#211 COVID Cakes: Remdesivir, Anticoagulation, Transmission

May 1, 2020 | By Emi Okamoto

Griddle is hot and the cakes are fresh

In this episode we tackle treatment with remdesivir, management with anticoagulation, and presymptomatic transmission. Welcome back to COVID Cakes, a rundown of recent COVID articles and news stories. What does the latest Gilead medication have to offer? Why should we wear masks? And if you thought 6 feet was THE safe distance…we’ve got some bad news about running. But it’s not all bad! We’re joined by everyone’s favorite Curbsider/Internist/Epidemiologist, Rahul Ganatra MD MPH (@rbganatra), who provides critical appraisal of the newest COVID-19 treatment article. Pull up a chair, bring your own syrup, and join us!

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Credits

• Producer: Sarah P. Roberts MPH, Rahul Ganatra MD MPH, Emi Okamoto MD   
• Writer: Emi Okamoto MD, Rahul Ganatra MD MPH,    
• Cover Art: Chris Chiu MD
• Hosts: Chris Chiu MD, Rahul Ganatra MD MPH, Emi Okamoto MD   
• Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com

Sponsors

If you’re a healthcare worker looking for an opportunity to volunteer with the COVID relief efforts or you’ve been furloughed and are in need of work, please check out apollohct.com to see jobs and volunteer opportunities in your area and across the states. All you have to do is make a profile, input your preferences, and Apollo will do the searching for you.

We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out curbsiders.vcuhealth.org for more information.

Time Stamps

• 00:30 Intro, disclaimer
• 02:30 Picks of the Week
• 6:36 Remdesivir trial rundown
• 21:52 Thrombosis in COVID-19
• 29:50 Asymptomatic/Presymptomatic transmission
• 41:42 Quick takes 
• 49:00 Outro

COVID Cakes Notes 

Remdesivir Rundown

**Updates: 1) NIH Press Release about Remdesivir RCT with accelerated recovery from April 27, 2020. 2) Wang Y et al article from Lancet published April 29, 2020.**

Grein, J et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM. April 10, 2020 [https://www.nejm.org/doi/full/10.1056/NEJMoa2007016]

For a step-by-step breakdown of the study, follow along with Dr Ganatra (@rbganatra) on his twitter learning thread, #HowIReadThisPaper.

Think about how data get in and come out of any study. How patients (and their data) get in is all about patient selection (and selection bias), and how data comes out is all about ascertainment (and ascertainment bias).

Even though the primary results of this study were descriptive, meaning no comparison was done, are there still sources of bias that could threaten the authors’ conclusion that remdesivir is promising? Yes.

How did patients get into the study? 

Sources of selection bias: The denominator (how many total compassionate use applications submitted) is unknown, time from symptom onset to treatment was 12 days (meaning patients had to survive the first 12 days of COVID-19), and 8 patients contributed no follow-up data. 

How did outcomes come out of the study? 

Sources of ascertainment bias: The likelihood of having complete follow-up data depended on how sick patients were – all patients with mild disease at enrollment achieved clinical improvement or discharge; 8 patients with severe disease (requiring ECMO or intubation) achieved neither clinical improvement, discharge, or death by day 28. 

Bottom line:

Without a control group, it is impossible to tell whether the observed outcomes in this selected population are due to RDV. Selection bias limits both comparison to other cohorts and the generalizability of these results. Well-designed RCTs are needed.

COVID and Thrombosis

Thachil J et al. ISTH interim guidance on recognition and management of coagulopathy in COVID19. J Thromb Haemost. 25 March 2020 [https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14810]

Tang, N et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 27 March 2020. [https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14817]

What is everyone’s hospital policy on this? 

Anticoagulation policies vary widely, from prophylactic to treatment dosing for hospitalized patients, depending on institution. We recommend that you follow your institutions guidelines until we have more data to guide practice.

International Society of Thrombosis and Hemostasis Interim Guidelines Review

• Check D-dimer, PT, and platelet count on all COVID admitted patients, can use to guide care (who needs to be considered for ICU, more aggressive care, or improvement). D-dimer may predict severe disease and mortality.
• Recommend prophylactic LMWH in all patients without contraindication.
  • Related Commentary to ISTH- therapeutic anticoagulation with LMWH should be considered in severe illness, and even consideration of fibrinolytics as salvage therapy. More research is needed.

Wuhan China observational data on heparin use (Tang Paper)

• 449 patients comparing heparin users versus nonusers
• No difference in 28d mortality among all patients (30% in both groups)- very high!
• Mortality difference was seen among those D-dimer 6x ULN (33% users vs 52% nonusers) and Sepsis Induced Coagulopathy score > 4 (40% vs 64%)
• Dr Ganatra pro tip: The benefit of prophylactic anticoagulation was seen in a subgroup analysis of this retrospective study – it is hard to extrapolate to therapeutic anticoagulation based on these data. Current guidelines recommend prophylactic anticoagulation in all patients with COVID19 who are critically ill.

Presymptomatic and Asymptomatic Transmission

Asymptomatic cases on NYC Delivery Ward

Sutton D et al. Universal Screening for SARS-CoV-2 in Women Admitted for Delivery. NEJM. 13 April 2020. [https://www.nejm.org/doi/full/10.1056/NEJMc2009316]

• 215 women presented for given birth in NYC hospital, 4 with symptoms and tested SARSCoV2+ (2%), of the remaining 29/211 asymptomatic persons had NP swab + disease (14%)- 88 of the positive had no sx! In the mean 2d hospital stay, 3 (10%) developed fever
• Not necessarily a representative population, patients not followed after discharged for symptom development

Estimations on presymptomatic transmissions

He, X et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature Medicine. 15 April 2020. [https://www.nature.com/articles/s41591-020-0869-5]

• 77 pairs of infectors transmitting SARS-CoV2 to infectees – clear transmission links without other likely exposure
• Compared:
  • incubation period distribution (median 5.2d)
  • serial interval distribution- time between symptoms of infector and symptoms of infectee
• The observed mean serial interval is shorter than the observed mean incubation period, this indicates that a significant portion of transmission may occur before symptoms.
  • Infector transmits on average 0.7 days prior to symptoms, and could occur earliest 2.3 days prior to symptoms
  • 44% likely transmitting before symptoms
• Bias: patient recall, more asymptomatic cases are caught when better contact tracing and early notification occurs

Face masks for preventing transmission?

Leung N et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nature Medicine. 2 April 2020 [https://www.nature.com/articles/s41591-020-0843-2]

Bae S et al. Effectiveness of surgical and cotton masks in blocking SARS–CoV-2: A controlled comparison in 4 patients. Annals of Internal Medicine. 6 April 2020. [https://annals.org/aim/fullarticle/2764367]

• Study 1: Surgical masks led to respiratory decrease of aerosols produced from patients with common coronavirus (40% to 0%) and decrease of droplets (30% to 0%) when breathed/coughed
• Study 2: Four patients with SARS-CoV2 coughed 5 times towards petri dish 20cm away, no difference and virus detectable in all situation (with no mask, surgical mask, and cloth mask)
  • 20cm is very close! And difficult to interpret what virus in a petri dish means in terms of clinical infectivity

Quick Bites

Antibody testing : Letter from FDA summarized (Jwatch summary)

• “Do not use serological (antibody) tests as the sole basis to diagnose COVID-19 but instead as information about whether a person may have been exposed.” 

Seroprevalence study from Santa Clara, CA (MedRxiv study): 

• “Under the three scenarios for test performance characteristics, the population prevalence of COVID-19 in Santa Clara ranged from 2.49% (95CI 1.80-3.17%) to 4.16% (2.58-5.70%). These prevalence estimates represent a range between 48,000 and 81,000 people infected in Santa Clara County by early April, 50-85-fold more than the number of confirmed cases.”
• Dr Ganatra pro-tip: Beware – when the prevalence of disease is low (<5%), small changes in test specificity (for example, from 96% to 94%) are enough to tip the positive predictive value below 50%, which means that a positive test result is more likely to be a false positive than a true positive! Don’t believe me? Prove it to yourself here: https://www.medcalc.org/calc/diagnostic_test.php

“Don’t just do something, stand there” – advice from Paul Sax blog re IDSA guidelines

• Bottom line: There is no proven treatment for COVID-19, and several are recommended (only) in the context of a clinical trial

More hydroxychloroquine: MedRxiv: Retrospective on US VA 368 patients 

• “We found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone.” 
• Dr Ganatra pro-tip: In any retrospective study of a treatment, beware of a phenomenon called “confounding by indication.” Because patients were not randomized, it may be the case that sicker patients were more likely to get hydroxychloroquine, which could explain the observation that those patients had higher mortality (not the fact that they received the drug).  

Is Coronavirus on my hair? My shoes? My newspaper? A reassuring read from the New York Times for family, friends, and all of us! 

For Runners, Is 15 Feet the New 6 Feet for Social Distancing? Another less reassuring but hopefully still helpful NYT article.   

Picks of the Week / Links

1. You Bet Your Garden podcast with Mike McGrath
2. Ologies podcast with Alie Ward
3. Frosted Mini Wheats

Goal

Listeners will hone their skills in critical appraisal as they update themselves on all things COVID-19

Learning objectives

After listening to this episode listeners will…

1. Critically appraise recent research on remdesivir as a treatment for COVID-19
2. Review emerging literature and guidelines on thrombotic complications of COVID-19 
3. Interpret new data on asymptomatic transmission of COVID-19 

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra R, Chiu CJ, Okamoto E, Roberts SP, Watto MF. “COVID Cakes: Remdesivir, anticoagulation, and presymptomatic transmission”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list April 29, 2020.