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By Christian Hoffmann &
Bernd S. Kamps

6 June

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Summary

First, develop a policy perspective to protect healthcare workers during the COVID-19 pandemic; write a systematic review about physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2; and investigate the effectiveness of N95 respirator decontamination and reuse against SARS-CoV-2.

Afterwards, build a mouse model of SARS-CoV-2 infection and pathogenesis; discuss the challenges and implications of false negative tests for SARS-CoV-2 infection; and ask 530 patients with upper respiratory infection to collect tongue, nasal, and mid-turbinate samples.

Finally, review the available evidence on asymptomatic SARS-CoV-2 infection; describe the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients; and analyze the effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19.

 

Virology

Sun SH, Chen Q, Gu HJ, et al. A Mouse Model of SARS-CoV-2 Infection and Pathogenesis. Cell Host Microbe. 2020 May 27:S1931-3128(20)30302-4. PubMed: https://pubmed.gov/32485164 . Full-text: https://doi.org/10.1016/j.chom.2020.05.020

Human ACE2 knockin mice were generated by using CRISPR-Cas9 technology. Bottom line: SARS-CoV-2 led to robust replication in the lung, trachea, and brain. SARS-CoV-2 caused interstitial pneumonia and elevated cytokines. A high dose of virus could establish infection via an intragastric route.

 

Transmission

Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19 Systematic Urgent Review Group Effort (SURGE) study authors. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. 2020 Jun 1. PubMed: https://pubmed.gov/32497510 . Full-text: https://doi.org/10.1016/S0140-6736(20)31142-9

Nothing really new, but this incredible work had to be done. This systematic review identified 172 observational studies across 16 countries and six continents and 44 relevant comparative studies in health-care and non-health-care settings. Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10,736, pooled adjusted odds ratio 0.18), protection was increased as distance was lengthened. Face mask use could result in a large reduction in risk of infection (n=2,647; AOR 0.15), stronger associations with N95 or similar respirators compared with disposable surgical masks or similar. Eye protection also was helpful (n=3,713; AOR 0.22). The findings support face masks, eye protection and physical distancing of 1 m or more.

 

Iannone P, Castellini G, Coclite D, et al. The need of health policy perspective to protect Healthcare Workers during COVID-19 pandemic. A GRADE rapid review on the N95 respirators effectiveness. PLoS One. 2020 Jun 3. PubMed: https://pubmed.gov/32492045 . Full-text: https://doi.org/10.1371/journal.pone.0234025. eCollection 2020

Another review of N95 masks. Four RCTs involving 8,736 HCWs were included. There was no direct high quality evidence on whether N95 respirators are better than surgical masks for HCWs protection from SARS-CoV-2. However, wearing N95 respirators could prevent 73 more clinical respiratory infections per 1000 HCWs compared to surgical masks (low quality evidence).

 

Fischer RJ, Morris DH, van Doremalen N, et al. Effectiveness of N95 Respirator Decontamination and Reuse against SARS-CoV-2 Virus. Emerg Infect Dis. 2020 Jun 3;26(9). PubMed: https://pubmed.gov/32491983 . Full-text: https://doi.org/10.3201/eid2609.201524

Recycle your masks 2-3 times but not more! Authors have analyzed 4 different decontamination methods – UV light (260–285 nm), 70ºC dry heat, 70% ethanol, and vaporized hydrogen peroxide (VHP), for their ability to reduce contamination with infectious SARS-CoV-2 and their effect on N95 respirator function. UV light inactivated virus rapidly from steel but more slowly on N95 fabric, probably because of its porous nature. Heat caused more rapid inactivation on N95 than on steel; inactivation rates on N95 were comparable to UV. In conclusion, N95 respirators can be decontaminated and reused up to 3 times by using UV light and VHP and 1–2 times by using dry heat. Subsequent rounds of decontamination caused sharp drops in filtration performance.

 

Diagnostics

Tu YP, Jennings R, Hart B, et al. Swabs Collected by Patients or Health Care Workers for SARS-CoV-2 Testing. N Engl J Med. 2020 Jun 3. PubMed: https://pubmed.gov/32492294 . Full-text: https://doi.org/10.1056/NEJMc2016321

Let the patients do their own swabs! A total of 530 patients with upper respiratory infection were provided with instructions and asked to collect tongue, nasal, and mid-turbinate samples. A nasopharyngeal (NP) sample was then collected from the patient by a HCW. When this NP sample was used as the comparator, the estimated sensitivities of the tongue, nasal, and mid-turbinate samples collected by the patients were 89.8%, 94.0% and 96.2%, respectively. This study shows the clinical usefulness of these samples. This may reduce PPE use and provide a more comfortable patient experience.

 

Woloshin S, Patel N, Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection — Challenges and Implications. NEJM June 5, 2020. DOI: 10.1056/NEJMp2015897

Important article on false negative tests (which are frequent), with several conclusions. According to the authors, FDA should ensure that manufacturers provide details of tests’ clinical sensitivity and specificity at the time of market authorization. It will also be important to develop prediction rules for estimating the pre-test probability of infection (for asymptomatic and symptomatic people) to allow calculation of post-test probabilities after positive or negative results.

 

Clinical

Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection: A Narrative Review. Ann Intern Med. 2020 Jun 3. PubMed: https://pubmed.gov/32491919. Full-text: https://doi.org/10.7326/M20-3012

Review of the available evidence on asymptomatic SARS-CoV-2 infection. Asymptomatic persons seem to account for approximately 40-45% of infections, and they can transmit the virus to others for an extended period, perhaps longer than 14 days. The absence of COVID-19 symptoms might not necessarily imply an absence of harm as subclinical lung abnormalities are frequent.

 

Severe COVID-19

Al-Samkari H, Karp Leaf RS, Dzik WH, et al. COVID and Coagulation: Bleeding and Thrombotic Manifestations of SARS-CoV2 Infection. Blood. 2020 Jun 3:blood.2020006520. PubMed: https://pubmed.gov/32492712. Full-text: https://doi.org/10.1182/blood.2020006520

Retrospective study, describing the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill), receiving standard-dose prophylactic anticoagulation. The overall and major bleeding rates were 4.8% and 2.3%. RCTs are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.

 

Treatment

Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Jun 3. PubMed: https://pubmed.gov/32492084. Full-text: https://doi.org/10.1001/jama.2020.10044

The first randomized trial of well-characterized plasma units with a high titer of antibody to SARS-CoV-2. Unfortunately, the study was terminated before it reached its targeted original sample size of 200 patients; only 103 were enrolled (when the epidemic was under control in China, no more patients could be recruited). Consequently, the study was underpowered. Of 103 patients who were randomized, clinical improvement (discharged alive or reduction of 2 points on a 6-point disease severity scale) occurred within 28 days in 52% vs 43%. There was no significant difference in 28-day mortality (16% vs 24%) or time from randomization to discharge. Of note, convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87% of the convalescent plasma group versus 38% (OR, 11.39). Main take-homes: convalescent plasma is not a silver bullet and antiviral efficacy does not necessarily lead to better survival.

 

Casadevall A, Joyner MJ, Pirofski LA. A Randomized Trial of Convalescent Plasma for COVID-19-Potentially Hopeful Signals. JAMA. 2020 Jun 3. PubMed: https://pubmed.gov/32492105. Full-text: https://doi.org/10.1001/jama.2020.10218

Careful discussion of the previous study. According to the authors, the study provides an important signal of possible benefit in the subgroup of severely ill patients and suggests that high titer antibody against SARS-CoV-2 may have antiviral efficacy. These results suggest that future studies should focus on determining efficacy in less severely ill patients.