Home | Daily Science: TOP 10 | TOP 10 BOOK (PDF)
By Christian Hoffmann &
Bernd S. Kamps
29 September
Vaccine
Helfland BK, Webb M, Gartaganis SL, et al. The Exclusion of Older Persons From Vaccine and Treatment Trials for Coronavirus Disease 2019—Missing the Target. JAMA Intern Med, September 28, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.5084
Those most in need are excluded: in this important review, Benjamin Helfland and colleagues analyzed clinical COVID-19 trials for age exclusions. In 232 Phase 3 clinical trials, 38 included age cut-offs and 77 had exclusions preferentially affecting older adults. Of 18 vaccine trials, 11 included age cut-offs, and the remaining 7 had broad non-specified exclusions. These findings indicate that older adults are likely to be excluded from more than 50% of COVID-19 clinical trials and 100% of vaccine trials. Why? Such exclusion will limit the ability to evaluate the efficacy, dosage, and adverse effects of the intended treatments.
Transmission
Khanh NC, Thai PQ, Quach H-L, Thi NA-H, Dinh PC, Duong TN, et al. Transmission of severe acute respiratory syndrome coronavirus 2 during long flight. Emerg Infect Dis. 2020 Nov [date cited]. Original Publication Date: September 18, 2020. Full-text: https://doi.org/10.3201/eid2611.203299
If you don’t wear a mask, business class does not protect you from infection: Nguyen Cong Khanh, Pham Quang Thai and colleagues report on a cluster among passengers on a 10-hour commercial flight from London to Hanoi on March 2 (at that time, the use of face masks was not mandatory on airplanes or at airports). Affected persons were passengers, crew, and their close contacts. The authors traced 217 passengers and crew to their final destinations and interviewed, tested, and quarantined them. Among the 16 persons in whom SARS-CoV-2 infection was detected, 12 (75%) were passengers seated in business class along with the only symptomatic person (attack rate 62%). Seating proximity was strongly associated with increased infection risk (risk ratio 7.3, 95% CI 1.2–46.2).
Diagnostics
Yokota I, Shane PY, Okada K, et al. Mass screening of asymptomatic persons for SARS-CoV-2 using saliva. Clin Infect Dis. 2020 Sep 25:ciaa1388. PubMed: https://pubmed.gov/32976596. Full-text: https://doi.org/10.1093/cid/ciaa1388
Self-collected saliva is a valuable specimen to detect SARS-CoV-2 in mass screening of asymptomatic persons. In this study including 1,924 individuals from Japan, the sensitivity of nucleic acid amplification testing with nasopharyngeal and saliva specimens were 86% (90% CI:77-93%) and 92% (90% CI:83-97%), respectively, with specificities greater than 99.9%. In positive individuals, viral load was highly correlated between NPS and saliva.
Clark AE, Lee FM. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Screening With Specimen Pools: Time to Swim, or Too Deep for Comfort? Clinical Infectious Diseases28 September 2020. Full-text: https://doi.org/10.1093/cid/ciaa1145
Sample pooling is an option to reduce costs and speed results. In this approach, small volumes of samples from multiple patients are combined into a single test, resulting in substantial reagent savings. If the pooled sample returns a negative result, all patients with specimens comprising that pool are considered not to be infected. Andrew Clark and Francesca Lee discuss several caveats and argue that careful and rigorous investigation is necessary to assure that the pooling of specimens does not impact the analytical sensitivity of the assay.
Salvatore PP, Dawson P, Wadhwa A, et al. Epidemiological Correlates of PCR Cycle Threshold Values in the Detection of SARS-CoV-2. Clinical Infectious Diseases 28 September 2020. Full-text: https://doi.org/10.1093/cid/ciaa1469
Phillip P Salvatore and colleagues from CDC examined the relationship between Ct (Cycle Threshold) values and demographic, clinical, and epidemiological characteristics collected through participant interviews and daily symptom diaries. Among 93 household members (including index cases) who tested positive for SARS-CoV-2 by NP swab, Ct values were lowest (corresponding to higher viral RNA concentration) soon after symptom onset and are significantly correlated with time elapsed since onset (p < 0.001); within 7 days after symptom onset, the median Ct value was 26.5 compared with a median Ct value of 35.0 occurring 21 days after onset. Ct values were significantly lower among participants under 18 years of age (p = 0.01) and those reporting upper respiratory symptoms at the time of sample collection (p = 0.001). Ct rates were higher among participants reporting no symptoms (probably due to high Ct values among post-symptomatic participants).
Clinical
El Moheb M, Naar L, Christensen MA, et al. Gastrointestinal Complications in Critically Ill Patients With and Without COVID-19. JAMA September 24, 2020. Full-text: https://doi.org/10.1001/jama.2020.19400
In their research letter, Mohamad El Moheb and colleagues compared the incidence of gastrointestinal complications of 92 critically ill patients with COVID-19–induced acute respiratory distress syndrome (ARDS) vs 92 comparably ill patients with non–COVID-19 ARDS using propensity score analysis. Patients with COVID-19 were more likely to develop gastrointestinal complications (74% vs 37%; P < 0.001). Specifically, patients with COVID-19 developed more transaminitis (55% vs 27%), severe ileus (48% vs 22%), and bowel ischemia (4% vs 0%). High expression of ACE 2 receptors along the epithelial lining of the gut that act as host-cell receptors for SARS-CoV-2 could explain this.
Thapa SB, Kakar TS, Mayer C, et al. Clinical Outcomes of In-Hospital Cardiac Arrest in COVID-19. JAMA Intern Med. Published online September 28, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.4796
Shrinjaya Thapa and colleagues from William Beaumont Hospital in Michigan deserve the award for the most sincere results of the day. Among 1,309 patients hospitalized with COVID-19, 60 (4.6%) developed in-hospital cardiac arrest (IHCA) and underwent CPR. Among 54 patients with CPR documentation, the initial rhythm was non-shockable for 52 patients (96.3%), with 44 with pulseless electrical activity and 8 with asystole. Return of spontaneous circulation (ROSC) was achieved in 29 patients (53.7%). Now guess how many patients of these 54 patients survived? 10? 5? Wrong. The number was zero. There was a 100% mortality rate following CPR. According to the authors, these outcomes “warrant further investigation into the risks and benefits of performing prolonged CPR in this subset of patients, especially because the resuscitation process generates aerosols that may place health care personnel at a higher risk of contracting the virus”. This devastating result is likely driven by several factors, including critical illness and non-shockable initial rhythms. Additionally, presumed respiratory etiology of arrest for most patients, lack of effective treatments and potential delays in response time for donning of personal protective equipment may have contributed.
Treatment
Vlaar AP, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatology September 28, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30341-6
In this open-label, randomized Phase 2 trial (part of the PANAMO trial), 15/30 patients with severe COVID-19 were treated with an anaphylatoxin and complement protein C5a blocking monoclonal antibody vilobelimab. Patients were randomly assigned 1:1 to receive vilobelimab (up to seven doses of 800 mg intravenously) or best supportive care only (control group). At day 5 after randomization, the primary endpoint of mean relative change in the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was not significantly different between groups. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab group and 27% (4–49) for the control group. The frequency of serious adverse events was similar between groups and no deaths were considered related to treatment assignment. These secondary outcome results support the investigation of vilobelimab in a Phase 3 trial using 28-day mortality as the primary endpoint.
Campbell CM. The opening salvo of anti-complement therapy against COVID-19. Lancet Rheumatology September 28, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30353-2
Comment on the above study, considering the safe use and tolerability of vilobelimab as an important milestone. According to Courtney Campbell, the secondary outcomes reported are notable – in particular the fewer pulmonary embolisms (13% versus 40%). An important caveat, however, is that pharmacokinetic and pharmacodynamic analysis, including C5a, are to be published separately. Investigators using the C5 complement pathway inhibitors eculizumab and ravulizumab have significantly increased their dose and dosing frequency in the acute setting of COVID-19 compared with the doses approved for use in atypical hemolytic uremic syndrome. Whether vilobelimab in this trial successfully inhibited complement C5a in the setting of severe COVID-19 remains uncertain.
Tortorici A, Beltramello M, Lempp FA. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science 24 Sep 2020: eabe3354. Full-text: https://doi.org/10.1126/science.abe3354
Alejandra Tortorici and colleagues report the isolation and characterization of two ultra-potent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that were identified among almost 800 screened Abs isolated from 12 individuals who recovered from COVID-19. Both nAbs protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. The authors propose that combinations of mAbs leveraging multiple distinct mechanisms of action with additive or synergistic effects could provide additional benefits for clinical application.