COVID-19 EVIDENCE BITES, FILTERED AND APPRAISED BY THENNT.COM
What Is The Overall Case Fatality Rate of Covid-19?
EVIDENCE BITE: This is not yet known, but the answer most likely lies between 0.3 and 0.8%
SUMMARY: Most major variation is probably attributable to reporting anomalies. Extremely high CFRs, 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 ranging from 0.5 to 0.8%. The CDC makes an important point of recognizing the thorny issue of asymptomatic infections (should they be counted in the denominator?). The bottom line: as of this writing testing isn’t widespread enough to know an answer.
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 seems to be overwhelmingly 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 examined swab results from body fluids in 205 hospitalized Covid patients. The virus was 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 missing all infections on the first day and 66% of infections at 3 weeks. One perspective piece explored this literature concluding 70% sensitivity is a best-case.
The problem may have worsened with the rapid PCR test. Medscape reports the rapid Abbot test missed half of infections compared to a non-rapid competitor in one study. If true, this would suggest an overall sensitivity well below 50% for the rapid Abbot test. In support of generally low PCR sensitivity, blood antibody response and CT scan reports find large false negative rates (half based on antibodies, a third based on CT), and 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 desperately needed. One approach has been suggested combining imaging and PCR testing , and we eagerly await further advances or innovations. In the meantime it is unsafe to rely on PCR testing for individual patients or their close contacts, and it is equally dangerous to make public health decisions using case rates and local spread data based on PCR testing.
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. Reports of hypercoagulable state, agitated delirium, abrupt renal failure, and worsening ARDS following intubation were, and remain, common.
In a prominent chart review of Chinese cases 86% in a small cohort of invasively ventilated patients died. Other pre-publication 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 and many were still intubated in the ICU on publication), but this was followed by a larger chart review of 5700 hospitalized patients from the same area 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 02, NIPPV, and other methods. According to virtually all involved, and limited case series data, this is yielding fruit. However current best estimates of mortality with mechanical ventilation remain high , though improved, at 30-40%.
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, or in some cases 1 hour), and watching for development of disease. According to the WHO and reports from the Chinese CDC and American 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, it is notable that tracing consistently shows low attack rates among even close contacts. The nature of contact matters: those in close quarters and crowded situations appear to be at higher risk. This strongly suggests social distancing, universal masking, and other physical measures can be effective means of lowering the R-naught.
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 possible asymptomatic transmission, and there continue to be reviews amplifying them. However establishing the role of asymptomatic spread, and even proving its existence, 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. They acknowledge reports of asymptomatic transmission, but state it is “not yet known how often it happens.” After extensive literature review, we agree.
A brief review: One commonly cited report of ‘asymptomatic transmission’ includes a supplementary appendix describing the index case as symptomatic. The second , describing an asymptomatic woman whose family became ill, may or may not have been asymptomatic transmission. A third case describes a gentleman who 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 some patients reporting no symptoms were likely transmitting. More than half, however, were cognitively impaired and others had baseline chronic cough, making the data fraught.
The United States CDC has p ublished an excellent review examining these papers, computer modeling studies, and reports describing asymptomatic people with likely transmissibility based on high viral load (though no instances of transmission). The authors also explore the implications of these data and important open questions.
In contrast, contact tracings of many hundreds of thousand s of cases around the world have identified index events of contact with a symptomatic patient in the overwhelming majority. Computer modeling studies have suggested 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 revealing South Korean report found important spreaders and ‘superspreaders’ with symptoms like sore throat and cough mild enough not to be apparent without careful examination and questioning.
Finally, the difference between asymptomatic and presymptomatic spread is probably important as well. While those with mild symptoms or in the incubation phase may transmit the virus, it remains less clear that those who never develop symptoms can. No such case report exists 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 low.
SUMMARY: There is no excellent evidence to answer this, but it is relevant to ‘pandemic thinking’. The prevalence of Covid-19 in quarantines and among fever clinic populations has been surprisingly low. Moreover, most state level testing in the U.S. shows low rates (<10%) of SARS-Cov-2. 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 likely be higher. Based on current disease activity in the United States it is reasonable to estimate a URI is more likely to be due to 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 immediately, watching for symptoms, and being 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’. All persons who quarantine should do so until they meet (at minimum) CDC clearance criteria described below, i.e. >10 days from onset, one day without fever, and improving.
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 other recent reports confirm infectiousness (based on viral load, a surrogate marker) 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—the issue that matters most. In fact by far the best examination of this issue , by the South Korean CDC, found zero transmissions famong 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 remain asymptomatic after recovery (even if they test positive) it seems even less likely they can transmit.
Can One Person Be Infected By Covid-19 Twice?
EVIDENCE BITE: If so, it seems to be vanishingly rare.
SUMMARY: First, the reason this issue is important is not individual risk (suffering a second bout). That is bound to be frustrating and 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.
We have reviewed emerging information including news and scientific reports about those who retest positive. By far the most useful and extensive data are from the South Korean CDC which describes 447 cases of testing positive after recovering from Covid-19. Of these, 285 were 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 (i.e. they weren’t infectious) and no new Covid-19 infections were found among contacts. These results jibe with extensive worldwide contact tracing , and monkey studies suggesting infection is protective.
Conversely, one non-peer reviewed examination of common (non-SARS) coronavirus infections found a meaningful percentage (12 of 86 infected patients, 14%) tested positive for the same coronavirus strain within the year. Most (9 of 12) were children, and the three adults experienced minimal or no symptoms. There was no evaluation of transmissibility. One press report we are aware of and a case report of two elderly patients both appear to document second symptomatic bouts (relapses?) of Covid-19 disease, though again no transmissions from these are known.
In addition, one concerning serum antibody study suggested 30% of patients mounted little or no detectable antibody response, feeding fears of non-immunity. A second study , along with a number of others, however, found 97-100% exhibiting strong responses. The reason for the discrepancy is unclear, but we believe the latter is correct, partially based on data suggesting immunity may well be mediated by immune factors unrelated to measurable antibody response.
For now, reinfection with documented transmissibility remains unreported. (Fingers crossed).
Are There Known Predictors of Severe Covid-19 Disease?
EVIDENCE BITE: No
SUMMARY: There have been many publications and pre-publications reporting associations between clinical characteristics and severity of Covid-19 infection or outcome. There are methodologically rigorous examples , even with a handy online risk calculator. We too summarized some early data on indicators of mortality . However while, for instance, increasing age correlates with outcome, and integrating this with existing judgment is wise, predictors from case reviews are inherently unreliable. They are cherry-picked retrospectively and often use limited follow-up. Prospective validation studies are always necessary, and until then physician judgment will be better. Even the most rigorous studies above have not been truly validated (despite language suggesting otherwise). For clinicians seeking to predict outcomes we suggest carefully considering these data as part of, not as a replacement for, best judgment.
Should Affected Populations Be Universally Wearing Masks In Public Settings?
EVIDENCE BITE: We think so
SUMMARY: The question of whether to wear masks is important. For broad psychology (‘pandemic thinking’) alone we believe this may be useful, but we have no hard data to support that belief.
It is worth understanding how this might work, however. While individuals not yet infected are theoretically not protected by masks (hands, touching, and droplets spread the virus) actively infected patients may spread less with a mask. Therefore the utility of widespread masking is based on hoping those infected are wearing them as well.
There are 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 modeling studies and reviews that support the idea, though all (necessarily) rely on confounded observational data. There is even a study suggesting those who contract Covid-19 while wearing a mask will experience less severe illness. Intuitively, many leading scientific voices have supported these conclusions as a risk-based approach to the pandemic. We agree with this approach because it reflects what we feel is smart pandemic thinking, but concede the science is shaky.
For now, combined with distancing, masks seem to be strongly associated with flattening curves, and based on the lack of a medical downside we see that as good enough.
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 in close quarters the virus can travel through the air.
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’) and most other respiratory viruses. However it is likely based on contract tracing data and SARS-CoV-2’s known properties it is more often spread through direct contact (touching a person or object with virus, then touching one’s own face).
The broad confusion about whether airborne spread occurs with SARS-CoV-2 is definitional and, frankly, not very important. When experts describe ‘airborne transmission’ they mean small aerosolized particles of high concentration that remain suspended long enough to infect people who contact the same airspace hours (or sometimes even days) later. Thus ‘airborne spread’ does not simply mean droplets in the air, which is common to all viruses. Measles, chicken pox, and smallpox exhibit true airborne spread. With measles each infected person routinely transmits the illness to 15 others. Covid-19 R0 has been estimated by the CDC at 5.7 (and some still believe it may be 2-3).
Thus, while travel of particles through the air may lead to infection in some cases, SARS-CoV-2 droplets are mostly heavy and fall quickly. They generally do not remain airborne and are also not small enough to travel to deep lungs. Moreover, most Covid cases around the world have reliably identified an instance of physical interaction or extended close contact (conversing within 6 feet for >15 minutes) with a Covid-19-infected person.
The important answer for clinicians and lay people then, is SARS-CoV-2 does not exhibit the frightening transmission properties of measles, chicken pox, or any other known virus with airborne transmission. It is worth keeping in mind, however, that like all other respiratory viruses it is often briefly transmitted through the air in close quarters.
What Antiviral Therapies Show Promise For Managing The Covid-19 Pandemic?
EVIDENCE BITE: Possibly dexamethasone
Dexamethasone : A single, large randomized trial found a 3% (NNT 33) absolute mortality reduction among >6000 subjects randomized to dexamethasone or no dexamethasone. This benefit seemed most robust among those receiving mechanical ventilation (nearly 12% reduction, or NNT 8), while the drug may have harmed those least ill and who received the drug early in their course. The trial was not placebo-controlled or blinded, points of potential bias, and will need to be replicated under more rigorous conditions for confidence. However use of the drug after hospitalization in patients requiring oxygen seems like a wise approach given these data. We eagerly await further trials.
Remdesivir : this nucleotide analog was developed to treat hepatitis, for which it failed, and later ebola, for which it also failed. The first published trial of 237 subjects in Wuhan failed to show benefit in any measure (even viral load was unchanged, theoretically the drug’s mechanism of action). A second, larger trial of over 1000 subjects, however, found a 4-day benefit (15 vs. 11) in ‘time to recovery’, though no effect on mortality. Problematically, the primary outcome of this trial was changed after data collection began . The original primary outcome was “percentage of subjects reporting each severity rating on an 8-point ordinal scale” including death, mechanical ventilation, and other important endpoints. The new primary outcome was not mentioned in the researchers’ original 30 outcomes of interest. Based on the drug’s history of failure our prior probability estimate for the effectiveness of remdesivir was very low. This combined with outcome switching and irregularities leave us skeptical. We await attempts to replicate this outlier result and hope to see future trials focus on mortality.
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 at least three rigorous , peer reviewed trials published in major journals ), though more and better data is always useful: no benefit and in at least one case well documented, considerable adverse effects. A large, recent trial using HCQ for post-exposure prophylaxis (median 3 days post) also showed no benefit. At this point there is ample data documenting adverse effects as well. The drug should be used only in research settings.
Convalescent plasma : This therapy was first formally reported in 5 people with severe, ventilated Covid-19 disease. We are aware of a single randomized trial of 103 subjects, terminated early. While no statistical benefits were found for any outcome, the results suggest clinically meaningful differences are possible and more rigorous, better trials should be conducted.
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 in a specific form of immunotherapy to treat certain cancers. Therefore, it has been proposed that tocilizumab could potentially treat the cytokine storm in COVID-19 infection. Unfortunately, so far only one case series of 20 patients has reported any benefit (clinical improvement such as decreased oxygen requirement and resolution of fever) in COVID-19 patients. The FDA recently approved a clinical trial to assess the efficacy and safety of tocilizumab for treatment of COVID-19 pneumonia in hospitalized patients.
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.
In summary, preliminary data support dexamethasone 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.
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 only chart review series we are aware of supports this notion, documenting 136 patients with known COVID-19 who underwent CPR after cardiac arrest. There was one neurologically intact survival.
In comparison, limited retrospective data from the SARS outbreak suggests baseline risk of infection among healthcare workers may be roughly 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 critical human resource that will now, at minimum, be quarantined for weeks. Recently released 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 in-hospital COVID-19 arrests represent near zero potential for functional survival. Exceptions will be younger patients without multi-organ failure or without comorbidities, or perhaps those arrested due to isolated hypoxia. In the absence of these variables, based on survival potential and provider risk, we feel CPR is best avoided.
Supervising editor: Shahriar Zehtabchi, MD