RESEARCH BRIEFING – WEEK IN REVIEW

Past covid-19 infection does not fully protect against future infection; vaccines required

Early in the pandemic, it seemed that reinfection with SARS-CoV-2 was unlikely. Then, case reports and anecdotal evidence started to indicate that this was not entirely the case. Now, a recent study out of Denmark, published in The Lancet suggests that fears of reinfection are not entirely unfounded. 

Denmark presented a unique opportunity to obtain this kind of robust data, as an impressive 69 percent of its population has been tested for covid-19 at some point during the pandemic, many of whom were tested more than once. With this in mind, the authors of this new study wanted to know if a prior SARS-CoV-2 infection provided some ample immunity to prevent reinfection. 

The researchers compared individual reinfections between the first wave of the pandemic (March to May of 2020) and the second wave (September to December of 2020). Of the more than 11,000 people who tested positive during the first round, 72 individuals tested positive again. This means that 0.65 percent—or one out of around 153 people—was reinfected. When factored into infection rates later in the pandemic, this also implies that initial infection is about 80 percent effective at preventing reinfection, a rate which is notably worse than the protection afforded by both the Pfizer/BioNTech and Moderna vaccines.

 But more worrisome were the data gleaned from individuals 65 years and older. Among that group, the data suggest just 47 percent protection against reinfection. Rates were similar between genders and there was no significant waning immunity after 7 months. 

This study had some limitations, though. The study did not correlate symptoms with the risk of reinfection, so it's unclear if the infected individuals had mild, moderate or severe covid-19, which of course vastly changes the implication of a repeat infection. Additionally, there were no data regarding protection from the various covid-19 variants of concern. 

Nevertheless, a national dataset that captured a significant proportion of the general population provides important information. Ultimately, it's clear that recovery from a SARS-CoV-2 infection affords some degree of immunity to the virus, but clearly not universally. The data certainly imply that protection from a prior infection is likely to be no better or inferior to that obtained by vaccination. In particular, older individuals with more vulnerable immune systems should not count on a prior infection to protect them going forward. We expect that more data will come out of other countries in the near future, and we hope that the people around the globe will continue to get vaccinated, regardless of whether they previously had SARS-Cov-2. 16 April 2021.

Inhaled steroids may prevent disease progression in mild covid-19

An important randomized clinical trial (RCT) recently published in The Lancet assessed the role of inhaled steroids in the treatment of covid-19. Of all of the proposed treatments for covid-19, inhaled steroids have been seen as among the most likely to be successful, since dexamethasone, another steroid taken by mouth or intravenously, was the first treatment to demonstrate improvement in mortality in patients with moderate to severe covid-19. Given that covid-19 pneumonia is a respiratory tract infection, researchers assessed whether inhaled steroids would have a net positive effect. The upshot is that the inhaled steroid that was studied, called budesonide, appears to have had a favorable effect in treating mild covid-19. But the reality is that this trial had some important methodologic issues that make this declaration somewhat less definitive than we had hoped. So, while this is a moment for optimism—indeed positive randomized trials of old medications being repurposed have been few-and-far-between, it's crucial that we understand the design and limitations of this particular trial.

In this study, 146 patients were randomized to receive either inhaled budesonide (a steroid medication) or no inhaled budesonide. Subjects were included if they sought medical attention within 7 days of the onset of mild covid-19 symptoms. Mild covid-19 symptoms were defined as new onset cough and fever, loss of smell, or both, without the need for supplemental oxygen. The primary outcome of the study was defined as subsequent covid-19-related urgent care visits, emergency departments visits, or hospitalizations.

Before we get to the results, a little digression on research methods is necessary. The authors shared the results of two distinct analyses: the per-protocol analysis and the intention-to-treat (ITT) analysis. Per-protocol analysis means that only data from the patients who actually completed the treatment as intended are considered. Conversely, ITT data includes all patients who were randomized to receive the treatment, regardless of whether or not they actually received or finished it. Per-protocol analyses are considered ideal for studying adverse events of medications. But when per-protocol data are used to assess whether a treatment "worked," potential biases can be introduced that muddy the picture. For example, a test subject who did not finish the treatment that they were assigned to receive is often not a random event. Meanwhile, ITT is considered the more ideal analysis for assessing the effectiveness of a treatment. That may seem strange; why include data from patients who did not actually get the treatment in the treatment group? The reason is that doing it this way reduces bias. By keeping the patients in the groups that they were initially assigned to be in, the investigators maintain the comparability between groups that was achieved through the process by which the subjects were randomized to receive either the steroid, or not. In this study, the authors presented both analyses.

In the intention-to-treat analysis, 3 percent of participants randomized to receive budesonide needed further medical care compared to 15 percent of patients in the non-budesonide group; the difference was statistically significant. In the per-protocol analysis, however, inhaled budesonide failed to decrease the further need for medical care. Based on these data, the authors determined that the number of patients who would need to be treated in order for one patient to not need further medical care was 8. In medical trials, this is actually quite impressive.

Other ("secondary") outcomes in this study were maintained mostly through surveying the patients enrolled in the trial. Overall, patients in the inhaled budesonide group recovered on average one day faster, had fewer days with fevers, and were less likely to have symptoms at days 14 and 28 as compared to no inhaled budesonide group. Overall, only 7 percent of the study participants reported self-limited adverse events, suggesting that inhaled budesonide is safe.

As with all trials, there are some imperfections to acknowledge. In this case, the most important of these is that the primary outcome did not directly assess mortality but instead assessed the need for "further medical care." Another limitation of this study is that the patients enrolled were overall fairly healthy in comparison to the general population, which may limit generalizability of these results. It's possible the sicker patients—the very ones we are most interested in helping—may have smaller or larger benefits from budesonide.

Nevertheless, the lack of need for further medical care can be considered a surrogate for disease progression, and it appears that inhaled budesonide may prevent progression of covid-19 severity in otherwise fairly healthy patients presenting within the first seven days of mild illness.

13 April 2021.

Research Section Editor

RESEARCH
  • Past covid-19 infection does not fully protect against future infection; vaccines required
POLICY
  • Johnson & Johnson vaccine pause still in effect

(Review)
POLICY
  • Johnson & Johnson vaccine pause still in effect
  • Medicare sequestration suspended through 2021
  • US approaching full vaccine eligibility
  • Supreme Court blocks California's restrictions on religious gatherings in private homes
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