COVID-19 Evidence Bites, Updated October 26, 2021

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

This article was published in collaboration with MDCalc. Please see the MDCalc COVID-19 Resource Center for more information, including a critical review of recommended calcs for resource-limited situations and more.

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

Updated October 15, 2021

 

Are the Covid-19 vaccines effective and safe?

EVIDENCE BITE: We believe trial data suggest high efficacy for all endpoints and short-term safety. We have lingering concerns about limitations in the data and a lack of transparency. 

SUMMARY: 

Efficacy: According to a report in the New England Journal of Medicine from an early Pfizer vaccine trial, among 37,000 subjects 170 developed COVID-19 (8 vaccine group; 162 placebo group). Infection rates were therefore 0.04% vs. 0.88%, a relative efficacy of >95%. The absolute difference between groups was 0.84%, meaning in this trial the vaccine prevented one COVID-19 infection for every 119 people vaccinated. Moderna, AZ, and J&J vaccines have shown similar results.

Oddly, however, the question of whether the vaccine reduces hospitalizations and deaths is unanswered by most trial data. As in the Pfizer trial, hospitalizations are strangely absent from most papers (‘severe’ COVID-19 has often been used as an unhelpful proxy), and too few deaths occurred to find differences. Instead, the best data we know of comes from a case-control study published by the CDC suggesting vaccinated people were much less likely to be hospitalized or die due to COVID-19 than unvaccinated. Protection was not absolute (and probably wanes), but being vaccinated was far better than not. 

In the end, we feel it is an embarrassing dereliction that vaccine trials performed in the shadow of the worst pandemic in a century have not produced answers to the world’s most pressing questions. That is a product of trial design and data transparency. These two matters were left, inexplicably, to the discretion of drug makers. The consequences of this decision have been explored by the BMJ’s Peter Doshi, with whom we share many concerns.

Safety: As Doshi has noted, we have only a keyhole view into this issue right now. Adverse events, most commonly headache, fever, injection site pain, and fatigue were more common in the vaccine group (27% vaccine; 12% placebo), in published data. This represents a number-needed-to-harm (NNH) of 6, so 1 of 6 vaccinated people experienced side effects. Life-threatening events were reportedly 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 for the Pfizer vaccine, p41. Moreover, issues like myocarditis in the mRNA vaccines and clotting syndromes with the J&J vaccine remain ongoing, poorly documented, under-studied phenomena that raise the specter of as yet undiscovered, serious adverse events (though more recent data on myocarditis are somewhat reassuring).

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

EVIDENCE BITE: Possibly corticosteroids

SUMMARY: 

Corticosteroids: An excellent Cochrane review finds that among 11 relevant trials an overall roughly 3% absolute reduction in mortality was seen with steroids among those requiring oxygen therapy. The review also suggests a roughly 2-3 day benefit in days ventilated.

The non-blinded RECOVERY trial may be the best trial data available thus far, finding a 3% (NNT 33) mortality reduction among >6000 subjects. The benefit was most robust among those receiving mechanical ventilation (12% reduction, NNT 8), but the drug may have harmed those less ill. Unfortunately, however, 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, in which the primary outcome was a composite of ‘days alive and non-ventilated (though neither outcome was individually different between groups at 28 days). 

 

Remdesivir: A comprehensive Cochrane review of trial data suggests remdesivir does not improve mortality. If there are other benefits available from remdesivir, the review finds, they are difficult to find or quantify and remain uncertain. This is despite 5 trials of over 7000 subjects, suggesting remdesivir probably does not help patients with COVID-19. The most recent Cochrane systematic review published in 2021 arrives at the following conclusion: “Based on the currently available evidence remdesivir probably has little or no effect on all-cause mortality at up to 28 days in hospitalized adults with SARS-CoV-2 infection. We are uncertain about the effects of remdesivir on clinical improvement and worsening.”

The recently published DisCOVery trial also failed to reproduce the finding of reduced hospitalization in patients receiving remdesivir. This trial concludes remdesivir does not offer any clinical benefit in patients who were admitted to the hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support.

 

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 multiple systematic reviews of the effects of HCQ and CQ, some published, others pre-publication. Results from randomized trials are uniform (including multiple rigorous, peer-reviewed trials published in major journals, and one massive pre-publication trial): no benefit and in at least one case well documented adverse effects. Multiple large trials using HCQ for post-exposure prophylaxis have also shown no benefit and hints of harm. There is ample data documenting 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 a handful of relevant 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. 

A small Argentinian trial showed promise early in 2021, reporting a reduction in progression to severe illness among older COVID-19 patients (mean age 76) treated within 72 hours of symptom onset. This first trial suggesting a benefit, however, is now challenged by a larger trial of >500 subjects treated at a mean of 4d after symptom onset, in which high-risk patients saw no benefit in disease progression or any other measure.

Ivermectin: A Cochrane review finds the trial data for ivermectin in COVID-19 is remarkably weak, and scant. No conclusions can be drawn from the work done so far, partly based on the poor quality of research, and partly based on results with wide confidence intervals. Large, rigorous RCTs are awaited. 

Of note, one of the largest ivermectin trials, Algazzar et al, was retracted for fear of data manipulation and fabrication, and flawed methodology. We hope that systematic reviews that have included this trial will update their results. A recent editorial on the use of ivermectin for COVID-19 describes why relying on low-quality and questionable studies in the current climate can cause serious harm on a global level. 



Tocilizumab (brand name: actemra): A Cochrane systematic review finds tocilizumab reduces mortality by 3% absolute (NNT 33) in severe COVID-19, based on 8 trials of >6,000 subjects. Oddly, it does not seem to have a clinical improvement effect, however. We are skeptical of the mortality findings because they appear to be largely dependent on one nonblinded trial (RECOVERY) that may not be easily reproduced. (We typically take a cautious approach to meta-analyses that suggest benefit in the face of multiple negative trials).

Protease inhibitors: Despite the 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. Next came a huge, randomized, WHO-sponsored trial of 2062 subjects given the combination lopinavir-ritonavir, compared to >4000 who did not found any benefit. Multiple low-quality systematic reviews seem to agree most with the WHO trial. 

Monoclonal antibody therapies: A careful review of randomized trials by the Cochrane group finds that evidence regarding the effects of monoclonal antibodies is scattered, and of low certainty. Each agent tends to have one or two relevant trials and conclusions are difficult to draw. Promising results in some trials suggest lower mortality and lower hospitalization rates for high-risk outpatients, but these are mostly un-reproduced and inadequately reported. In fact, one of the most cited trials conducted by Eli Lilly reported reduced hospitalization in a secondary subgroup analysis but defined emergency department visits as hospitalizations.

Despite the variable evidence, these agents are seeing common use in the first days of symptoms among high-risk individuals, and more recent trials suggest potentially more reliable benefits. As more trials roll in the role of these agents as an early treatment. For now, this seems like a potentially promising option for the highest-risk people with COVID-19 infection.

Prone positioning: Placing patients with COVID-19 and low oxygen levels in a prone position (face down, also known as proning) has been suggested to increase oxygenation and decrease lung injury. Many intensive care units have been using this strategy for COVID-19 patients on mechanical ventilation but it has also been used on awake patients with low oxygen levels. While proning appears largely safe for patients, one downside, particularly in intubated patients, is that repositioning requires the help of several people several times a day. These interactions could increase the risk of transmission of COVID-19 to the staff.

One randomized controlled trial that enrolled adults with COVID-19 infection who required high-flow nasal oxygen for respiratory support, showed that awake prone positioning was associated with a lower risk of treatment failure (need for mechanical ventilation). A recent systematic review that included 25 observational studies with COVID-19 patients not on mechanical ventilation also showed promising results. Despite variation in setting, duration, and frequency, the review concluded awake proning improved oxygenation. Whether this translates into patient-centered outcomes (improved survival, less intubation) or not, remains to be seen.

Treatment

Evidence Summary

NNT Color recommendation*

Hydroxychloroquine

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

  • Black

Corticosteroids

· 3% absolute risk reduction (NNT of 33) in all-cause mortality in hospitalized patients

· No harms apparent

  • Green

Remdesivir

Multiple trials find no survival benefit and no reduction in the need for ventilation. Several recent systematic reviews have shown a lack of benefit for mortality, invasive ventilation requirement, and hospitalization. 

  • Red

Convalescent plasma

 

Five randomized trials, four showing no benefit. One small trial suggested possible benefit when given early (within 3 days of symptoms) but a second, larger trial did not.

  • Red

Tocilizumab

Non-beneficial in multiple trials thus far

  • Red

Protease inhibitors (Lopinavir–Ritonavir)

No benefit 

  • Red

Monoclonal antibody therapies

A few trials suggest benefit (reducing hospitalization) in high-risk outpatients (low certainty evidence). 

  • Yellow

Awake Proning

Promising data suggest improvement in oxygenation (surrogate endpoint) and possibly a reduction in risk of treatment failure (need for intubation). Inadequate evidence for other outcomes. Harms unlikely.

  • Yellow

Heparin for high D-dimer/SIC score

Inadequate evidence. Multiple trials are ongoing.

  • Yellow

Ivermectin

No discernible evidence of benefit. Potential serious harms.

  • Red
     

* 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



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

EVIDENCE BITE: Perfect data for this remain elusive, 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, and John Ioannidis offers an excellent analysis of early reports compared to later reports. For best-updated data see Johns Hopkins, world meterorldometer, 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, with estimates for those under age 70 being lower. 

 

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 flawed. When the test finds SARS-CoV-2 it is very likely correct, but it often misses the virus. There are few reliable studies, but one study suggests the test misses 20% of infections at 3 days after symptom onset, but more than that for all other days, including 66% at 3 weeks. One perspective concluded 70% sensitivity is a best-case. Bottom line: not enough resources have been spent researching and addressing this hugely problematic gap in current knowledge.

 

 

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

 

EVIDENCE BITE: Not likely, though some superspreader events can be anomalies. Roughly <1-5% of close contacts fall ill with Covid-19, and about 15-40% of household 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 the 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, contact leads to higher transmission at 10-15%, and in some studies up to 40% for the closest contacts.

 

 

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

 

EVIDENCE BITE: Asymptomatic transmission probably occurs

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 recognizes asymptomatic spread, but also acknowledges how weak the existing science is on this question. 

 

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

 

EVIDENCE BITE: In mild cases, infectiousness probably ends once the 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 no great data to inform this. The CDC has accepted the best guess, suggesting 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 the onset. 

 

 

Can One Person Be Infected By Covid-19 Twice?

 

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

SUMMARY: The public health concern is transmissibility

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. Generally, it appears the most effective protection against COVID-19 is having experienced COVID-19.

 

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

 

EVIDENCE BITE: No

SUMMARY: There have been many publications attempting to address this question. While individual variables (hypoxia, shortness of breath, lymphocyte counts, inflammatory markers, etc.) appear to be correlated with Covid severity, no validated clinical prediction tool exists yet. 

 

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. There is a single large randomized trial comparing masking to nonmasking. 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 new infection for the wearer. Even mildly symptomatic and 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 and modeling studies that do as well. 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 to most scientists in the field of infectious disease a level of contagiousness not occurring with Covid-19. Travel through the air and resultant transmission, however, seems 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 on this issue may therefore be 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 even days later. Thus to most experts ‘airborne spread’ does not simply mean droplets can be transmitted through the air, a feature common to all viruses. Measles, chickenpox, 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 chickenpox, 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 ‘airborne spread’ infections.

Thus, while the 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 are aware of is from a blog site known as First10EM; periodically updated, it is highly recommended reading for curious minds on the subject of airborne transmission of COVID.

 

 

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 the 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 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 are 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

 

Supervising editor: Shahriar Zehtabchi, MD