COVID-19 Evidence Bites, Updated February 13, 2021

Filtered and Appraised by theNNT.com
Supervising Editor: Shahriar Zehtabchi, MD

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COVID-19 EVIDENCE BITES, FILTERED AND APPRAISED BY THENNT.COM



Updated February 13, 2021

Are the Covid-19 vaccines effective and safe?

EVIDENCE BITE: We believe trial data suggest high efficacy and short term safety. Considering the lack of good treatments for COVID-19 and the abject failure of mitigation measures, vaccination represents the most hopeful option for reducing illness and deaths. We do, however, have concerns about the results reported from a number of the vaccine trials.

SUMMARY:

Efficacy: According to data published in the New England Journal of Medicine from an ongoing Pfizer vaccine trial, among approximately 37,000 subjects with at least 2 months follow up, 170 had confirmed COVID-19 (8 in the vaccine group; 162 in the placebo group). This represents infection rates of 0.04% and 0.88% respectively, and a relative efficacy >95%. In other words >95% of confirmed infections occurred in the placebo group. The absolute difference between groups is 0.84%, thus the vaccine prevented one COVID-19 infection for every 119 people vaccinated.

Safety: The trial is still ongoing. Therefore, this report includes data only 2 months after injection. Adverse events, most commonly headache, fever, injection site pain, and fatigue were more common in the vaccine group as expected (27% vaccine; 12% placebo). This represents a number-needed-to-harm (NNH) of 6, meaning one out of 6 vaccinated people experienced side effects. Life threatening events were rare and similar between groups (0.1% in both).

Some safety signals for future monitoring, it should be noted, are apparent in the FDA briefing document, p41. For instance very small, and statistically non-significant but numerically higher rates of appendicitis, myocardial infarction, and stroke occurred in the vaccine group. Deaths, conversely, were numerically less in the vaccine group (2 vs 4).

While the duration of follow up is short, theoretically and based on previous vaccine trials, most adverse events occur in the first 6-8 weeks after vaccination.

Some notable facts about the Pfizer vaccine:

  • The vaccine appeared equally effective in a large number of individuals with a BMI >30, a risk factor for both infection and severe COVID-19.
  • Individuals >75 years of age are under-represented: <800 per group, and <5% overall despite representing >60% of U.S. deaths during the pandemic.
  • Most subjects are white (83%) and <10% were African-Americans, a known vulnerable population.

What we are concerned about: We are very concerned about data mentioned exclusively in an FDA briefing document (p.42) describing 3410 ‘suspected but unconfirmed’ cases of COVID-19, including 1594 vaccine and 1816 placebo subjects. This statistic points to a critical, but missing, datapoint: the number tested for COVID-19 in each group. As per the study protocol (p89) all subjects should have been tested. However, neither the published manuscript nor the FDA document describes how many in each group were tested.

In a sensitivity analysis presuming all ‘suspected’ cases were COVID-19 (while removing those developing symptoms within 7 days of injection due to overlap with vaccine side effects), vaccine efficacy would drop significantly. The trial COVID-19 infection rate would be 6.6% in the vaccine group and 9.2% in the placebo group (with a vaccine efficacy of 29%).

This is an implausible worst-case scenario. After all, it is unlikely all suspected cases were COVID-19, and equally unlikely 9% of placebo subjects contracted the disease in a period of two months. But the analysis raises a point: all suspected cases should have been tested for COVID-19. The language in the FDA document implies they were not. If ‘suspected but unconfirmed’ cases all had a negative test then the FDA document is written clumsily. No harm, no foul. However, some subjects were tested (8 in the vaccine group, for instance, and 162 in the placebo group, were found to be positive). The question is how many in each group were tested to find these positives, the study’s main result. If the trial was conducted properly an equal proportion of suspected cases were tested in each group. We hope and believe this was the case. But transparency on this issue is necessary—without it, sensitivity analyses like the one above will represent legitimate concerns.

Pfizer and the FDA can clarify. Undoubtedly Pfizer is recording all the PCR tests in the trial. These numbers must be made public, and not just for Pfizer. Remarkably, testing numbers are absent for virtually all the major vaccine trials, despite this number being a long accepted staple of trials for influenza and other vaccines.

On a final note, even presuming a worst-case scenario with a much lower efficacy rate than reported, we recommend widespread vaccination, regardless of vaccine product. Other than brief fever, fatigue, headache, and other typical vaccine side effects, the harms documented are, at this stage, both less common and less severe than COVID-19 infection, and any large movement toward herd immunity would be profoundly helpful.

Special thanks to Joe Fraiman, MD for his contribution to this section.

Other vaccines: Since the release of data for the BioNTech/Pfizer vaccine, the data for other vaccines such as those produced by Moderna (mRNA) , Oxford-AstraZeneca (a chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface spike protein), and Gam-COVID-Vac from Russia (a heterologous recombinant adenovirus-based vaccine) have also been published.





What Is The Overall Case Fatality Rate of Covid-19?

EVIDENCE BITE: This is not yet known, but the answer most likely lies between 0.2 and 0.7%

SUMMARY: Most major variation is probably attributable to reporting anomalies. Extremely high Case Fatality Rates (CFR), as seen early in Italy, reflected an elderly population and limited testing. Lower rates, like those seen at first in Germany, reflected a younger sample and widespread testing. The WHO provides an excellent, helpful, and concise exploration of issues in reporting CFR. Up-to-date case and CFR numbers are reported by Johns Hopkins, worldometer, and 91-Divoc.

The CDC, meanwhile, offers its own best guesses, and makes an important point of recognizing the thorny issue of asymptomatic infections (should they be counted?). The bottom line: as of this writing, testing may still be lagging too much for certainty, but 0.2 to 0.7% appears to be a reasonable guess.

What Is The True Accuracy of The Swab (RNA-PCR) Test?

EVIDENCE BITE: When results are positive the test is usually correct, but it misses a lot of Covid-19.

SUMMARY: The Reverse Transcriptase-Polymerase Chain Reaction test is deeply flawed. When the test finds SARS-CoV-2 it is very likely correct, but it often misses the virus. One official in China reported in February the PCR test was detecting 30-50% of cases. There are few well reported, reliable studies, but one study shows swab results detected in just 32% of pharyngeal specimens and 63% of nasal specimens. Another suggests the test misses only 20% of infections at 3 days after symptom onset, but more than that for all other days, including all infections on the first day and 66% at 3 weeks. One perspective piece explored this literature concluding 70% sensitivity is a best-case.

The problem may also have worsened with the rapid PCR tests, and in support of generally low PCR sensitivity, blood antibody response and CT scan reports find large false negative rates, while reports comparing PCR to CT find the same.

At least one author group has explored the potentially catastrophic ramifications of relying on PCR testing for pandemic management, as we are doing. Innovations are still being sought. In the meantime it is unsafe to rely on PCR testing for individual patients or close contacts, and equally fraught to make public health decisions based on uncorrected PCR testing data.

What is the Survival Rate for Covid-19 With Invasive Mechanical Ventilation?

EVIDENCE BITE: Anecdotes and case series suggest overall survival is low with endotracheal intubation and ventilation, but improving.

SUMMARY: This is a moving target. Based mostly on aggregated anecdotes it appeared, early on, most endotracheally intubated patients quickly exhibited major physiologic decompensation. In a prominent chart review of Chinese cases 86% of invasively ventilated patients died. Other reports found varying, but often similar rates. Case series' from two academic centers in New York offered a more hopeful picture (15% and 26% of intubated patients died, though time of follow-up was limited), but this was followed by a larger review of 5700 hospitalized patients in which 88% of ventilated patients died, including 97% of those over age 65.

As a result there has been a push to innovate before invasive ventilation using proning, nasal oxygen, non-invasive positive pressure ventilation (NIPPV), and other methods. According to virtually all involved, and data, this is yielding fruit.

How Likely Is Someone To Contract Covid-19 After Close Contact With Symptomatic Cases?

EVIDENCE BITE: Not likely. Roughly <1-5% of close contacts end up falling ill with Covid-19, and about 10-15% of within-household close contacts do.

SUMMARY: There is a broad experience with rigorous contact tracing mostly outside of the US, quarantining close contacts (usually defined as those within 1 meter for more than 15 minutes), and watching for development of disease. According to the WHO, Chinese CDC, American CDC, and South Korean CDC, the overall rate of new Covid-19 infection in these settings ranges from 0.5% to nearly 5%. Within households, close contact led to predictably higher transmission, but still only 10-15%.

Obviously, avoiding all contact with patients suffering any level of illness from Covid-19 is the safest approach. However, tracing consistently shows low attack rates among close contacts. The nature of contact matters: those in close quarters and crowded situations are at higher risk. This strongly suggests social distancing, masking, and avoiding crowds are highly effective measures.

Can Covid-19 Be Transmitted by Asymptomatic and Pre-symptomatc People?

EVIDENCE BITE: While asymptomatic transmission probably occurs it is less important (in public health terms) than symptomatic transmission

SUMMARY: There are a number of reports of asymptomatic transmission, and there continue to be reviews amplifying them. However establishing the role of asymptomatic spread in the pandemic has been elusive. The WHO continues to assert symptomatic patients, even with mild symptoms (e.g. minimal cough or fever) are the main transmission source.

A brief review: One commonly cited report of asymptomatic transmission includes a supplementary appendix describing the index case as being symptomatic, though mildly so. The second, describing an asymptomatic woman whose family became ill, may or may not have been the index case causing illnesses. A third case describes a gentleman who apparently transmitted to family and others in a hospital before reporting symptoms. One contact tracing report from Singapore found 6% of new infections could only have been from presymptomatic persons. Finally, a well investigated nursing home outbreak suggests that some patients reporting no symptoms were likely transmitting. More than half, however, were cognitively impaired and others had baseline chronic cough, making it very difficult to know who did and did not have symptoms.

The United States CDC has published an excellent review of papers, computer modeling studies, and published reports of asymptomatic people with high viral load. This is worth reading.

In contrast, contact tracings of hundreds of thousands of cases around the world have identified index events of contact with a symptomatic patient in the overwhelming majority of cases. Computer modeling studies have suggested that patients with incubating infection may be infectious up to 2 or more days prior to symptoms, though these studies and tracings rely on recall, and often come to implausible conclusions (e.g. serial intervals shorter than the virus’ incubation period). In addition, one South Korean report found some spreaders and superspreaders had only mild sore throat and cough.

Finally, the difference between asymptomatic and presymptomatic is important. While those with mild symptoms or in the incubation phase (presymptomatic) may transmit the virus, it is unclear if those who never develop symptoms (asymptomatic) can. No clear report exists of such a case at the time of this writing.

As the world becomes increasingly aware of Covid-19 and its dangers, presymptomatic or subclinical spread may be increasingly important. With physical distancing and mask wearing, one would expect to see asymptomatic transmissions quickly overtake all other forms. At this point, however, pre- and asymptomatic transmission, based on contact tracing and existing evidence, remains a minority of discoverable transmissions.

If You Have An Upper Respiratory Infection, How Likely Is It To Be Covid-19?

EVIDENCE BITE: Likely. We’re in the midst of a global pandemic of Covid-19, and influenza activity is surprisingly low.

SUMMARY: There is no solid evidence to answer this, but it is relevant to ‘pandemic thinking’. The prevalence of Covid-19 in quarantines and fever clinics has been low. This may be misleading since both asymptomatic and hospitalized patients with known alternative diagnoses are included. If exclusively people with symptoms in active pandemic areas were tested, the positive rate would be higher. Based on disease activity in the United States it is reasonable to estimate a URI is more likely Covid-19 than any other single cause, particularly in areas with outbreaks.

Therefore, based on sound reasoning and cautious (pandemic) thinking, everyone with even mild URI or influenza-like symptoms should be self quarantining, and get tested. As noted above based on the properties of the test, a negative test does not mean a person with symptoms does not have Covid. However a positive test is helpful for identifying hotspots.

How Long Am I Infectious Once I Have Covid-19?

EVIDENCE BITE: In mild cases infectiousness probably ends once fever is gone and other signs and symptoms have improved for at least 2-3 days. In severe and persistent cases infectiousness may continue for weeks.

SUMMARY: There is minimal data to inform this. The CDC has accepted a best guess using known properties of other coronaviruses and observed experience thus far. With this background they suggest people are no longer infectious when a) symptoms are improving, b) fever has been absent for a day, and c) at least 10 days have passed from onset. Case series’ and otherreports confirm infectiousness is probably greatest in the early days of symptoms.

None of this is well studied, and one chart review from China, and now many subsequent reports, all suggest ‘viral shedding’ can occur for weeks after clinical recovery. However, ‘viral shedding’ means a positive viral RNA (PCR) test, which is very different from being able to transmit Covid-19. In fact by far the best examination of this issue, by the South Korean CDC, found zero transmissions among close contacts of 285 patients who initially recovered but then developed a second apparent Covid illness (and tested positive a second time). Thus even among those with active symptoms it appears exceedingly unlikely the virus can be transmitted after recovery. For those who are asymptomatic after recovering it seems even less likely they can transmit.

Can One Person Be Infected By Covid-19 Twice?

EVIDENCE BITE: Yes, but it seems to be vanishingly rare.

SUMMARY: First, the reason this issue is important is not an individual risk (suffering a second bout). That may be difficult for individuals, but the public health concern is transmissibility. If those with prior infection can still infect others, re-population of public spaces may be unsafe.

There is a smattering of case reports of reinfection from around the globe, most confirmed with molecular testing showing a different strain caused the first and second bouts. However chicken pox and other infections that famously confer future immunity virtually all have a miniscule, but consistent, reinfection rate.Therefore the phenomenon does exist with Covid and was expected, and frankly it is surprising how long it took to document.

However a more concerning issue is transmissibility among those who seem to experience reinfection. By far the most useful and extensive data are from the South Korean CDC which describes 447 cases of persons testing positive after recovering from Covid-19. Of these, 285 were again symptomatic when tested and therefore seem to have experienced a ‘relapse’, a median of 44 days after first infection onset. These patients underwent viral culture and 790 persons with prior contact to them were quarantined. No viral cultures grew from the patients (i.e. they weren’t infectious) and no new Covid-19 infections were found among their contacts.

Therefore reinfection can occur, suggesting it is wise for everyone, even those with a history of infection, to undertake basic distancing, masking, and crowd avoidance measures. It is, however, almost certain that the overwhelming majority of those who experience Covid disease have a strong and effective measure of immunity to future infections. However, how long this immunity lasts, remains unknown.

Are There Known or Established Predictors of Severe Covid-19 Disease?

EVIDENCE BITE: No

SUMMARY: There have been many publications and pre-publications attempting to address this question. While many individual variables (hypoxia, shortness of breath, lymphocyte counts, inflammatory markers, etc.) appear to be correlated with Covid severity, this information is only useful if it can be fit into a larger picture, i.e. a clinical prediction tool. These tend to use scores or constellations of findings to accurately predict need for hospitalization or ventilation, and mortality.

Unfortunately no reliable tool exists yet. Recent reviews have examined the availableliterature and found it to be lacking. Promising tools may be on the way, but require reliable, prospective external validation studies. For now, physicians will have to continue to use clinical judgment.

Should Affected Populations Be Universally Wearing Masks In Public Settings?

EVIDENCE BITE: Definitely

SUMMARY: The question of masking is important but scientific certainty is not available. Large randomized trials assigning some to wear a mask and others not to are uncommon (we know of one). Keep in mind, however, the same can be said of cigarette smoking and links to cancer. At this point we believe the evidence for masking as an effective preventive measure for Covid disease is similar.

There is a single large randomized trial comparing masking to non masking. While the study found no difference in COVID-19 infection rates, unfortunately these were tallied only among mask wearers, rather than the clusters of people exposed to those mask wearers.

This raises the issue of how masking might work. The purpose of masking is to reduce spread by those wearing the mask, not to protect against contracting new infection for the wearer. Even mildly symptomatic (and less commonly asymptomatic) people are capable of spreading COVID-19.

Therefore the greatest utility can be achieved only if everyone in a group wears a mask. We are not aware of reports demonstrating transmission in settings where individuals are consistently masked. Similar to vaccination, a high percentage must be masked for a community to reap the full benefits of masking. Non-masked individuals, like non-vaccinated individuals, are often not risking themselves as much as they are risking others.

There are some recent data from healthcare settings to support masking, and interesting case reports (an infected hair stylist who served 139 people but wore a mask and did not transmit), as well as modeling studies that support masking. There is also a study suggesting those who contract Covid-19 while wearing a mask will experience less severe illness. The WHO points out masking is, by itself, however, inadequate for full protection. Masks are not a panacea. But with distancing and outdoor interaction they are likely the best tool for preventing transmission.



Can Covid-19 Be Transmitted Through Airborne Spread?

EVIDENCE BITE: The term ‘airborne transmission’ suggests a level of contagiousness not occurring with Covid-19, but travel through air and resultant transmission in close quarters does seem to be the predominant form of transmission.

SUMMARY: It is possible to cough, sneeze, breathe, speak, sing, or sputter droplets into the air, and thus onto other people or surfaces in proximity. This occurs with influenza (not a virus of ‘airborne transmission’) as well, and most other respiratory viruses.

The broad confusion about whether airborne spread occurs with SARS-CoV-2 is to some degree definitional. When experts describe ‘airborne transmission’ they mean small aerosolized particles of high concentration that remain suspended long enough to infect people in the same airspace hours or sometimes days later. Thus to most experts ‘airborne spread’ does not simply mean droplets in the air, a feature common to all viruses. Measles, chicken pox, and smallpox exhibit airborne spread with small particles and long durations of airborne suspension. With measles each infected person routinely transmits the illness to 15 others. For chicken pox it is up to 20. For Covid-19, in contrast, the number has been estimated by the CDC at 5.7 and by others at 2 to 3. Newer strains may reportedly be more transmissible, though none reaches the level of typical ‘airborne spread’ infections.

Thus, while travel of particles through the air almost certainly leads to infection, SARS-CoV-2 droplets are mostly heavy and fall quickly and probably do not remain airborne for long. They are also not small enough to travel into deep lung spaces. The best review of data we know is from a blog site known as First10EM; it is highly recommended reading for curious minds.

The important answer for clinicians and lay people then, is SARS-CoV-2 does not exhibit the frightening properties of measles, chicken pox, or any other known virus with airborne transmission. However it is commonly transmitted through the air in close quarters and people should therefore use mitigation measures (outdoor interactions, distancing, and masks) with this in mind.

What Antiviral Therapies Show Promise For Managing The Covid-19 Pandemic?

EVIDENCE BITE: Possibly steroids

SUMMARY:

Steroids: A meta-analysis of seven trials, mostly examining patients mechanically ventilated or with active ARDS, was performed by the World Health Organization and published September 2nd, 2020. This accompanied the publication of threenewsteroid trials, and incorporated their results. The findings hint at a pooled 8% absolute reduction (41% vs 33%) and 21% relative reduction in mortality. This difference, however, was not statistically significant and six of seven trials did not use double-blinding or placebo controls. Moreover, a recent double-blinded trial not included in the WHO paper found no suggestion of benefit among 393 subjects. Nonetheless, with no clear harms thus far and evidence that leans in the direction of benefit, we are hopeful, and the use of steroids seems reasonable in the current pandemic.

Of note, one heavily weighted, non-blinded study is the RECOVERY trial, which found a 3% (NNT 33) absolute mortality reduction among >6000 subjects. This was most robust among those receiving mechanical ventilation (12% reduction, NNT 8), but the drug may have harmed those least ill. It is also worth noting no trial except RECOVERY found a mortality benefit, and the only other we are aware of to find a benefit in a primary outcome is CoDEX. The 28-day outcome was a composite (‘days alive and non-ventilated’), though neither mortality nor days ventilated was individually different between groups at 28 days.

Remdesivir: this nucleotide analog was developed to treat hepatitis, for which it failed, and later Ebola, for which it also failed. The drug failed again in the first manufacturer-sponsored Covid-19 trial of 237 subjects in China. The study was stopped early for slow enrollment but found no benefit in any measure including viral load, theoretically the drug’s mechanism of action. A second, larger trial of over 1000 subjects found a 4-day benefit (15 vs. 11) in ‘time to recovery’, but no effect on mortality. On closer review, the primary outcome of this trial was changed after data collection began, calling into question the veracity of any benefit. The original outcome was “percentage of subjects reporting each severity rating on an 8-point ordinal scale”, while the new outcome (days to recovery) was never mentioned in the researchers’ originally posted list of 30 outcomes of interest (see trial registry).

A third, non-blinded trial enrolling subjects with moderate severity Covid assigned subjects to 10-days of remdesivir, 5-days of remdesivir, or usual care. This trial reported a borderline benefit in ‘clinical improvement’ for the 5-day remdesivir group, but no difference for the 10-day group. The benefit was small and at 28 days outcomes were reversed (a small benefit was seen for 10-day, but not 5-day). As in the prior trial, there were midstream changes in methodology, and no benefits in mortality.

Finally, any controversy seems to have been put to rest by a much larger international randomized trial of 5451 subjects which finds no benefit with remdesivir, in any of the outcomes.

In summary, of four trials on remdesivir none found a mortality benefit or a reduction in need for ventilation (the two outcomes of interest for this pandemic), and the great majority of data suggests remdesivir yields no benefit of any kind. Based on the drug’s history of failures our prior probability estimate for benefit was low, these data confirm that estimate, and fit intuitively.

Hydroxychloroquine: Excitement emerged in the wake of a case series suggesting HCQ reduced viral load; this was then refuted by a similar second series. At this point there are multiplesystematicreviews of the effects of HCQ and CQ, some published, others pre-publication. Results from randomized trials are uniform (including multiple rigorous, peer reviewed trialspublished in major journals, and one massive pre-publication trial), though more and better data is always useful: no benefit and in at least one case well documented adverse effects. Multiple large trialsusing HCQfor post-exposure prophylaxis have also showed no benefit, and hints of harm. There is ampledatadocumenting adverse effects as well. The drug should not be used.

Convalescent plasma: This therapy was first formally reported in 5 people with severe, ventilated Covid-19 disease. We are aware of five relevant randomized trials. The first enrolled 103 subjects but was terminated early because the region’s cases dropped to near zero. No benefits were found but the sample size was small. The second, enrolled 86 subjects and was also stopped early when the researchers found most subjects already had native antibodies (53/66), despite being only 10 days into their illness. This finding suggests convalescent plasma, which would ostensibly help by providing antibodies to those who don’t yet have them, cannot be helpful to most with Covid-19. The trial was again small, but found no benefit. Two larger, more rigorous trials, one Indian, multicenter, open label trial, and a second Spanish trial found no benefit in any measure. Finally, a small Argentinian trial reports a reduction in progression to severe illness among older COVID-19 patients (mean age 76) when they were treated within 72 hours of symptom onset. This is the first rigorous trial suggesting a benefit, the numbers are small, and the difference between groups just barely reaches statistical significance. These findings will therefore have to be reproduced by others to be considered reliable or actionable.

Tocilizumab (brand name: actemra): Tocilizumab is a recombinant monoclonal antibody used to treat moderate to severe rheumatoid arthritis and idiopathic juvenile arthritis. Since the drug blocks the interleukin-6 (IL-6) receptor, it has also been used to treat the cytokine release syndrome with certain cancer therapies, and proposed for cytokine hyperactivity in COVID-19. Reviewing the trial data we are aware of: the first peer-reviewed rigorous randomized, phase 3 trial of 243 carefully selected hospitalized subjects, a preprint server report of 452 hospitalized subjects randomized to tocilizumab or placebo, a trial (with a host of methodologic red flags) of 131 subjects, and a fourth trial of 126 subjects all found no benefit. The latter two were non-blinded, the first two were placebo-controlled. In the wake of these efforts came three additional trials, one stopped early because of increased deaths with tocilizumab, a second showing no benefit again, and a recent third which finds a statistically borderline benefit in the composite of ‘need for ventilation or death’.

In summary there is no major or important benefit in trials of tocilizumab thus far. The one trial suggesting a possible benefit is balanced out by another showing an increase in deaths, and the remainder find no benefit.

Protease inhibitors: Despite theoretical promise, the drugs failed to show a benefit in ‘time to improvement’ among 199 patients with severe Covid-19 in China. In a second trial of ‘triple therapy’ with a protease inhibitor, interferon, and ribavirin, 127 patients with mild Covid-19 experienced a 5-day benefit in the time it took for swab tests to become negative. There were also mild symptom benefits. Finally, a huge, randomized, WHO sponsored trial of 2062 subjects given the combination lopinavir-ritonavir, compared to >4000 who did not, found no benefit.

Monoclonal antibody therapies: The Regeneron corporation famously administered their experimental monoclonal antibody drug to the president of the United States, who recovered from a Covid infection. However we are unaware of trial data supporting this or any other antibody drug for reducing deaths or ventilator needs in COVID-19. The published studies we know of are quite discouraging: one was stopped early for futility, and a second showed no clinical impact with an antibody ‘cocktail’ (though some see promise in an ‘exploratory analysis’ of these results).

In addition, some antibody products and cocktails have apparently received FDA emergency use authorization either as a treatment in mild, very early COVID infection, or as a treatment to prevent infection. These authorizations are based mostly on unpublished data described through press releases, thus we cannot evaluate the claims. One study that is the basis for an FDA EUA found a reduction in viral load with early use (within 3 days of diagnosis), but was not designed to test clinical outcomes. Indeed, the reported viral load reduction was not seen in groups receiving smaller or higher doses in the same trial, suggesting the finding may have been anomalous and unreliable. Moreover, since monoclonal antibodies are a synthetic version of the natural antibodies convalescent plasma is intended to deliver, and convalescent plasma has been a roundly disappointing treatment, we don’t have high hopes for this new class of drug.

In summary, preliminary data support steroids as a Covid-19- therapy that may reduce mortality or need for mechanical ventilation. No other agents appear to have demonstrated an important effect as of this writing.




Treatment

Evidence Summary

NNT Color recommendation*

Hydroxychloroquine

Multiple randomized trials, all fail to show benefit (prophylaxis or treatment). Observational data show harm.

■    Black

Corticosteroids

· One large trial, RECOVERY, with major validity threats (no placebos or blinding) shows 3% mortality reduction in hypoxic patients (NNT 33)

 · Meta-analysis of 7 trials reported a non-significant tendency to reduce mortality by 8% (absolute risk reduction).

· No harms yet apparent

■    Green

Remdesivir

Multiple trials find no survival benefit and no reduction in need for ventilation. One trial with a switched primary outcome reports reduced time-to-recovery, other trials either do not, or are equivocal

■    Red

Convalescent plasma

 

· Two small, negative trials terminated early; one found most subjects were already generating native antibodies

· One large, multicenter, open label trial (n=464) found no benefit, pre-publication

■    Red

Tocilizumab

Inadequate evidence. Trials ongoing.

■    Red

Protease inhibitors (Lopinavir–Ritonavir)

No benefit in two trials

■    Red

Awake Pronation

Promising data suggest improvement in oxygenation (surrogate endpoint). Inadequate evidence for other outcomes. Harm unlikely.

■    Yellow

Heparin for high D-dimer/SIC score

Inadequate evidence. Multiple trials ongoing.

■    Yellow

* TheNNT.com color recommendation: Green: clear evidence of patient-important benefits; Yellow: data is inconclusive or inadequate; Red: no benefit, or benefits and harms similar; Black: harms trump benefits

Abbreviations: NNT: Number-Needed-To-Treat



Is N95 Mask Reuse Safe After Contact With COVID-19 Patients?

EVIDENCE BITE: N95 mask reuse is probably less safe for the wearer than single use, but certain measures reduce risk

SUMMARY: The COVID-19 pandemic has led to severe shortages of N95 masks, forcing hospital workers to reuse them. There is no data from COVID-19 patient settings, but studies performed with similar viruses probably provide the best available approximation of risk. On a practical note, wearing masks constantly for long periods is exhausting, makes communication difficult, and many practitioners will break safety routines. The procedures described here are difficult to follow.

COVID-19 seems to be transmitted primarily via hand contact with respiratory droplets (WHO). With mask reuse self-inoculation is possible, just as it is during doffing procedures. Modeling studies with influenza suggest a moderate risk of self-inoculation with reuse. Studies also suggest the risk conferred by mask contamination during aerosol-generating procedures can probably be reduced by washing hands before donning and doffing, placing a surgical mask over one’s N95, and by having patients wear a mask whenever possible.

Mask fit problems, common after donning and doffing, can probably be mitigated by fit testing periodically, or after donning, with a diluted saccharine spray (something that might be easily improvised with Sweet N Low and an atomizer). The risk of nosocomial spread from a contaminated N95 via a sneeze or cough is probably negligible.

Based on our review we would suggest extended mask use rather than removing a mask between patients. Multiple masks per provider is best (the CDC recommends 5, one to be used each day, then rotated). Ideally these would be worn all day, with 3 being used for roughly 4 hours each during a 12-hour shift to allow for removal when eating, and during a presumptive second break. Leaving masks to self-decontaminate over 2-3 days is probably effective, and other methods such as hydrogen peroxide vapor, 70% ethanol spray, and heat or UV light, show mixed results.

For aerosol generating procedures, particularly intubation, if possible it is safest to use a new mask (even over one’s N95) and discard or decontaminate immediately afterward.

What is The Likely Success Rate of CPR Among Patients With COVID-19?

EVIDENCE BITE: For most hospitalized COVID-19 patients with cardiac arrest, functional survival is probably <1%, and risk for healthcare workers during CPR is high; CPR should be rare when COVID-19 patients arrest.

SUMMARY: COVID-19 is primarily characterized by pneumonia. As such, there are two precipitating scenarios representing the majority of cardiac arrest events during the illness. The first is hypoxia, a potential precipitant in out-of-hospital arrests, or in the peri-intubation period. The second, by far more common, occurs in critical care settings following mechanical ventilation, sepsis, ARDS, and multi-organ failure. The validated GO-FAR score suggests functional survival after CPR in such a scenario is near zero (<1%), regardless of age.

The three chart review studies we are aware of support this notion, documenting 136, 54, and 400 patients with known COVID-19 who underwent CPR after cardiac arrest. Neurologically intact survival was <1%, 0%, and 7% in these studies, suggesting extremely poor survival consistent with other critical care populations.

In comparison, limited retrospective data from the SARS outbreak suggests baseline risk of infection among healthcare workers may be 10%, while involvement in CPR by, for instance, performing chest compressions is associated with a 3-5x higher risk. If causative, this represents an absolute risk increase of 40%, an enormous potential for harm. Provider infections also, by extension, harm patients via nosocomial spread and, in pandemic settings, via loss of a provider who will be quarantined for weeks. AHA guidelines implicitly recognize these issues, suggesting the two first steps after cardiac arrest in COVID-19 patients should be 1) “limit personnel”, and 2) “consider resuscitation appropriateness.”

In summary, most patients with in-hospital COVID-19 arrests will have a survival rate approaching zero. Exceptions will be younger patients without multi-organ failure or without comorbidities, or perhaps those arresting due to isolated hypoxia. In the absence of these variables we feel CPR is best avoided.

 

Supervising editor: Shahriar Zehtabchi, MD