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.

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