Six new advances in COVID-19 the week of June 1st-June 7th
1) Finding a positive PCR after infection does not necessarily reflect infectivity.
Numerous studies have found patients with a positive PCR for SARS-CoV-2 after recovery from clinical illness. The question has been, “Does this reflect infectivity?” There is now data suggesting that the answer is not necessarily.
This is a retrospective study of 92 PCR positive samples which were submitted for culture. Overall, 29% of cultures were positive for SARS-CoV-2. However, no cultures were positive in those with a symptom onset > 8 days before the PCR or a RT-PCR cycle threshold (Ct) of >24 (the number of cycles of amplification before detection, with a Ct of > 24 being is a strong reaction suggesting a large amount of SARS-CoV-2 nucleic acids). The study concluded that the infectivity of patients with Ct >24 (e.g. even some of those with a large amount of viral RNA) and/or a duration of symptoms >8 days may be low.
It is reassuring that not all patients with a positive PCR after COVID-19 are infectious and that at 8 days after symptom onset none were culture positive. More information is needed on this topic to make definitive claims.
Accepted prepublication manuscript: Clinical Infectious Diseases, ciaa638, https://doi.org/10.1093/cid/ciaa638 Published: 22 May 2020
2) Post-exposure prophylaxis does not seem to reduce the occurrence of symptomatic COVID-19.
This is a randomized, double blind, placebo-controlled trial of hydroxychloroquine in the prevention of COVID-19. The study included 821 individuals who were exposed to a known COVID-19 case. Exposure was defined as an occupational or household exposure within 6 feet for at least 10 minutes without the use of protective equipment (high risk, 719 participants) or with a mask but no eye protection (moderate risk, 108 participants). Participants were randomized to hydroxychloroquine 800mg followed by 600mg in 6-8 hours, then 600mg for 4 days) within 4 days of exposure. The outcome was laboratory confirmed COVID-19 or symptoms consistent with COVID-19.
There was no difference in the infection rate between the two groups (11.8% vs. 14.3% (difference of 2.5% CI 95 -7.0-2.2)). Discontinuation was significantly higher in the hydroxychloroquine group (75% compliance in hydroxychloroquine group vs. 83% in the placebo group). Side effects were reported by 40% of the active treatment group vs. 17% of the placebo group.
This study shows no benefit to hydroxychloroquine in reducing infection after a COVID-19 exposure. The weakness of this study is that it relied partly on participant symptom report and not all infections were verified by PCR. Additionally, it does not tell us about the rate of asymptomatic infection. There are ongoing studies of pre-exposure prophylaxis including a large study in health care workers.
NEJM June 3, 2020 DOI: 10.1056/NEJMoa2016638
3) We still don’t have an answer on convalescent plasma.
Anecdotal reports suggest that convalescent plasma therapy in patients with severe COVID-19 may be beneficial. The results of an open label, randomized trial of 103 select patients with life threatening COVID-19 who all got standard care with 52 getting convalescent plasma added to their regimen was released. There were multiple exclusion criteria.
Looking only at mortality, there was a non-statistically significant benefit to convalescent plasma (mortality 15.7% versus 24.0% 95% CI 0.29-1.46).
Why is an 8% difference not significant? The study was underpowered to find a difference. The study was designed to include 200 patients and only enrolled 103. This is called a “Type II error”. You can remember this by the mnemonic that in a type II error there are “too few” participants to find a difference that actually exists. This study suggests a difference, but more data is needed to make a definitive conclusion.
JAMA. Published online June 3, 2020. doi:10.1001/jama.2020.10044
4) A plea to treat air hunger in those with COVID-19 related ARDS who need intubation.
This pre-publication commentary reminds us to treat air hunger in those who are intubated and receiving low tidal volume ventilation. Low tidal volume ventilation leads to “permissive hypercapnia” with an increase in pCO2. This leads to a sensation of air hunger, which in other studies, is associated with psychological trauma leading to PTSD in some survivors of ARDS. The authors of this study point out that this is the same mechanism that is operative in torture (e.g. waterboarding).
They make several points including:
- Include narcotics in the initial sedation protocol and continued sedation management of intubated patients. Morphine 5mg IV has been shown to be very effective at reducing air hunger.
- Benzodiazepines do not reduce air hunger although they may reduce the resultant psychological trauma.
- Paralysis alone does not reduce air hunger, contrary to popular belief. It should also be noted that patients should not be paralyzed until they are fully sedated. While paralyzed, sedatives should not be weaned. Institutional protocols for paralysis should be followed.
5) Masks, Social Distancing or Both?
Adoption of social distancing and masks has not been universal at least partly because of the belief that these measures do not help reduce COVID-19 transmission. This study questions that rationale.
This is a systematic review and meta-analysis of 172 studies looking at transmission of coronaviruses (specifically COVID-19 but also SARS and MERS). All studies were ranked using Cochrane and GRADE methods. Forty-four studies met quality criteria and were included in the meta-analysis (a total of 25,697 patients). None were randomized controlled trials.
Social distancing of at least one meter was associated with a 10.2% reduction in transmission (CI 11.5 to 7.5) (n=10,736). The risk of transmission decreased by a relative risk of 2 per additional meter-distance (moderate certainty). Masks (n=2647), had a large effect on transmission with a risk difference of 14.3%. As one would expect, N95 masks performed better than disposable surgical masks or those with 12-16 layers of cotton (low certainty). Eye protection (n=3713) also reduced transmission (10.6%-low certainty). Subgroup and sensitivity analyses lead to the same conclusion.
It isn’t likely that a randomized trial of masks will be done given the ethical implications of knowingly exposing patients to a potentially fatal virus. The best data to date reinforces the directives to maintain social distancing and to wear masks to prevent disease transmission.
The Lancet June 1, 2020 https://doi.org/10.1016/S0140-6736(20)31142-9
6) And, as one might expect, even more stringent precautions work better.
This is an MMWR report on the results of stringent measures to reduce COVID-19 transmission in a high-density military population of 10,579 trainees. Steps taken include:
- Quarantine for 2 weeks upon arrival
- Social distancing of at least 6 feet
- Testing if the individual had symptoms
- The use of cloth masks
- Travel restrictions on those wanting to enter the base
Using these techniques, they were able to limit transmission to a total of 5 cases of whom 3 were contacts of the first case. The spread was extrapolated to be 47/100,000 people.
How this applies to the general public is not known. Military bases are a very structured and closed environment and behavior can be mandated unlike in the general population.
Marcus JE, Frankel DN, Pawlak MT, et al. COVID-19 Monitoring and Response Among U.S. Air Force Basic Military Trainees — Texas, March–April 2020. MMWR Morb Mortal Wkly Rep. ePub: 2 June 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6922e2external icon.