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By Christian Hoffmann &
Bernd S. Kamps

17 May

Voice: Google Cloud Text-to-Speech: US

Summary

First, investigate a 2.5 hour choir practice involving a 61 person choir with 32 confirmed and 20 probable secondary cases of SARS-CoV-2 infection. Transmission was likely facilitated by close proximity (within 6 feet) during practice and augmented by the act of singing. The superspreading event underscores the importance of physical distancing, including avoiding gathering in large groups, to control the spread of COVID-19.

Afterwards, build an online tool for understanding excess mortality in the UK; determine infectiousness before or on the day of symptom onset in a German outbreak; use cryoelectron microscopy to determine a 2.9 angstrom resolution structure of the virus’s RNA synthesizing machine; and show the total excess of all cause deaths in New York by COVID-19.

Finally, analyze the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and… COVID-19 patients! In particular measure type I and III interferons as well as chemokines and IL-6; demonstrate that the overabundance of ACE2 in the lungs of smokers may partially explain why smokers are significantly more likely to develop severe COVID-19; propose prone positioning to non-intubated patients with hypoxemic acute respiratory failure requiring oxygen supplementation; and discuss with your colleagues an editorial which summarizes the current knowledge on the prone position.

 

Epidemiology

Banerjee A, Pasea L, Harris S, et al. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study. Lancet. 2020 May 12. PubMed: https://pubmed.gov/32405103. Full-text: https://doi.org/10.1016/S0140-6736(20)30854-0 – OurRisk.CoV (online tool): http://covid19-phenomics.org/PrototypeOurRiskCoV.html

The authors provide a  simple  model  and  an  online  tool  for  understanding  excess  mortality  over  1  year  from  the  COVID-19  pandemic,  based  on  age,  sex,  and  underlying  condition-specific estimates. For the UK, 293,991 deaths would be expected in a “do-nothing scenario”. With mitigation (ie, less rigorous and voluntary measures), authors predict between 18,000 and 37,000 deaths.

 

Virology

Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science  15 May 2020: Vol. 368, Issue 6492, pp. 779-782. Full-text:  https://doi.org/10.1126/science.abb7498

Another study analyzing the RNA synthesizing machine. Using cryoelectron microscopy, the authors determined a 2.9 angstrom resolution structure of the RNA-dependent RNA polymerase (also known as nsp12), which catalyzes the synthesis of viral RNA, in complex with two cofactors, nsp7 and nsp8.

 

Immunology

Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell May 15, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.04.026

Incredible in-depth analysis of host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. Data consistently revealed a unique and inappropriate inflammatory response to SARS-CoV-2 which is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. It is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. The authors propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation.

 

Transmission

Böhmer MM, Buchholz U, Corman VM. Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series. Lancet Infect Dis 2020, May 15. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30314-5/fulltext

The German patient zero was a Chinese person who visited Germany for professional reasons. Sixteen persons became infected. This thorough description of transmission dynamics revealed that attack rates were 75% among members of a household cluster in common isolation, 10% among household contacts only together until isolation of case, and 5% among non-household high-risk contacts. Although most patients presented with only mild and non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred.

 

Hamner L, Dubbel P, Capron I, et al. High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice – Skagit County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020 May 15;69(19):606-610. PubMed: https://pubmed.gov/32407303. Full-text: https://doi.org/10.15585/mmwr.mm6919e6

What a disaster! Among 61 persons who attended a March 10 choir practice, 32 confirmed and 20 probable secondary COVID-19 cases occurred. Three were hospitalized (5.7%), and two died (3.7%). The 2.5 hour singing practice provided several opportunities for droplet and fomite transmission, including members sitting close to one another, sharing snacks, and stacking chairs at the end of the practice. Chairs were arranged in six rows of 20 chairs each, spaced 6–10 inches apart with a center aisle dividing left and right stages. Most choir members sat in their usual rehearsal seats (see full paper for more details). The act of singing itself might have contributed to transmission through emission of aerosols, which is affected by the loudness of vocalization.

 

Clinical

New York City Department of Health and Mental Hygiene (DOHMH) COVID-19 Response Team. Preliminary Estimate of Excess Mortality During the COVID-19 Outbreak — New York City, March 11–May 2, 2020. Morb Mortal Wkly Rep 2020; 69:603-605. Full-text:  http://dx.doi.org/10.15585/mmwr.mm6919e5

Anybody out there still doubting excess mortality? Please show them this paper, including the most impressive figure of the day. It depicts the total excess all-cause deaths in New York, calculated as observed deaths minus expected deaths as determined by a seasonal regression model using mortality data from the period January 1, 2015–May 2, 2020.

 

Smith JC, Sauswille EL, Girish V, et al. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Development Cell, May 16, 2020. Full-text: https://doi.org/10.1016/j.devcel.2020.05.012

Quit smoking, immediately! Lung ACE2 levels do not vary by age or sex, but smokers exhibit upregulated ACE2. Cigarette smoke triggers an increase in ACE2+ cells by driving secretory cell expansion. The overabundance of ACE2 in the lungs of smokers may partially explain why smokers are significantly more likely to develop severe COVID-19.

 

Lusignan S, Dorward J, Correa A, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Inf Dis 2020, May 15. Full-text: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30371-6/fulltext – PDF: https://doi.org/10.1016/S1473-3099(20)30371-6

Well, it’s not that easy (quitting smoking and finding clinical correlations to cell experiments). Within a surveillance centre primary care sentinel network, multivariable logistic regression models were used to identify risk factors for positive SARS-CoV-2 tests. Of note, active smoking was associated with decreased odds (yes, decreased: adjusted OR 0.49, 95% CI 0.34–0.71). According to the authors, their findings should not be used to conclude that smoking prevents SARS-CoV-2 infection, or to encourage ongoing smoking. Several explanations are given, such as selection bias (smokers are more likely to have a cough, more frequent testing could increase the proportion of smokers with negative results). Active smoking might also affect RT-PCR test sensitivity.

 

Severe COVID-19

Elharrar X, Trigui Y, Dols AM, et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA. May 15, 2020. Full-text: https://jamanetwork.com/journals/jama/fullarticle/2766292

This prospective, before-after study was conducted in Aix-en-Provence (France) among 24 awake, non-intubated, spontaneously breathing patients with COVID-19 and hypoxemic acute respiratory failure requiring oxygen supplementation. Efficacy of prone positioning was only moderate. Only 63% were able to tolerate PP for more than 3 hours. Oxygenation increased in only 25% and was not sustained in half of those after resupination. However, prone sessions were short, partly because of limited patient tolerance.

 

Telias I, Katira BH, Brochard L, et al. Is the Prone Position Helpful During Spontaneous Breathing in Patients With COVID-19? JAMA. Published online May 15, 2020. Full-text: https://doi.org/10.1001/jama.2020.8539

This editorial summarizes current knowledge on prone position. PP during spontaneous and assisted breathing may become a therapeutic intervention. Tolerance may be a limitation of the technique and the benefits of short sessions remain to be seen. Several larger trials are ongoing, addressing the question whether PP prevents intubation.