NEJM Journal Watch Audio General Medicine

After hearing and assimilating this program, the listener will be better able to:
1. Increase his/her basic knowledge of important advances in medicine;
2. Identify a broad range of clinical research reported in the medical literature;
3. Synthesize research findings through one-on-one interviews with authors, editorialists, or experts in the field;
4. Integrate new treatments reviewed in the summaries into current practice;
5. Challenge oneself with thoughtful, clinically relevant questions.

HOW MANY LIVES COULD BE SAVED BY MASK WEARING?
Unfortunately, mask wearing has become politically polarizing: Some people regard it as a silly constraint on their freedom. Studies show that mask use reduces the transmission of respiratory viruses, including SARS-CoV-2, by about 40%. In the United States, only about half of people were wearing masks in public in November of 2020. In countries with much higher rates of mask use — like South Korea and New Zealand — sustained reductions in the cases of COVID-19 have been achieved, and their economies are rebounding.

The Institute for Health Metrics and Evaluation (IHME) in Seattle, Washington, has collected data from all states since the onset of the pandemic. Details appear on the website of Nature Medicine (https://doi.org/10.1038/s41591-020-1132-9). Their models estimate that universal mask use (defined as 95% mask use in public) could save 130,000 lives between September 22, 2020, and February 28, 2021.

Sometimes, disease modeling is disparaged as “just a model, not reality.” That’s true, but future reality can only be estimated by models. The projections from the Institute for Health Metrics and Evaluation about the future of this pandemic have been used extensively by the U.S. government’s COVID-19 task force and have proven to be quite accurate. So the IHME estimate, that 130,000 lives could be saved in the U.S. in just 4 months by universal mask wearing, should be taken seriously — and it would likely help keep the economy open, too. These points are worth discussing with patients.

SOCIAL DISTANCING’S EFFECTS ON COVID-19: ROLES OF TIMING AND ADHERENCE

The effectiveness of social distancing measures on lowering COVID-19 case counts remains unknown. In a study on the website of the Annals of Internal Medicine (https://doi.org/10.7326/M20-4096), researchers used cell phone mobility data to model complex social network interactions (taking into account population density, the daily number of contacts per person without social distancing measures, and the adherence to these measures) among people in three regions in the United States, namely: Dane County in Wisconsin; the Milwaukee metropolitan area; and New York City (NYC); the population density of Milwaukee is roughly 3 times that of Dane County (home to Madison), and the population density of New York City is roughly 20 times that of Milwaukee.

The timing of and adherence to locally imposed social distancing mandates had major influences on the incidence of new COVID-19 cases. For example, implementing social distancing measures a week sooner in New York City would have reduced confirmed cases by the end of May from about 200,000 to 40,000, whereas implementing those measures a week later would have increased confirmed cases to about 1.4 million. The patterns of change were similar in the other regions, but less dramatically so, owing to specific characteristics, like population density.

Small changes in the timing of social distancing mandates yielded dramatic effects on the exponential growth (or abatement) of COVID-19 cases in each region, so early policy interventions — notably, social distancing mandates — save lives (https://doi.org/10.7326/M20-6934). To curb further morbidity and mortality from this pandemic, the U.S. needs a national plan that guides and directs local policies and mandates.

ATTRIBUTES THAT DETERMINE LIKELIHOOD OF ACCEPTING A COVID-19 VACCINE

The population-wide effect of a COVID-19 vaccine is determined as much by its acceptance as by its immunologic properties. In a study online in JAMA Network Open (https://doi.org/10.1001/jamanetworkopen.2020.25594), researchers surveyed nearly 2000 adults in July of 2020 to see what factors were associated with the acceptance of a COVID-19 vaccine. The respondents were asked whether they would get a hypothetical vaccine based on variations in seven categories.

Based on all of the combinations of the variables, the acceptance rate was 56%. Acceptance was significantly higher with greater efficacy (i.e., 90% vs. 50%), a longer duration of protection (i.e., 5 years vs. 1 year), and less-frequent severe adverse effects (i.e., 1 in 1 million vs. 1 in 10,000); acceptance was moderately influenced by the frequency of minor adverse effects (i.e., 1 in 30 vs. 1 in 10) and the type of approval issued by the Food and Drug Administration (i.e., higher for full approval vs. emergency-use authorization). The influence of vaccine origin was almost as great as vaccine efficacy (i.e., much lower for China vs. U.S.). Endorsement by the U.S. Centers for Disease Control and Prevention or the World Health Organization was more strongly predictive of acceptance than was endorsement by U.S. presidential candidates.

Not surprisingly, an individual’s acceptance of a COVID-19 vaccine will depend on reported efficacy and safety — but the origin of the vaccine and the perceived legitimacy of endorsement will also be factors.

MONOCLONAL ANTIBODY AGAINST SARS-CoV-2

Monoclonal antibodies against the SARS-CoV-2 spike protein are being evaluated for preventing and treating COVID-19. The interim results of a phase 2, industry-sponsored, randomized trial have now been published on the website of the New England Journal of Medicine (https://doi.org/10.1056/NEJMoa2029849): 450 outpatients with mild or moderate COVID-19 got single intravenous infusions of either placebo or one of three doses (700 mg, 2800 mg, or 7000 mg) of the monoclonal antibody LY-CoV555, which is not yet approved by the Food and Drug Administration.

The average viral load substantially decreased in all of the groups from baseline to day 11 (which was the primary endpoint), but the decrease was 3-fold greater with an antibody dose of 2800 mg than with placebo — that’s a significant difference. Symptom-severity scores were slightly lower in the pooled antibody groups than in the placebo group. COVID-19–related hospitalization rates were 1.6% in the pooled antibody group and 6.3% in the placebo group.

One dose of monoclonal antibody hastened the clearance of SARS-CoV-2 in outpatients with COVID-19, but surprisingly, there wasn’t a dose–response effect. There were too few hospitalizations to confirm a clinical benefit — more data are needed, and many questions remain. For instance: How does timing affect efficacy? (Monoclonal antibody trials in hospitalized patients were stopped https://www.niaid.nih.gov/news-events/statement-nih-sponsored-activ-3-trial-closes-ly-cov555-sub-study, suggesting that this approach might be too late in patients with more-severe disease.) Will treating patients with early COVID-19 prevent the transmission of SARS-CoV-2? Would antibody combinations be more effective? If monoclonal antibodies improve clinical outcomes, how will clinicians deliver them to the staggering number of COVID-19 outpatients? Answering these questions is critical to understanding whether and how this strategy should be deployed.

FINAL ACTT-1: REMDESIVIR RESULTS

In May of 2020, the preliminary results of ACTT-1 were published; ACTT-1 is the trial in which more than 1000 patients hospitalized with COVID-19 and lower respiratory tract infections were randomized to 10 days of either intravenous remdesivir (trade name: Veklury) or placebo ( https://www.jwatch.org/na51682 and https://www.nejm.org/doi/suppl/10.1056/NEJMoa2007764/suppl_file/nejmoa2007764_preliminary-report.pdf). Now, in the November 5, 2020 New England Journal of Medicine ( https://doi.org/10.1056/NEJMoa2007764), we have final results after a complete follow-up. The main findings were:

• The remdesivir group had a shorter median time to recovery than did the placebo group: 10 days vs. 15 days.
• The mortality estimate by day 29 was 11.4% with remdesivir and 15.2% with placebo (hazard ratio, 0.73; 95% confidence interval, 0.52-1.03).
• Differences in mortality between the remdesivir and placebo patients varied by disease severity. In the subgroup of patients getting supplemental oxygen at baseline (but not through a high-flow device, noninvasive or mechanical ventilation, or extracorporeal membrane oxygenation), mortality estimates were 4% with remdesivir and 12.7% with placebo (hazard ratio for death, 0.3; 95% CI, 0.14-0.64).

These results support the use of remdesivir in patients hospitalized with COVID-19. Since the publication of the preliminary ACTT-1 report, the RECOVERY trial has shown that dexamethasone lowers mortality in patients hospitalized with COVID-19 who need supplemental oxygen, particularly those on mechanical ventilation (https://www.jwatch.org/na52072). Whether dexamethasone should be combined with remdesivir in patients with severe COVID-19 is unknown, but a theoretic rationale exists for doing so: Dexamethasone likely diminishes injurious inflammation, whereas remdesivir might counteract any effect dexamethasone might have on slowing viral clearance.

Soon after this publication, a preprint of the SOLIDARITY trial, sponsored by the World Health Organization, raised questions about the benefit of remdesivir (https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1). As more information is released and peer-reviewed, a vigorous discussion will undoubtedly unfold about the role of remdesivir.

ECMO FOR COVID-19

Some patients hospitalized with COVID-19 and acute respiratory distress syndrome (ARDS) develop refractory hypoxemia that warrants considering treatment with extracorporeal membrane oxygenation (ECMO). In a study in the October 10, 2020 issue of The Lancet (https://doi.org/10.1016/S0140-6736(20)32008-0), researchers examined the records (from a registry of 213 international ECMO-referral hospitals) of nearly 800 patients with a median age of 49 and with COVID-19 and ARDS supported by venovenous ECMO. Three quarters of the patients were men, 40% were Black or Hispanic, and obesity and diabetes were common. The average partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) was 72 before cannulation, with a median duration of pre-ECMO mechanical ventilation of 4 days.

At 3 months, a third of the patients had been discharged home or to acute rehabilitation, 10% had been discharged to long-term acute care, and 12% had been transferred to another hospital. The median duration of hospital stay for survivors was 27 days. Slightly more than a third of the patients had died, almost always because of the discontinuation of ECMO due to poor prognosis. Complications included central nervous system hemorrhage (6%), hemolysis (5%), and mechanical complications of the circuit (23%). Older age, acute kidney injury, chronic respiratory insufficiency, immunocompromise, and pre-ECMO cardiac arrest were associated with a higher risk for mortality.

In this study, a much larger percentage of patients with COVID-19 who were treated with ECMO survived than had been reported at the start of the pandemic. As resources permit, treating acute respiratory distress syndrome that’s caused by COVID-19 with ECMO (at an ECMO referral center) is reasonable. The long-term outcomes of these patients are unknown, as most were still in healthcare settings, and substantial disability remains possible.

These summaries are presented to facilitate your understanding of ongoing medical research. They aren’t intended for use as the sole basis for clinical treatment nor as a substitute for reading the original research. Journal Watch is a registered trademark of the Massachusetts Medical Society, publishers of the New England Journal of Medicine.