS-CoV-2 infection rates were low & clinical manifestations were typically mild. Black, Hispanic & Asian race/ethnicity; adolescence & young adulthood; & non-respiratory chronic medical conditions were associated with identified infection.

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Bajema KL, Wiegand RE, Cuffe K, et al. Estimated SARS-CoV-2 Seroprevalence in the US as of September 2020. JAMA Intern Med. Published online November 24, 2020. doi:10.1001/jamainternmed.2020.7976

• ·      To estimate the prevalence of SARS-CoV-2 antibodies, this repeated, cross-sectional study conducted across all 50 states, DC and Puerto Rico used a convenience sample of residual serum specimens originally submitted for routine screening/clinical management from 2 private commercial labs.
• ·      Samples were obtained during 4 collection periods: July 27 to August 13, August 10 to August 27, August 24 to September 10, and September 7 to September 24, 2020.
• ·      MAIN OUTCOME: The proportion of persons previously infected with SARS-CoV-2 as measured by the presence of antibodies to SARS-CoV-2 by 1 of 3 chemiluminescent immunoassays.
• ·      RESULTS:  Of 177 919 serum samples tested, 58.3% were from women, 15% from persons <17 yrs, 26.7% from persons > 65 yrs, & 14.8% from individuals living in nonmetropolitan areas.
• ·      Seroprevalence over 4 collection periods ranged from < 1% to 23%. In 42/49 jurisdictions, <10% of people had detectable SARS-CoV-2 antibodies. Seroprevalence varied between sexes, across age groups, and between metropolitan/nonmetropolitan areas.
• ·      Changes from period 1 to 4 were less than 7 %age points in all jurisdictions and across sites.
• ·      Seroprevalence ranged from 0.0% (95% bootstrap CI, 0.0%-4.4%) in South Dakota in period 2 to 23.3% (95% bootstrap CI, 20.1%-26.3%) in NY in period 1.
• ·      Changes from period 1 to 4 varied across sites. The largest absolute decreases occurred in NY (6.3%) and North Dakota (6.1%), while large increases occurred in Georgia (6.2%) and Minnesota (4.5%).
• ·      CONCLUSIONS: As of September 2020, most persons in the US did not have serologic evidence of previous SARS-CoV-2 infection.

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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 Oct, 76 (18) 2043–2055.

• ·      To characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in pts with COVID-19, investigators reviewed ERs of all inpts from 7 hospitals with confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and ECG evaluation during their index hospitalization.
• ·      Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization.
• ·      RESULTS: A total of 305 pts were included, 67.2% male. Overall, myocardial injury was observed in 62.3%. Compared with pts without myocardial injury, those with myocardial injury had significantly more ECG abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities.
• ·      Pts with myocardial injury also had significantly more baseline HT, pre-existing cardiac problems and renal failure.
• ·      TTE abnormalities included LV wall motion abnormalities, global LV dysfunction, LV diastolic dysfunction grade II or III, RV dysfunction and pericardial effusions.
• ·      Rates of in-hospital mortality were 5.2% in patients without myocardial injury, 18.6% with myocardial injury without TTE abnormalities, and 31.7% with myocardial injury and TTE abnormalities. By MVA, myocardial injury with TTE abnormalities was associated with higher risk of death.

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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. doi:10.1001/jamanetworkopen.2020.19722

• ·      Vitamin D treatment decreases the incidence of viral respiratory tract infection, especially with vitamin D deficiency.  To examine association of vitamin D status with COVID-19 test results, this retrospective cohort study at an urban academic medical center included all pts with a 25-hydroxycholecalciferol/ 1,25-dihydroxycholecalciferol level measured within 1 yr before COVID-19 testing, from 3/3 -4/10/2020.
• ·      Vitamin D deficiency was defined by the last measurement of 25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL before 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: 489 pts (mean age, 49.2 [18.4] years; 75% women; 68% race other than White) had a vitamin D level measured in the year before COVID-19 testing. Vitamin D status was categorized as likely deficient for 124 pts (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%).
• ·      Overall, 71 pts (15%) tested positive for COVID-19. In MVA,  (+) COVID-19 test was associated with increasing age up to age 50 yrs (RR 1.06; 95% CI, 1.01-1.09; P = .02); non-White race (RR 2.54; 95% CI, 1.26-5.12; P = .009), and likely deficient vitamin D status (RR 1.77; 95% CI, 1.12-2.81; P = .02).
• ·      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.
• ·      àIn this single-center, retrospective cohort study, likely deficient vitamin D status was associated with increased COVID-19 risk.

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Woolf SH, Chapman DA, Lee JH. COVID-19 as the Leading Cause of Death in the United States. JAMA. Published online December 17, 2020. doi:10.1001/jama.2020.24865

• ·      COVID-19–related mortality rates were compared with the leading causes of death that, under ordinary circumstances, would pose the greatest threat to different age groups.
• ·      The 3 leading causes of death in each of the 10 age groups from infancy to old age were compared during the period of March through October 2018(the most recent year for which detailed cause-of-death data are available) with COVID-19 mortality rates during March through October 2020
• ·      By October 2020 COVID-19 had become the third leading cause of death for persons aged 45 through 84 yrs and the second leading cause of death for those aged >/= 85 yrs.
• ·      Adults >/= 45 yrs were more likely to die from COVID-19 during those months than from chronic lower respiratory disease, transport accidents (eg, MVAs), drug overdoses, suicide, or homicide.
• ·      In contrast, for individuals younger <45 yrs, other causes of death, such as drug overdoses, suicide, transport accidents, cancer, and homicide exceeded those from COVID-19.
• ·      These numbers are an underestimate because they represent aggregate data.  In fact, between 11/1/2020 & 12/13/2020, the 7-day moving average for daily COVID-19 deaths tripled, so that as occurred in the spring, COVID-19 has become the leading cause of death in the United States.
• ·      Daily mortality rates for heart disease and cancer, which for decades have been the 2 leading causes of death, are approximately 1700 and 1600 deaths per day, respectively. COVID-19 mortality rates now exceed these thresholds so that this infectious disease has become the leading cause of mortality in the USA, deadlier than heart disease and cancer.

TREATMENT/PREVENTION

Lernze EJ, Mattar C, Zorumski CF et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. Published online November 12, 2020. doi:10.1001/jama.2020.22760

• ·      COVID-19 may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production.
• ·      To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease.
• ·      Double-blind RCT of fluvoxamine vs placebo. 152 participants were community-living, non- hospitalized adults with confirmed severe ARDS acute respiratory syndrome & COVID-19 with symptom onset within 7 days and oxygen saturation of 92% or greater.
• ·      Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days
• ·      Primary outcome was clinical deterioration within 15 days defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) O2 saturation less than 92% on room air or need for supplemental O2 to achieve saturation of >/=92%.
• ·      Results:  115 pts completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (8.7% [95% CI, 1.8%-16.4%]; P = .009. The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events.
• ·      In this preliminary study of adult outpatients with symptomatic COVID-19, pts treated with fluvoxamine had a lower likelihood of clinical deterioration over 15 days.

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Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with COVID-19. N Engl J Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33113295.

• ·      Background: Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.
• ·      Methods: 452 outpatients with recently diagnosed mild/moderate Covid-19 were randomly assigned to receive a single IV infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo. Quantitative virologic end points and clinical outcomes were analyzed.
• ·      Results: Mean decrease from baseline in the log viral load for the entire population was -3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was -0.53 (95% confidence interval [CI], -0.98 to -0.08; P = 0.02), lower by a factor of 3.4. Smaller differences in change from baseline were observed among the pts who received the 700-mg doseor the 7000 mg dose.  
• On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19-related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.

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Simonovich  VA, Pratx LDB, Scibona P et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. NEJM: November 24, 2020.   DOI: 10.1056/NEJMoa2031304

• ·      To assess potential benefit of convalescent plasma, hospitalized adult pts with severe Covid-19 pneumonia were randomized in a 2:1 ratio to receive convalescent plasma or placebo. Primary outcome was clinical status 30 days post intervention, measured on a 6-point ordinal scale ranging from total recovery to death.
• ·      RESULTS 228 pts were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment.
• ·      At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46).
• ·      Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Adverse events were similar in the two groups.

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Kalil AC, Patterson TF, Mehta AK et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. New Engl J Med; December 11, 2020.                                                                                                                   DOI: 10.1056/NEJMoa2031994

• ·      Double-blind, randomized, placebo-controlled trial evaluating baricitinib (anti-inflammatory arthritis drug) plus remdesivir in hospitalized adults with Covid-19. All pts received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control).
• ·      Primary outcome was time to recovery. Key secondary outcome was clinical status at day 15.
• ·      515 pts assigned to combination treatment and 518 to control.
• ·      Baricitinib pts had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), vs 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).
• ·      Pts receiving high-flow O2 or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination Rx and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08).
• ·      28-day mortality was 5.1% in the combination group & 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)

àBaricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status in pts with Covid-19.

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Polack FP, Thomas SJ, Kitchin N et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New Engl J Med; December 10, 2020.                                                                                                                           DOI: 10.1056/NEJMoa2034577

• ·      BNT162b2 vaccine is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.
• ·      43,538 persons 16 years of age or older were randomized in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose)
• ·      Primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.
• ·      RESULTS: There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo à BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6).
• ·      Vaccine efficacy was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions.
• ·      Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient.
• ·      The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

àA two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines.

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Hranjec T, Estreicher M, Rogrs B et al.  Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019–Related Coagulopathy. Critical Care Explorations: December 2020 - Volume 2 - Issue 12 - p e0287                                                   doi: 10.1097/CCE.0000000000000287

• ·      To evaluate if algorithm-guided thromboelastography (TEG) with platelet mapping could better characterize COVID-19-related coagulopathic state & improve outcomes, 100 pts receiving TEG with platelet mapping assay upon admission were followed prospectively by a hospital-based TEG team.
• ·      Treating clinicians were provided with the option of using a pre-established algorithm for anticoagulation, including follow-up TEG with platelet mapping à 2 groups evolved: 1) patients managed by algorithm-guided TEG; and 2) those treated without algorithm-guided TEG.
• ·      RESULTS: Elevated d-dimer, C-reactive protein, and ferritin in critically ill pts did not distinguish between coagulopathic and noncoagulopathic patients.
• ·      Platelet hyperactivity (maximum amplitude-arachidonic acid/adenosine diphosphate > 50 min), with or without thrombocytosis, was associated with thrombotic/ischemic complications, whereas severe thrombocytopenia (platelet count < 100,000/μL) was uniformly fatal.
• ·      Hemorrhagic complications were observed with decreased factor activity (reaction time > 8 min).
• ·      Non-algorithm-guided patients had increased risk for subsequent mechanical ventilation (relative risk = 10.9; p < 0.0001), acute kidney injury (relative risk = 2.3; p = 0.0017), dialysis (relative risk = 7.8; p < 0.0001), and death (relative risk = 7.7; p < 0.0001), with 17 of 28 non-algorithm-guided patients (60.7%) dying versus four algorithm-guided-thromboelastography patients (5.6%) (p < 0.0001).
• ·      TEG with platelet mapping–guided antiplatelet treatment decreased mortality 82% (p = 0.0002), whereas non-algorithm-guided use of antifactor therapy (heparin/enoxaparin) resulted in 10.3-fold increased mortality risk (p = 0.0001).
• ·      CONCLUSION: TEG with platelet mapping better characterizes the spectrum of COVID-19 coagulation-related abnormalities and guides more tailored, pt-specific therapies in these pts.

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Clapp PW, Sickbert-Bennett EE, Samet JM, et al. Evaluation of Cloth Masks and Modified Procedure Masks as Personal Protective Equipment for the Public During the COVID-19 Pandemic. JAMA Intern Med. Published online December 10, 2020. doi:10.1001/jamainternmed.2020.8168

• ·      The Occupational Safety and Health Administration (OSHA) Fit Test was used to determine the fitted filtration efficiency (FFE) of various consumer-grade and improvised face masks and popular modifications of medical procedure masks.
• ·      a TSI 8026 Particle Generator was used to supplement the chamber with sodium chloride (NaCl) particles that had a count median diameter of 0.05 μm (range, 0.02-0.60 μm) as measured by a scanning mobility particle sizer. The test atmosphere reflects typical indoor conditions, with exposure to particles that are slightly smaller than individual SARS-CoV-2 virions (reported to range between 0.06 μm and 0.14 μm).
• ·      All masks were fitted on a non-obese man with no beard. A pair of TSI 3775 Condensation Particle Counters were run in single-particle analysis mode to continuously monitor ambient particles (0.02 μm-3 μm) in the chamber just outside the face mask and particles in the breathing space behind the face mask at a sampling rate of 1 second.
• ·      The FFE corresponds to the concentration of particles behind the mask expressed as a percentage of the particle concentration in the chamber air, and was measured for the duration of each test during multiple changes in position.
• ·      Two categories of products were tested for this study: consumer-grade face masks and medical procedure masks with and without enhancements.
• ·      RESULTS:
• ·     

à Simple modifications to improve medical mask fit can substantially improve filtration efficiency. However, when FFE is considered (combined fit and material filtration), we demonstrated the practical effectiveness of consumer-grade masks is nearly equivalent to or better than their non-respirator medical mask counterparts.

Home.

RAOM COVID-19 ARCHIVE: JANUARY-MARCH 2021

THE VIRUS

Washington NL, Karthik Gangavarapu K, Mark Zeller M et al. Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States. https://doi.org/10.1101/2021.02.06.21251159.

• ·      As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the U.K., has gained a strong foothold across the world.
• ·      We investigated the prevalence and growth dynamics of B.1.1.7 variant of SARS-CoV-2 in the U.S., tracking it back to its early emergence and onward local transmission.
• ·      Using the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K. as a reliable proxy for B.1.1.7 detection, we sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021.
• ·      While the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. enabling the variant to spread to at least 30 states as of January 2021.
• ·      Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

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Hodcraft EB, Domman DB, Oguntuyo K et al. Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677. medRxiv 2021.02.12.21251658;                    doi: https://doi.org/10.1101/2021.02.12.21251658

• ·      The SARS-CoV-2 spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, ACE2.
• ·      Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively.
• ·      Q677P cases have been detected predominantly in the south central and southwest US; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid August to late November, 2020.
• ·      Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission.

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Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission from People Without COVID-19 Symptoms. JAMA Network Open. 2021;4(1):e2035057. Published 1/7/2021. doi:10.1001/jamanetworkopen.2020.35057

• ·      To assess the proportion of SARS-CoV-2 transmissions in the community that likely occur from persons without symptoms, a decision analytic model was created to estimate the relative amount of transmission from presymptomatic, never symptomatic, and symptomatic individuals across a range of scenarios in which the proportion of transmission from people who never develop symptoms and the infectious period were varied according to published best estimates.
• ·      The incubation period was set at a median of 5 days, the infectious period duration was maintained at 10 days, and peak infectiousness was varied between 3 and 7 days (−2 and +2 days relative to the median incubation period).
• ·      The baseline assumptions for the model were that peak infectiousness occurred at the median of symptom onset and that 30% of individuals with infection never develop symptoms and are 75% as infectious as those who do develop symptoms.
• ·      RESULTS: In this base case, 59% of all transmission came from asymptomatic transmission, 35% from presymptomatic individuals and 24% from individuals who never develop symptoms.
• ·      Under a broad range of values for each of these assumptions, at least 50% of new SARS-CoV-2 infections was estimated to have originated from exposure to individuals with infection but without symptoms.
• ·      àEffective control of SARS-CoV-2 spread will require reducing the risk of transmission from people with infection who do not have symptoms by social mitigation measures until safe and effective vaccines are widely used.

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Beyer RM, Manica A, Mora C. Shifts in global bat diversity suggest a possible role of climate change in the emergence of SARS-CoV-1 and SARS-CoV-2. Science of The Total Environment, 2021. https://doi.org/10.1016/j.scitotenv.2021.145413.

• ·      Bats have a special place amongst animal pathogen hosts in that they carry the highest proportion of zoonotic viruses of all mammalian orders. Coronaviruses (CoVs) account for over a third of the sequenced bat virome, corresponding to an estimated more than 3000 different CoVs carried by the world's bats. Several CoVs known to infect humans have very likely originated in bats including the 3 types associated with human fatalities: MERS CoV, SARS (CoV-1) and SARS-CoV-2.
• ·      The number of CoVs present in an area is strongly correlated with local bat species richness, which in turn is affected by climatic conditions that drive the geographical distributions of species.
• ·      Strains of CoV found in bats in the southern Chinese Yunnan province currently most closely resemble both SARS-CoV-1 and SARS CoV-2, suggesting this area is a plausible place of origin of the bat-borne ancestors of the two lineages. These regions also comprise the native habitat of masked palm civits and Sunda pangolins which are assumed to have acted as intermediate hosts that eventually transmitted SARS-CoV-1 and SARS-CoV-2 to humans.
• ·      This study estimated species-specific geographical ranges of the world's bats based on global climatic conditions in the early 20th century and at present day, by first determining the global distribution of natural vegetation corresponding to a given climate, and then combining the derived vegetation maps with data on the spatial distribution and vegetation requirements of individual species.
• ·      The global distribution of bats at each of the two time periods was then determined by combining the relevant vegetation map with species-specific data available for all known bats: extents of occurrence (the outermost geographic limits of a species' observed/projected occurrence) & habitat requirements.
• ·      àIn this way, the geographical range of each individual bat species was estimated for the early 20th century and for the present. Finally, the total bat species richness in each grid cell was obtained as the number of species whose estimated geographic range included the grid cell at the relevant time period.
• ·      RESULTS: Areas estimated to have experienced significant increases in bat species richness as the result of climate change-driven range shifts include regions around Central Africa, several scattered patches in Central and South America, and notably a large spatial cluster located in the southern Chinese Yunnan province and neighboring regions in Myanmar and Laos.
• ·      This region coincides with the likely spatial origin of bat-borne ancestors of SARS-CoV-1 and SARS-CoV-2. Accounting for an estimated increase in the order of 100 bat-borne CoVs across the region, climate change may have played a key role in the evolution or transmission of the two SARS CoVs.

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Challen R, Brooks-Polek E, Read JM et al. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n579 (Published 10 March 2021)

• ·      To establish whether there is any change in mortality from infection with the new UK variant of SARS-CoV-2, 54 906 matched pairs of participants who tested positive for SARS-CoV-2 between 1 October 2020 and 29 January 2021, were followed-up until 12 February 2021.
• ·      Participants were matched on age, sex, ethnicity, multiple deprivation index, lower tier local authority region & sample date of (+) specimens, & differed only by detectability of the spike protein gene using the TaqPath assay, a proxy identifier for the UK variant of concern (VOC202012/1)aka B.1.1.7.
• ·      Main outcome measure was death within 28 days of the first positive SARS-CoV-2 test result.
• ·      RESULTS: The mortality hazard ratio associated with infection with B.1.1.7 compared with infection with previously circulating variants was 1.64 (95% confidence interval 1.32 to 2.04) in patients who tested positive for covid-19 in the community. In this comparatively low risk group, this represents an increase in deaths from 2.5 to 4.1 per 1000 detected cases.
• ·      CONCLUSIONS: The probability that the risk of mortality is increased by infection with VOC-202012/01/B.1.1.7 is high. If this finding is generalizable to other populations, infection with VOC-202012/1 has the potential to cause substantial additional mortality compared with previously circulating variants.

Davies, N.G., Jarvis, C.I., CMMID COVID-19 Working Group. et al. Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature 2021. https://doi.org/10.1038/s41586-021-03426-1

• ·      By analyzing a dataset linking 2,245,263 positive SARS-CoV-2 community tests and 17,452 COVID-19 deaths in England from 1 September 2020 to 14 February 2021, these investigators assessed disease severity related to infection with the B.1.1.7 variant.
• ·      For 1,146,534 (51%) of these tests, the presence or absence of B.1.1.7 can be identified because of mutations in this lineage preventing PCR amplification of the spike gene target, S gene target failure, SGTF1.
• ·      RESULTS: Based on 4,945 deaths with known SGTF status, we estimate that the hazard of death associated with SGTF is 55% (95% CI 39–72%) higher after adjustment for age, sex, ethnicity, deprivation, care home residence, local authority of residence and test date.
• ·      This corresponds to the absolute risk of death for a 55–69-year-old male increasing from 0.6% to 0.9% (95% CI 0.8–1.0%) within 28 days after a positive test in the community. Correcting for misclassification of SGTF and missingness in SGTF status, we estimate a 61% (42–82%) higher hazard of death associated with B.1.1.7.
• ·      CONCLUSION: Our analysis suggests that B.1.1.7 is not only more transmissible than preexisting SARS-CoV-2 variants, but may also cause more severe illness.

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Mendes Coutinho R, Marquitti FMD, Souto Ferreira L et al. Model-based evaluation of transmissibility and reinfection for the P.1 variant of SARS-CoV-2. medRxiv preprint, posted March 5, 2021.          https://doi.org/10.1101/2021.03.03.21252706.

• ·      The P.1 variant of SARS-VoV-2 emerged in the Amazonas state (Brazil) and was sequenced for the first time on 6-Jan-2021. It contains a constellation of mutations, ten in the spike protein. From December-2020 to February-2021, the Manaus province of Brazil was devastated by 4X more cases vs, the previous peak (April-2020). Prevalence of P.1 increased sharply from 0% in November 2020 to 73% in January 2021; in <2 mos, P.1 replaced previous lineages as the dominant pattern.
• ·      In this study, data from the national health surveillance of hospitalized individuals were analyzed using a model-based approach to estimate P.1 transmissibility & reinfection parameters by maximum likelihood. Sensitivity analysis was performed changing pathogenicity & the analysis period.
• ·      RESULTS: In all analyzed cases, the new variant transmissibility is found to be ~2.5 times higher compared to the previous variant in Manaus (CI: 2.1-2.8).  The reinfection probability due to the new variant is 6.4% (95% CI: 5.7 - 7.1%). The model estimated that at the time the new variant emerged, the prevalence of the wild variant was 68% (95% CI: 63-74%).
• ·      CONCLUSION: The consequences of the introduction of a highly transmissible variant have already been observed with the B.1.1.7 variant in the UK, USA and Europe. Higher transmissibility of the P.1 variant raises important concerns about more accelerated upsurges in the number of cases once P.1 spreads in the community in other parts of Brazil. Urgent mitigation measures are needed to control the spread of P.1.
• ·

THE DISEASE

Pandanaboyana S, Moir J, Leeds JS et al.  SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study. Gut 2021. Epub ahead of print. Feb. 5, 2021. http://dx.doi.org/10.1136/gutjnl-2020-323364.

• ·      Emerging evidence indicates that the pancreas may be a target organ of SARS-CoV-2 infection. To investigate the outcome of pts with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection, a prospective international multicentre cohort study of consecutive pts admitted with AP during the current pandemic was undertaken.
• ·      Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality.
• ·      1777 pts with AP were included during the study period from 1 March to 23 July 2020. 149 pts (8.3%) had concomitant SARS-CoV-2 infection.
• ·      RESULTS: Overall, SARS-CoV-2-positive pts were older, male and more likely to develop severe AP and ARDS (all, p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive pts with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001).
• ·      Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection.
• ·      CONCLUSION: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.

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Villerabel C, Makinson A, Jaussent A, et al. Diagnostic Value of Patient-Reported and Clinically Tested Olfactory Dysfunction in a Population Screened for COVID-19. JAMA Otolaryngol Head Neck Surg. Published online January 07, 2021. doi:10.1001/jamaoto.2020.5074

• ·      To prospectively evaluate the diagnostic value of a semiobjective olfactory test to assess patient-reported chemosensory dysfunction prior to testing for the presence of SARS-CoV-2, 809 consecutively screened pts were evaluated
• ·      Pts were screened for symptoms and underwent Clinical Olfactory Dysfunction Assessment (CODA), via rapid evaluation of olfactory function using identification and rated intensity of lavender, lemongrass, and mint to achieve a summed score ranging from 0 to 6.
• ·      COVID-19 status was assessed using reverse transcriptase–polymerase chain reaction to detect the presence of SARS-CoV-2 in samples collected via N-P swab.
• ·      RESULTS: Of 809 participants, 58 (7.2%) tested positive for SARS-CoV-2. Chemosensory dysfunction was reported by 20 of 58 participants (34.5%) with confirmed COVID-19 vs 29 of 751 participants (3.9%) who tested negative for COVID-19 (absolute difference, 30.6% [95% CI, 18.3%-42.9%]).
• ·      Olfactory dysfunction, either self-reported or clinically ascertained (CODA score ≤3), yielded similar sensitivity (0.31 [95% CI, 0.20-0.45] vs 0.34 [95% CI, 0.22-0.48]) and specificity (0.97 [95% CI, 0.96-0.98) vs 0.98 [95% CI, 0.96-0.99]) for COVID-19 diagnosis. The CODA score also revealed 5 of 19 participants (26.3%) with confirmed COVID-19 who had previously unperceived olfactory dysfunction.
• ·      CONCLUSIONS: In this prospective diagnostic study of outpts with asymptomatic to moderate COVID-19, olfactory dysfunction was present in 34.5% and was strongly suggestive of COVID-19.

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Nauen DW, Hooper JE, Stewart M, Solomon IH.  Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol. Published online February 12, 2021. doi:10.1001/jamaneurol.2021.0225

• ·         Acutely ill COVID-19 pts often have confusion and alteration of consciousness and in recovery, many experience continued neurologic symptoms. However, in autopsies from COVID-19 pts, neurologic abnormalities have largely not identified the chronic inflammation or marked neural changes typically associated with viral infection, and viral genetic material has been minimal or absent.
• ·         To evaluate this, brain tissue from 15 pts with COVID-19 & neurologic symptoms and 2 control pts in the same age group who died of hypoxia/ischemia underwent detailed histopathologic evaluation.
• ·         RESULTS: In 5 cases in cortical capillaries, we identified large cell nuclei morphologically consistent with megakaryocytes. To further characterize these cells, we performed immunohistochemistry for CD61 and CD42b, markers of platelets and megakaryocytes. CD61 labels these cells, as does CD42b, confirming their megakaryocyte identity. The cells were distinct from platelet clusters, which were found in postmortem intravascular precipitates. Evaluation of the cortex of 2 patients who tested negative for COVID-19 who had hypoxic brain changes demonstrated no megakaryocytes on CD61.
• ·         CONCLUSION/IMPLICATIONS: Multiple lines of evidence indicate endothelial dysfunction in severe COVID-19 illness. Lung examination demonstrates megakaryocytes and the cells have now been reported in other organs. One possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs. Megakaryocytes were found in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable. By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment.

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Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Network Open. 2021;4(2):e210830. doi:10.1001/jamanetworkopen.2021.0830.

• ·      A longitudinal prospective cohort of adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was enrolled at the University of Washington with a concurrent cohort of healthy patients in a control group. A total of 234 participants with COVID-19 were contacted to complete a single follow-up questionnaire between 3 and 9 months after illness onset between August and November 2020.
• ·      A total of 177 of 234 participants (75.6%; mean [range] age, 48.0 [18-94] years; 101 [57.1%] women) with COVID-19 completed the survey. Overall, 11 (6.2%) had been asymptomatic, 150 (84.7%) were outpatients with mild illness, and 16 (9.0%) had moderate or severe disease requiring hospitalization. The follow-up survey was completed a median (range) of 169 (31-300) days after illness onset among participants with COVID-19.
• ·      RESULTS: Among COVID-19 pts, persistent symptoms were reported by 17 of 64 (26.6%) aged 18 to 39 years, 25 of 83 (30.1%) aged 40 to 64 years, and 13 of 30 (43.3%) aged 65 years and older. Overall, 49 of 150 outpatients (32.7%), 5 of 16 hospitalized patients (31.3%), and 1 of 21 healthy participants (4.8%) in the control group reported at least 1 persistent symptom.
• ·      The most common persistent symptoms were fatigue (24 of 177 patients [13.6%]) and loss of sense of smell or taste (24 patients [13.6%]). A total of 51 outpatients and hospitalized patients (30.7%) reported worse HRQoL compared with baseline vs 4 healthy participants and asymptomatic patients (12.5%); 14 patients (7.9%) reported negative impacts on at least 1 activity of daily living (ADL), the most common being household chores.
• ·      CONCLUSION: In this cohort of individuals with COVID-19 who were followed up for as long as 9 months after illness, approximately 30% reported persistent symptoms.

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Ayoubkhani D, Khunti K, Nafilyan V et al. Post-COVID syndrome in individuals admitted to hospital with COVID-19: retrospective cohort study. BMJ 2021; 372: n693. Published 31 March 2021. doi: https://doi.org/10.1136/bmj.n693

• ·      To quantify rates of organ specific dysfunction in individuals with COVID-19 after hospital discharge, a retrospective cohort study was performed in 47,780 individuals(mean age 65, 55% men) after discharge from NHS hospitals compared with a matched control group from the general population.
• ·      Main outcome measures: Rates of hospital readmission (or any admission for controls), all-cause mortality, diagnoses of respiratory, cardiovascular, metabolic, kidney, and liver diseases until 30 September 2020. Variations in rate ratios by age, sex, and ethnicity.
• ·      RESULTS: Over a mean follow-up of 140 days, nearly a third of individuals who were discharged from hospital after acute COVID-19 were readmitted (14 060 of 47 780) and more than 1 in 10 (5875) died, with these events occurring at rates four and eight times greater than in the matched control group.
• ·      Rates of respiratory disease (P<0.001), diabetes (P<0.001), and cardiovascular disease (P<0.001) were significantly raised in COVID-19 pts, with 770 (95% confidence interval 758 to 783), 127 (122 to 132), and 126 (121 to 131) diagnoses per 1000 person years, respectively.
• ·      Rate ratios were greater for individuals aged less than 70 than for those aged 70 or older, and in ethnic minority groups compared with the white population, with the largest differences seen for respiratory disease (10.5 (95% confidence interval 9.7 to 11.4) for age less than 70 years v 4.6 (4.3 to 4.8) for age ≥70, and 11.4 (9.8 to 13.3) for non-white v 5.2 (5.0 to 5.5) for white individuals).
• ·      CONCLUSION: Individuals discharged from hospital after COVID-19 had increased rates of multiorgan dysfunction compared with the expected risk in the general population. The increase in risk was not confined to the elderly and was not uniform across ethnicities. The diagnosis, treatment, and prevention of post-covid syndrome requires integrated rather than organ or disease specific approaches, and urgent research is needed to establish the risk factors.

EPIDEMIOLOGY

• Falk A, Benda A, Falk P, Steffen S, Wallace Z, Høeg TB. COVID-19 Cases and Transmission in 17 K–12 Schools — Wood County, Wisconsin, August 31–November 29, 2020. MMWR Morb Mortal Wkly Rep 2021;70:136–140. DOI: http://dx.doi.org/10.15585/mmwr.mm7004e3
• ·      To assess in-school transmission of SARS-CoV-2, COVID-19 cases, spread, and compliance with mask use were investigated among 4,876 students and 654 staff members who participated in in-person learning in 17 K–12 schools in rural Wisconsin from August 31–November 29, 2020.
• ·      Participating schools were from three public school districts, one private school district, and one independent private school. Eight schools were elementary (grades K–6) with 1,529 students attending in-person, and 9 were secondary (grades 7–12) with 3,347 students attending in-person.
• ·      Basic COVID-19 precautions were in place: (1) Masking was required for all students and staff members at all schools. Students were asked to wear masks when within 6 feet of another person outdoors and at all times indoors. (2) Classroom cohorts of 10-12 students from one grade level were created with avoidance of mixing between cohorts. (3) Staff members were instructed to wear masks, maintain a distance of 6 feet from all persons and limit time in shared indoor spaces.
• ·      COVID-19 cases in schools were reported by public health or school administration officials using deidentified data. Infection source was determined by case investigations conducted by school administration and the public health department.
• ·      When a school was alerted to a positive case in a student or staff member, school officials identified persons who had had close contact and close contacts were required to quarantine in their homes.  If they experienced symptoms during the quarantine period, they were further investigated to determine whether in-school spread might have occurred.
• ·      RESULTS:  4,876 students and 654 staff members contributed data to the study. During the 13-week study period, a total of 3,393 COVID cases were reported in Wood County (cumulative incidence = 5,466 per 100,000 persons), including 191 cases within the participating schools (cumulative incidence = 3,454 per 100,000).
• ·      Cases occurred in 133 students and 58 staff members. Among these 191 cases, seven (3.7%) were attributed to in-school SARS-CoV-2 transmission, all among students. Five cases of transmission occurred in elementary school cohorts, and two in secondary school cohorts. Three of these seven cases occurred in one class in one elementary school, and the other four occurred at separate schools. No in-school transmission between separate classroom cohorts was reported.
• ·      Weekly COVID-19 incidence ranged from 34 to 1,189/100,000 persons in the community, and from 72 to 699 cases/100,000 among students and staff in the schools. COVID-19 incidence in schools conducting in-person instruction was 37% lower than that in the surrounding community.
• ·      Observed student masking compliance ranged from 92.1% to 97.4% and did not vary by student age.

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Flannery DD, Gouma S, Dhudasia MB et al. Assessment of Maternal and Neonatal Cord Blood SARS-CoV-2 Antibodies and Placental Transfer Ratios. JAMA Pediatr. Published online January 29, 2021. doi:10.1001/jamapediatrics.2021.0038.

• ·      To assess maternal and neonatal SARS-CoV-2–specific antibody concentrations, maternal and cord blood sera were assessed for antibodies in 1471 mother/newborn dyads. IgG and IgM antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein were measured by enzyme-linked immunosorbent assay.
• ·      Among the 1471 mother/newborn pairs for whom matched sera were available, SARS-CoV-2 IgG and IgM antibodies were detected in 6% of the women (83/1471) at the time of delivery, and IgG was detected in the cord blood of 87% of their newborns (72/83). IgM antibodies were not detected in any cord blood samples.
• ·      Antibody transfer ratios were not associated with the severity of maternal SARS-CoV-2 infection but were associated with the time between maternal infection and delivery.
• ·      These findings of transplacental transfer of SARS-CoV-2 antibodies indicate the potential of the antibodies to confer protection to the newborn from infection with COVID-19.

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Wang QQ, Davis PB, Gurney ME, Xu R. COVID‐19 and dementia: Analyses of risk, disparity, and outcomes from electronic health records in the US.  Alzheimer’s & Dementia 2021. First published: 09/02/2021.  https://doi.org/10.1002/alz.12296

• ·      To assess risk for COVID-19 in pts with dementia, a retrospective case‐control analysis of EHRs of 61.9 million adult and senior pts (≥ 18 years) in the United States up to August 21, 2020 was conducted.
• ·      RESULTS: Pts with dementia were at increased risk for COVID‐19 compared to pts without dementia (adjusted odds ratio [AOR]: 2.00 (CI), 1.94–2.06], P < .001).
• ·      The effect was strongest for vascular dementia (AOR: 3.17 [CI, 2.97–3.37], P < .001), followed by presenile dementia (AOR: 2.62 [CI, 2.28–3.00], P < .001), Alzheimer's disease (AOR: 1.86 [CI, 1.77–1.96], P < .001), senile dementia (AOR: 1.99 [CI, 1.86–2.13], P < .001) and post‐traumatic dementia (AOR: 1.67 [CI, 1.51–1.86] P < .001).
• ·      Blacks with dementia had higher risk of COVID‐19 than Whites (AOR: 2.86 [CI, 2.67–3.06], P < .001).
• ·      The 6‐month mortality and hospitalization risks in pts with dementia and COVID‐19 were 20.99% and 59.26%, respectively.

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Tönshoff B, Muller B, Elling R et al. Prevalence of SARS-CoV-2 Infection in Children and Their Parents in Southwest Germany. JAMA Pediatr 2021; Jan 22, 2021.e210001.                                                                  doi: 10.1001/jamapediatrics.2021.0001.

• ·      To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, this large-scale, multicenter, cross-sectional investigation enrolled children aged 1 to 10 years and a corresponding parent between 4/22 & 5/15/2020, in southwest Germany.
• ·      Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription–polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests.
• ·      RESULTS: This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2–2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%).
• ·      CONCLUSIONS: In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic.

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Williamson, E.J., Walker, A.J., Bhaskaran, K. et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 584, 430–436 (2020). https://doi.org/10.1038/s41586-020-2521-4

• ·      OpenSAFELY—a secure health analytics platform that covers 40% of all pts in England and holds patient data in electronic health records – was used to examine factors associated with COVID-19-related death. From 17,278,392 adults, 10,926 COVID-19-related deaths were identified.
• ·      RESULTS: Increasing age was strongly associated with risk, with people aged 80 or over having a >20-fold-increased risk compared to 50–59-year-olds (fully adjusted HR 20.60; 95% confidence interval (CI) With age fitted as a flexible spline, an approximately log-linear relationship was observed.
• ·      People from all Black, Asian & mixed ethnic groups were at higher risk than those of white ethnicity. When adjusted only for age and sex, hazard ratios ranged from 1.62–1.88 for Blacks, South Asians & people of mixed ethnicities, decreasing to 1.43–1.48 after adjustment for all included factors.
• ·      Increasing risks were seen with increasing obesity (adjusted HR 1.92 [1.72–2.13] for a BMI> 40kg/m2.
• ·      Comorbidities associated with a higher risk of COVID-19-related death included DM, severe asthma (defined as asthma with recent use of an oral corticosteroid), respiratory disease, chronic heart disease, liver disease, stroke, dementia, reduced kidney function and autoimmune diseases.
• ·      Those with a history of hematological malignancy in the last 5 yrs had a >2.5-fold increased risk, which decreased slightly after five years.
• ·      CONCLUSIONS: In this very large study, previously identified risk factors for death from COVID-19 were confirmed and amplified. The most striking finding was the profound impact of increasing age.

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Nguyen NT, Chinn J, Nahmias J et al. Outcomes and Mortality Among Adults Hospitalized With COVID-19 at US Medical Centers. JAMA Network Open. 2021;4(3):e210417. Published March 5,2021. doi:10.1001/jamanetworkopen.2021.0417

• ·      To examine outcomes among adults hospitalized with COVID-19 at US medical centers and analyze changes in mortality over the initial 6-month period of the pandemic, data were obtained from the Vizient clinical database, an administrative, clinical, and financial database of more than 650 academic centers and their affiliates from 47 US states.
• ·      Primary outcome was in-hospital mortality, analyzed according to the month of admission and age group, and in a subgroup of pts requiring intensive care unit (ICU) admission. Secondary outcomes included length of hospital stay, length of ICU stay, and median cost of ICU stay vs non-ICU stay.
• ·      Among 192 550 adults hospitalized with COVID-19, 101 089 (52.5%) were men, 83 567 (43.3%) were White, and 125 543 (65.2%) had Medicare or Medicaid insurance. The most common comorbidities included hypertension (118 418 [61.5%]), diabetes (73 939 [38.4%]), and obesity (52 759 [27.4%]).
• ·      RESULTS: 55 593 of pts (28.9%) were admitted to the ICU, 26 221 (13.6%) died during the index hospitalization, and 5839 (3.0%) were transferred to hospice care.
• ·      In-hospital mortality increased with increasing age: 179 of 12 644 pts (1.4%) aged 18 to 29 years died vs. 8277 of 31 135 patients (26.6%) 80 years or older. Of pts admitted to the ICU, 15 431 of 55 593 (27.8%) died.
• ·      There was a significant reduction in mortality over the course of the 6-month period, with the highest mortality in March (3657 of 16 517 patients died [22.1%]); mortality decreased each month until the end of the study period in August (1154 of 17 776 patients died [6.5%]) (χ2 for trend, 3592.3; P < .001)

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Hattoriab T, Amishimaa M, Morinaga D et al. Older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples. Journal of Infection 2021; 82:159-198.

• ·      Records of 66 pts diagnosed with COVID-19 between 3/1 & 4/30/2020 at National Hospital Organization, Hokkaido Medical Center were analyzed. PCR tests were performed daily on N/P samples.
• ·      42 subjects were mild cases, who did not require supplemental oxygen treatment. 18 subjects were moderate cases who needed oxygen treatment. 6 subjects were severe cases who needed ventilator or/and ECMO.
• ·      RESULTS: Older age was significantly associated with prolonged positive PCR tests (P = 0.0053). This relationship remained unchanged when the findings were adjusted for the potential impact of severity of the disease and the use of medication (P = 0.026). When we analyzed only mild cases of COVID-19, the result remained significant (P = 0.036).
• ·      In summary, old age is significantly associated with prolonged duration of positive PCR results from nasopharyngeal swab samples, regardless of disease severity. Further studies will be needed in order to clarify how long these patients are actually contagious.

TREATMENT

• Schoof M, Faust B, Reuben A. Saunders RA et al. An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation. BioRxiv 8/2020.                                                                      https://doi.org/10.1101/2020.08.08.238469.
• ·      SARS-CoV-2 gains entry into host cells via interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). à Disruption of this interaction confers potent neutralization of viral entry.
• ·      By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike & block ACE2 interaction via 2 distinct mechanisms.
• ·      Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2.
• ·      Affinity maturation & structure-guided multivalency design yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike & picomolar neutralization of SARS-CoV-2 infection.
• ·      mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated nasal spray delivery of this potent neutralizer directly to the airway epithelia, promising a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

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Gottlieb RL, Nirula A, Chen P et al. Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. Published online January 21, 2021. doi:10.1001/jama.2021.0202.

• ·      To determine the effect of antispike neutralizing antibodies, bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab were compared in outpts with mild to moderate COVID-19.
• ·      Ambulatory pts who tested positive for SARS-CoV-2 infection and had 1 or more mild to moderate symptoms were first randomized to receive bamlanivimab monotherapy or placebo from 6/17-8/21/2020, followed by bamlanivimab and etesevimab or placebo (8/22-9/3).
• ·      The primary end point was change in SARS-CoV-2 log viral load at day 11 (±4 days). Nine prespecified secondary outcome measures were evaluated including the proportion of patients with a COVID-19–related hospitalization, an emergency department [ED] visit, or death at day 29.
• ·      Results: Among the 577 patients who were randomized and received an infusion, the mean decrease in log viral load from baseline at day 11 was significantly greater for highest dose combination treatment vs placebo.
• ·      Among the secondary outcome measures, the proportion of patients with COVID-19–related hospitalizations or ED visits was significantly lower for combination treatment.
• ·      Conclusion: Among nonhospitalized patients with mild to moderate COVID-19 illness, treatment with bamlanivimab and etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; no significant difference in viral load reduction was observed for bamlanivimab monotherapy.

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Horby PW, Campbell M, Staplin N et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv – posted 2/11/2021. doi: https://doi.org/10.1101/2021.02.11.21249258.

• ·      Between 4/23/2020 & 1/25/2021, 4116 adults were included in the assessment of tocilizumab, including 562 (14%) patients receiving invasive mechanical ventilation, 1686 (41%) receiving non-invasive respiratory support, and. 1868 (45%) receiving no respiratory support other than oxygen. 3385 (82%) patients were receiving systemic corticosteroids at randomisation.
• ·      RESULTS: Overall, 596 (29%) of 2022 pts allocated to tocilizumab and 694 (33%) of 2094 pts allocated to usual care died within 28 days (rate ratio 0.86; 95% confidence interval [CI] 0.77-0.96; p=0.007).
• ·      Consistent results were seen in all pre-specified subgroups of pts, including those receiving systemic corticosteroids: Pts allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (54% vs. 47%; rate ratio 1.23; 95% CI 1.12-1.34; p<0.0001); among those not receiving invasive mechanical ventilation at baseline, pts allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs. 38%; risk ratio 0.85; 95% CI 0.78-0.93; p=0.0005).
• ·      INTERPRETATION: In hospitalized COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes regardless of the level of respiratory support received and in addition to the use of systemic corticosteroids.

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Thomas S, Patel D, Bittel B, et al. Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial. JAMA Netw Open. 2021;4(2):e210369. doi:10.1001/jamanetworkopen.2021.0369

• ·      To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory pts with SARS-CoV-2 infection, a multicenter, single health system RCT enrolled 214 adult pts with a PCR-confirmed diagnosis of SARS-CoV-2 infection who received outpt care in sites in Ohio and Florida between 4/27 and 10/14/2020.
• ·      Pts were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care.
• ·      The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements.
• ·      RESULTS: A total of 214 pts were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Pts who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups.
• ·      CONCLUSIONS: In this randomized clinical trial of ambulatory pts diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care.

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Rentsch CT, Beckham JA, Tomlinson L et al. Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ 2021; 372:n311.  (Published 11 February 2021)                                                                                                                                          doi: https://doi.org/10.1136/bmj.n311

• ·      To evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among pts admitted to hospital with COVID-19 in the US, all 4297 pts admitted to VA hospitals from 1 March to 31 July 2020 with laboratory confirmed SARS-CoV-2 infection and without a history of anticoagulation were enrolled.
• ·      The main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.
• ·      RESULTS: Of 4297 patients admitted to hospital with COVID-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay.
• ·      Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with pts who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation.
• ·      Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05).
• ·      CONCLUSIONS: Early initiation of prophylactic anticoagulation compared with no anticoagulation among pts admitted to hospital with COVID-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real-world evidence to support the use of prophylactic anticoagulation as initial treatment for pts with COVID-19 on hospital admission.

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Murai IH, Fernandes AL, Sales LP et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients with Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. Published online February 17, 2021. doi:10.1001/jama.2020.26848.

• ·      To investigate the effect of a single 200,000 IU dose of vitamin D3 on hospital length of stay in 420 hospitalized pts with COVID-19, a multicenter, double-blind, randomized, placebo-controlled trial was conducted in 2 sites from 6/2-8/27/2020.
• ·      The primary outcome was length of stay = time from randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; ICU admissions; # of pts who required mechanical ventilation/ duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein.
• ·      RESULTS:  Of 237 includeded pts, median length of stay was not significantly different between the vitamin D3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62).
• ·      There were no significant differences between the vitamin D3 group & placebo groups for any secondary outcome.
• ·      CONCLUSIONS: Among hospitalized pts with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay.

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López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults with Mild COVID-19: A Randomized Clinical Trial. JAMA. Published March 04, 2021. doi:10.1001/jama.2021.3071

• ·      To determine whether the anti-parasitic drug ivermectin is an efficacious treatment for mild COVID-19, a double-blind, RCT was conducted at a single site in Cali, Colombia.
• ·      A total of 476 adult pts with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between 7/15 and 11/30, 2020, and followed up through December 21, 2020.
• ·      Pts were randomized to receive ivermectin, 300 μg/kg/day for 5 days (n = 200) or placebo (n = 200).
• ·      Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.
• ·      RESULTS: Among 400 randomized pts who were randomized in the primary analysis, 398 (99.5%) completed the trial. Median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms.
• ·      The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).
• ·      CONCLUSION: Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms.

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Intravenous Aviptadil for Critical COVID-19 With Respiratory Failure (COVID-AIV). Reported by manufacturer, NeuroRx. Peer-reviewed publication pending.

• ·      Aviptadil (Zyesami), an investigational formulation of vasoactive intestinal peptide delivered by IV infusion was evaluated in a 196-patient randomized trial.
• ·      Primary endpoint of the phase IIb/III trial was defined as recovery from respiratory failure without relapse & discharge from acute care plus survival through a 60 day observation period.
• ·      In a subgroup of 127 pts receiving high-flow nasal cannula support (n=127), those treated with aviptadil acetate had a 71% chance of successful recovery by day 28 compared with 48% of those receiving placebo (P=0.017); this increased to a 75% chance of recovery by day 60 versus 55% in the placebo group (P=0.036).
• ·      84% of patients in this high flow nasal cannula group receiving the intervention treated at tertiary medical centers survived to day 60 versus 60% of the placebo group (P=0.007).
• ·      Aviptadil is the first COVID-19 therapeutic to demonstrate advantages in both survival and recovery from critical COVID-19 in a randomized, double-blind multicenter trial.

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Chow JH, Khanna AK, Tethireddy S et al. Aspirin Use Is Associated with Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients with Coronavirus Disease 2019.  Anesthesia & Analgesia: April 2021 - Volume 132 - Issue 4 - p 930-941       doi: 10.1213/ANE.0000000000005292

• ·      To evaluate COVID-19 SEQUELAE, COVID-19 patients admitted to the hospital between March 2020 and July 2020 were abstracted from the multicenter collaborative research DATABASE.
• ·      Four hundred twelve patients were included in the study. Median age was 55 years (IQR, 41–66 yrs), & 59.2% of patients were male. 98 pts (23.7%) received aspirin, while 314 pts (76.3%) did not.
• ·      On unadjusted analysis, patients receiving aspirin had significantly lower rates of mechanical ventilation (35.7% [35/98] aspirin versus 48.4% [152/314] nonaspirin, P = .03) and ICU admission (38.8% [38/98] aspirin versus 51.0% [160/314] nonaspirin, P = .04).
• ·      There was no crude difference in in-hospital mortality (26.5% [26/98] aspirin versus 23.2% [73/314] nonaspirin, P = .51) between groups.
• ·      In addition, there was no difference in the rate of major bleeding (6.1% aspirin [6/98] versus 7.6% nonaspirin [24/314], P = .61), or overt thrombosis (8.2% [8/98] aspirin versus 8.9% [28/314] nonaspirin, P = .82) between groups.
• ·      In this retrospective observational study, aspirin use was associated with a significantly lower rate of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality after controlling for confounding variables.
• ·      CONCLUSIONS: Aspirin may have lung-protective effects and reduce the need for mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized COVID-19 patients.

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Grieco DL, Menga LS, Cesarano M et al.  Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA. Published online March 25, 2021. doi:10.1001/jama.2021.4682

• ·      To assess whether helmet noninvasive ventilation can increase days free of respiratory support in 109 COVID-19 pts with moderate to severe hypoxemic respiratory failure, compared with high-flow nasal oxygen alone, a multi-center RCT was performed in 4 ICUs in Italy between 10 & 12/2020 with end of F/U, 2/11/2021.
• ·      Pts were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal O2 (n = 54) or high-flow O2 alone (60 L/min) (n = 55).
• ·      Primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU & hospital length of stay.
• ·      RESULTS:  109 pts (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). Median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group & 18 (IQR, 0-22) in the high-flow nasal O2 group, a difference that was not statistically significant (mean difference, 2 days [95% CI, −2 to 6]; P = .26). The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal O2 group (30% vs 51%; difference, −21% [95% CI, −38% to −3%]; P = .03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal O2 group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P = .04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, −1% [95% CI, −17% to 15%]; P > .99).
• ·      CONCLUSIONS & RELEVANCE:  Among pts with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal O2, resulted in no significant difference in the number of days free of respiratory support within 28 days but significantly fewer HELMET pts required intubation or mechanical ventilation.

PREVENTION

Butler-Laporte G, Lawandi A, Schiller I et al. Comparison of Saliva and Nasopharyngeal Swab Nucleic Acid Amplification Testing for Detection of SARS-CoV-2: A Systematic Review and Meta-analysis. JAMA Intern Med. Published online January 15, 2021. doi:10.1001/jamainternmed.2020.8876.

• ·      To assess the diagnostic accuracy of saliva NAAT for COVID-19, a systematic review of was performed, using all studies with enough data to measure salivary NAAT sensitivity and specificity.
• ·      Results were compared with the standard, imperfect nasopharyngeal swab NAAT as a reference test. To account for the imperfect reference test sensitivity, a Bayesian latent class bivariate model was used for the meta-analysis.
• ·      The search strategy yielded 385 references, and 16 unique studies were identified for quantitative synthesis. Ultimately, 8 peer-reviewed studies and 8 preprints were included in the meta-analyses (5922 unique pts). There was significant variability in pt selection, with 15 studies including ambulatory pts, and 9 exclusively enrolled from an outpatient population with mild or no symptoms.
• ·      RESULTS: In the primary analysis, the saliva NAAT pooled sensitivity was 83.2% (95% credible interval [CrI], 74.7%-91.4%) and the pooled specificity was 99.2% (95% CrI, 98.2%-99.8%). The nasopharyngeal swab NAAT had a sensitivity of 84.8% (95% CrI,76.8%-92.4%) and a specificity of 98.9% (95% CrI, 97.4%-99.8%). Results were similar in secondary analyses.
• ·      CONCLUSIONS: These results suggest that saliva NAAT diagnostic accuracy is similar to that of nasopharyngeal swab NAAT, especially in the ambulatory setting. These findings support larger-scale research on the use of saliva NAAT as an alternative to nasopharyngeal swabs.

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Wu K, Werner AP, Moliva JI et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv preprint.                                                                             doi: https://doi.org/10.1101/2021.01.25.427948; this version posted January 25, 2021

• ·      Moderna’s SARS-CoV-2 vaccine, mRNA-1273, elicits high viral neutralizing titers in Phase 1 trial participants and is highly efficacious in prevention of symptomatic & severe COVID-19 disease.
• ·      To assess the efficacy of the vaccine against SARS-CoV-2 variants with mutations in the spike protein, most recently circulating isolates from the UK (B.1.1.7) and South Africa (B.1.351), neutralization of sera from mRNA-1273 vaccinated clinical trial participants against recombinant VSV-based SARS-CoV-2 PsVN assay with S protein from the original Wuhan-Hu-1 isolate, D614G variant, the B.1.1.7 and B.1.351 variants was assessed.
• ·      Results demonstrate that the antibody response elicited by mRNA-1273 provides similar levels of
• neutralization against these SARS-CoV-2 S variants as against the Wuhan-Hu-1 (D614) strain.
• ·      The mutations present in the B.1.1.7 variant (UK), either the complete set of S mutations or the
• specific mutations (N501Y, ∆H69∆V70) of key interest had no significant effect on neutralization in any assay. In contrast, a significant decrease in neutralizing titers was measured against both the full set of S mutations and the partial list of RBD mutations in the B.1.351 variant(South Africa).
• à CONCLUSION: mRNA-1273 maintained activity against all circulating strain variants tested to date, and only the B.1.351 variant showed reduced neutralizing titers, as assessed from vaccinated human and NHP sera.

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Logunov DY, Dolzhikova IV, Shcheblyakov DV et al.  Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomized controlled phase 3 trial in Russia. The Lancet. Published online: February 02, 2021 DOI:https://doi.org/10.1016/S0140-6736(21)00234-8

• ·      A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial.
• ·      A randomized, double-blind, placebo-controlled, phase 3 trial was performed at 25 hospitals and polyclinics in Moscow, Russia. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S.
• ·      The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. Serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses.
• ·      RESULTS: Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2).
• ·      Adverse events occurred at the same frequency in both groups.
• ·      CONCLUSION: This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19; the vaccine was well tolerated in a large cohort.

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Hall V,  Foulkes S,  Charlett A et al.   Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020. MedRXiv; Published Jan 15, 2021.                           https://doi.org/10.1101/2021.01.13.21249642.

• ·      To assess duration & protection of antibodies to SARS-CoV-2, PCR, antibody (Ab) testing & clinical F/U for COVID-19 were performed prospectively every 2-4 weeks in 20,787 volunteers. At enrolment, participants were assigned to either the positive cohort (Ab positive or prior PCR/Ab test positive) or negative cohort (Ab negative, not previously known to be PCR/Ab positive). 
• ·      FINDINGS: Between 6/18 & 9/11/2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up.
• ·      The incidence density per 100,000 person days was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days.
• ·      àA prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection.

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Brooks JT, Beezhold DH, Noti JD, et al. Maximizing Fit for Cloth and Medical Procedure Masks to Improve Performance and Reduce SARS-CoV-2 Transmission and Exposure, 2021. MMWR Morb Mortal Wkly Rep. ePub: 10 February 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7007e1.

• ·      To evaluate changes in mask fit to improve performance, the CDC assessed the impact of 1) double masking and 2) knotting and tucking the medical procedure mask, on the amount of particles emitted during a cough.
• ·      A pliable elastomeric headform was used to simulate a person coughing by producing aerosols from a mouthpiece. The effectiveness of three mask configurations to block these aerosols was assessed: a three-ply medical procedure mask alone, a three-ply cloth cotton mask alone, and the three-ply cloth mask covering the three-ply medical procedure mask (double masking).
• ·      The second experiment assessed how effectively the two modifications to medical procedure masks reduced exposure to aerosols emitted during a period of breathing. Ten mask combinations, using various configurations of no mask, double masks, and unknotted or knotted and tucked medical procedure masks, were assessed.
• ·      A knotted and tucked medical procedure mask is created by bringing together the corners and ear loops on each side, knotting the ears loops together where they attach to the mask, and then tucking in and flattening the resulting extra mask material to minimize the side gaps.
• ·      A modified simulator with two pliable elastomeric headforms (a source and a receiver) was used to simulate the receiver’s exposure to aerosols produced by the source during quiet breathing, light work, & moderate work. For each masking configurations, three 15-minute runs were completed.
• ·      RESULTS: The first experiment demonstrated that the unknotted medical procedure mask alone blocked 42.0% of the particles from a simulated cough (standard deviation [SD] = 6.70), and the cloth mask alone blocked 44.3% (SD = 14.0). The combination of the cloth mask covering the medical procedure mask (double mask) blocked 92.5% of the cough particles (SD = 1.9).
• ·      In the second experiment, adding a cloth mask over the source medical procedure mask or knotting and tucking the medical procedure mask reduced the cumulative exposure of the unmasked receiver by 82.2% (SD = 0.16) and 62.9% (SD = 0.08), respectively. When the source was unmasked and the receiver was fitted with the double mask or the knotted and tucked medical procedure mask, the receiver’s cumulative exposure was reduced by 83.0% (SD = 0.15) and 64.5% (SD = 0.03), respectively. When the source and receiver were both fitted with double masks or knotted and tucked masks, the cumulative exposure of the receiver was reduced 96.4% (SD = 0.02) and 95.9% (SD = 0.02), respectively.

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Voysey M, Costa C, Madhi SA et al.  Shabir A. Single dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine. The Lancet Preprints, January 2021. Available at SSRN: https://ssrn.com/abstract=3777268

• ·      The timing of the booster dose of Astra Zeneca’s CoV-19 vaccine is important because proof that a longer delay does not affect immunogenicity would free up doses for use as primers when COVID-19 vaccines are in short supply.  This analysis of the AZD1222 vaccine trial evaluates immunogenicity when the booster dose is given after 12 weeks.
• ·      RESULTS: (1) The primary analysis of overall vaccine efficacy >14 days after the second dose based on the prespecified criteria was 66.7% (57.4%,  74.0%). There were no hospitalizations in the ChAdOx1 nCoV-19 group after the initial 21 day exclusion period, and 15 in the control group. (2) Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and protection did not wane during this initial 3 month period. These observations are supported by immunogenicity data which showed binding antibody responses more than 2-fold higher after an interval of 12 or more weeks compared with and interval of less than 6 weeks GMR 2.19 (2.12, 2.26) in those who were 18-55 years of age. Analysis of weekly nasal cultures for SARS-CoV-2 showed overall cases of any PCR+ were reduced by 67% (95%CI 49%, 78%) after a single SD
• vaccine suggesting the potential for a substantial reduction in transmission
• ·      CONCLUSION: With ChAdOx1 nCoV-19 higher vaccine efficacy is obtained with a longer interval between the first and second dose, and a single dose of vaccine is highly efficacious in the first 90 days. Preliminary data also suggest the potential for a substantial reduction in transmission.

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Levine-Tiefenbrun M, Yelin I, Katz R et al. Decreased SARS-CoV-2 viral load following vaccination. medRxiv 2021; posted Feb 8, 2021.  https://doi.org/10.1101/2021.02.06.21251283.

• ·      To analyze the effect of vaccination on viral loads in COVID-19 post-vaccination, we retrospectively collected and analyzed the RT-qPCR test measurements of the 3 viral genes, E, N and RdRp for positive post-vaccination tests performed between December 23rd 2020 and January 25th 2021 (n=2,897 patients)
• ·      Results in vaccinated subjects were compared to results in unvaccinated subjects during the same time period, matched for age and sex.
• ·      Viral load was significantly lower in vaccinated subjects beginning 12 days or longer post vaccination.
• ·      Analyzing positive SARS-CoV-2 test results following vaccination, we find that the viral load is reduced 4-fold for infections occurring 12-28 days after the first dose of vaccine. These reduced viral loads support lower infectiousness, further contributing to vaccine impact on virus spread.
• ·      CONCLUSION: Results show that infections occurring 12 days or longer following vaccination have significantly reduced viral loads, potentially affecting viral shedding and contagiousness as well as severity of disease.

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KIM H, Hegde S, LaFiur C et al. Access to personal protective equipment in exposed healthcare workers and COVID-19 illness, severity, symptoms and duration: a population-based case-control study in six countries.  BMJ Glob Health. 2021; 6(1): e004611.  Published online 1/28/2021.                                                                                      doi: 10.1136/bmjgh-2020-004611

• ·      To assess the risk, severity & duration of COVID-19 in relation to access to PPE, at-risk healthcare workers (HCWs) (physicians & nurses) from a provider network in 6 countries (the UK, Germany, France, Italy, Spain, USA) were identified based on adult medical specialties with frequent & close contact with pts with COVID-19.
• ·      Exposed HCWs completed a detailed questionnaire including demographics, medical, social and lifestyle factors. COVID-19 cases were defined as COVID-19 symptoms (fever, cough, fatigue, loss of taste or smell) and asymptomatic COVID-19 test positive cases.
• ·      RESULTS: Among 2884 exposed HCWs (94% MDs/6% RNs/PAs), there were 514 reports of COVID-19 illness and 54 asymptomatic COVID-19 test positive cases. COVID-19 risk was significantly associated with close contact with COVID-19 cases in & outside the workplace, number of work shifts and hours worked per week.
• ·      Limited access to PPE compared with access to a fresh mask, gown, gloves & face shield with each pt encounter was associated with a 2.2-fold to 22-fold increased risk of reporting COVID-19 symptoms (p<0.0001), a pattern consistent across all six countries.
• ·      Limited access to PPE was associated with symptom duration greater than 2 weeks & the presence of moderate to severe symptoms such as difficulty breathing, abnormal chest X-ray, low oxygen saturations, respiratory distress and acute lung injury.
• ·      CONCLUSION: In six countries, less access to PPE was strongly associated with increased risk of reporting COVID-19 illness & more prolonged & severe disease course in frontline HCWs.

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Van den Berg P, Schecter-Perkins EM, Jack RS et al. Effectiveness of three versus six feet of physical distancing for controlling spread of COVID-19 among primary and secondary students and staff: A retrospective, state-wide cohort study. Clinical Infectious Diseases, March 10,2021.  https://doi.org/10.1093/cid/ciab230

• ·      STUDY DESIGN: Community incidence rates of SARS-CoV-2, SARS-CoV-2 cases among students in grades K-12 and staff participating in-person learning and district infection control plans were linked. Incidence rate ratios (IRR) for students and staff members in districts with ≥3 versus ≥6 feet of physical distancing were estimated using log-binomial regression; models adjusted for community incidence are also reported.
• ·      RESULTS: Among 251 eligible school districts, 537,336 students and 99,390 staff attended in-person instruction during the 16-week study period, representing 6,400,175 student learning weeks and 1,342,574 staff learning weeks. Student case rates were similar in the 242 districts with ≥3 feet versus ≥6 feet of physical distancing between students (IRR, 0.891, 95% CI, 0.594-1.335); results were similar after adjusting for community incidence (adjusted IRR, 0.904, 95% CI, 0.616-1.325). Cases among school staff in districts with ≥3 feet versus ≥6 feet of physical distancing were also similar (IRR, 1.015, 95% CI, 0.754-1.365).
• ·      CONCLUSIONS: Lower physical distancing policies can be adopted in school settings with masking mandates without negatively impacting student or staff safety.

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Thompson MG, Burgess JL, Naleway AL et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR 2021; Early Release/ March 29, 2021 / 70

• ·      Prospective cohorts of 3,950 health care personnel, first responders, and other essential and frontline workers who had received m-RNA vaccines against SARS-CoV-2 infection completed weekly SARS-CoV-2 testing for 13 consecutive weeks regardless of symptoms.
• ·      Among participants with no previous laboratory documentation of SARS-CoV-2 infection, 2,479/3950 (62.8%) received both recommended mRNA doses & 477/3950 (12.1%) received only 1 dose of mRNA vaccine.
• ·      RESULTS: Among unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed by reverse transcription–polymerase chain reaction (RT-PCR) per 1,000 person-days.  58% of infections were detected before people had symptoms. 10.2% of infected people never developed symptoms.
• ·      By contrast, among fully immunized (≥14 days after second dose) persons, 0.04 infections per 1,000 person-days were reported, and among partially immunized (≥14 days after first dose and before second dose) persons, 0.19 infections per 1,000 person-days were reported.
• ·      Troubling variants were circulating during the time of the study — from Dec. 14, 2020, to March 13, 2021 — yet the vaccines still provided powerful protection.
• ·      CONCLUSION: Estimated mRNA vaccine effectiveness for prevention of infection, adjusted for study site, was 90% for full immunization and 80% for partial immunization. Authorized mRNA COVID-19 vaccines (Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273) are highly effective in real-world conditions.

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Madhi SA, Baillie V, Cutland CL et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. New Engl J Med.  March 16, 2021; DOI: 10.1056/NEJMoa2102214.

• ·      A multicenter, double-blind RCT was conducted in South Africa between 6 & 11/2020, involving 750 vaccine recipients and 717 placebo recipients. Individuals received two doses, 21 to 35 days apart.
• ·      During the ascertainment period, 42 individuals developed mild to moderate COVID-19, and 39 (93%) of these cases were attributed to the B.1.351 variant.
• ·      Serological studies in a small subset of participants demonstrated greatly reduced live virus neutralization of the B.1.351 variant compared with the original SARS-CoV-2 strain.
• ·      The vaccine showed almost no efficacy for prevention of mild to moderate COVID-19 in this trial (VE: 21.9%; 95% CI: −49.9–59.8). When limited to only B.1.351 cases, the estimated vaccine efficacy was 10.4% (−76.8–54.8).
• ·      CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant.

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