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By Christian Hoffmann &
Bernd S. Kamps
Voice: Google Cloud Text-to-Speech: US
First, inoculate three domestic cats with SARS-CoV-2. One day later, cohouse an uninfected cat with each of the inoculated cats. Find out how many cats become infected, measure antibody titers on day 24 and count the number of infected cats that show symptoms. If cats are silent intermediate carriers of SARS-CoV-2, what would we recommend to cat owners?
Afterward, describe a scalable serological enzyme-linked immunosorbent assay (ELISA) for the screening and identification of human SARS-CoV-2 seroconverters; build a model to estimate the percentage of infected individuals who were hospitalized in France and how many died; establish an expandable organoid culture system of bat intestinal epithelium; and quantify SARS-CoV-2 viral load in autopsy tissue samples from 22 patients. You will detect the highest levels in the respiratory tract. Where will you find the lowest viral loads?
Finally, discuss with your colleagues what we know about SARS-CoV-2 infection in children; find out that BCG vaccination does not protect against SARS-CoV-2 infection; isolate human-origin monoclonal antibodies from a convalescent patient that show neutralization abilities; and develop and validate a clinical risk score to predict the risk of critical illness in hospitalized patients with COVID-19.
Salje J, Kiem CT, Lefrancq N, et al. Estimating the burden of SARS-CoV-2 in France. Science 13 May 2020. Full-text: https://doi.org/10.1126/science.abc3517
A suite of modeling analyses was used to characterize the dynamics of SARS-CoV-2 transmission in France and the impact of the lockdown on these dynamics. The authors estimated that 3.6% of infected individuals were hospitalized and 0.7% died. The lockdown reduced the reproductive number from 2.90 to 0.67. By 11 May 2020, authors project 2.8 million infections in France (or 4.4% of the population (range: 2.8–7.2)). Population immunity appeared to be insufficient to avoid a second wave.
Halfmann PJ, Hatta M, Chiba S, et al. Transmission of SARS-CoV-2 in Domestic Cats. N Engl J Med. 2020 May 13. PubMed: https://pubmed.gov/32402157. Full-text: https://doi.org/10.1056/NEJMc2013400
Three domestic cats were inoculated with SARS-CoV-2. One day later, an uninfected cat was co-housed with each of the inoculated cats. All six cats became infected but none showed any symptoms. All cats had developed antibody titers on day 24. Are cats potential intermediate hosts in chains of human–cat–human transmission?
Hamiel U, Kozer E, Youngster I. SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA. 2020 May 13. PubMed: https://pubmed.gov/32401274. Full-text: https://doi.org/10.1001/jama.2020.8189
Could it be possible that a BCG vaccination is protective? No. In this very large cohort of Israeli adults aged 35 to 41 years, BCG vaccination in childhood was associated with a very similar rate of positive test results for SARS-CoV-2 compared with no vaccination.
Amanat F, Stadlbauer D, Strohmeier S, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat Med. 2020 May 12. PubMed: https://pubmed.gov/32398876. Full-text: https://doi.org/10.1038/s41591-020-0913-5
A simple solution is the use of a binding assay, e.g. an enzyme-linked immunosorbent assay (ELISA), with recombinant antigen as substrate, especially if ELISA results correlate with neutralization assay results. The authors report the development of such an assay and provide a protocol for both recombinant antigen production as well as the ELISA methodology. The method is based on reactivity to the immunogenic S protein of the virus, is relatively simple and quick in its execution and can be performed at biosafety level 2 as it does not involve live virus.
Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and Renal Tropism of SARS-CoV-2. NEJM May 13, 2020 DOI: 10.1056/NEJMc2011400. https://www.nejm.org/doi/full/10.1056/NEJMc2011400?query=featured_home
SARS-CoV-2 viral load was quantified in autopsy tissue samples obtained from 22 deceased patients. The highest levels were detected in the respiratory tract, but lower levels were also detected in the kidneys, liver, heart, brain, and blood, indicating a broad organotropism of SARS-CoV-2.
Zhou J, Li C, Liu X et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat Medicine 2020. https://doi.org/10.1038/s41591-020-0912-6
Authors demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. They also established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells.
Liang W, Liang H, Ou L, et al. Development and Validation of a Clinical Risk Score to Predict the Occurrence of Critical Illness in Hospitalized Patients With COVID-19. JAMA Intern Med. 2020 May 12. PubMed: https://pubmed.gov/32396163. Full-text: https://doi.org/10.1001/jamainternmed.2020.2033
Using a development cohort of 1590 patients and a validation cohort of 710 patients, a risk score was developed (COVID-GRAM) to predict development of critical illness. The risk factors used in the score were: chest radiography abnormality, age, hemoptysis, dyspnea, unconsciousness, number of comorbidities, cancer history, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and direct bilirubin. The score has been translated into an online risk calculator that is freely available to the public (http://22.214.171.124/)
Latif F, Farr MA, Clerkin KJ, et al. Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease 2019. JAMA Cardiol. 2020 May 13. pii: 2766123. PubMed: https://pubmed.gov/32402056. Full-text: https://doi.org/10.1001/jamacardio.2020.2159
Is there a higher mortality risk in heart transplanted patients? Probably yes. In this case series of 28 patients who had received a heart transplant in a large academic center (New York), 22 patients (79%) were hospitalized. At the end of the follow-up, 4 remained hospitalized and 7 (25%) had died.
Wu Y, Wang F, Shen C, et al. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science 13 May 2020. eabc2241. DOI: 10.1126/science.abc2241. Full-text: https://science.sciencemag.org/content/early/2020/05/12/science.abc2241
Neutralizing antibodies are promising candidates for prophylactic and therapeutic treatment against COVID-19 virus. Four human-origin monoclonal antibodies were isolated from a convalescent patient, all of which displayed neutralization abilities. B38 and H4 block the binding between virus S protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD. In a mouse model, both antibodies reduced virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity.
Mehta NS, Mytton OT, Mullins EWS, et al. SARS-CoV-2 (COVID-19): What do we know about children? A systematic review. Clin Infect Dis. 2020 May 11. pii: 5835843. PubMed: https://pubmed.gov/32392337. Full-text: https://doi.org/10.1093/cid/ciaa556
According to this review of 24 studies, children appear to be less affected by COVID-19 than adults by observed rate of cases in large epidemiological studies. Limited data on attack rate indicate that children are just as susceptible to infection. Data on clinical outcomes are scarce but include several reports of asymptomatic infection and a milder course of disease in young children, though radiological abnormalities have been noted.