DHM COVID-19 Clinical Dispatch
Bite-sized, weekly clinical updates
Issue #11: A Look Back - Recaps and Updates
Like bell-bottoms and leg warmers, everything comes back into style eventually.
This week we're going back to give you important updates on four prior issues! Each section starts out with a quiz refresher, then digs into some of the key literature since the last issue was released.
On a personal note: we have an amazing team that puts in a lot of hours every week and we have been so thrilled to work with them. Aline Zorian, Karly Hampshire, Ethel Wu, Shradha Kulkarni, Rashmi Manjunath, Lauren Meyer and Mike Wang - you all are such rockstars and it's been a pleasure digging into the morass of COVID with you.
This issue will be our last for the time being - we're taking a break to think about how best to use this platform in the future, and we need YOUR input to make sure it’s something you’d want to find in your inbox! (Look out for a quick survey from us soon!)
- Peter and Avromi, for the COVID Clinical Working Group
Issue 2 - Clinical Predictors of Severe Disease
In our second issue our lit one-pager focused on several comorbidities associated with in-hospital death. Which of the following was NOT associated with death in this study?
A) Diabetes
B) Hypertension
C) COPD
D) Age
One-line update: New research has begun to provide predictive models to help prognosticate regarding potential disease severity.
Back in late April this issue highlighted the challenge in predicting clinical decompensation, and noted several clinical and laboratory findings that seem to correlate with severe disease.
Since then, an article by Liang et al in JAMA Internal Med used a multivariate regression analysis of 1590 patients to create a prediction tool (found here) for the development of critical illness. These findings track with most prior literature, though do not include CRP, D-dimer, and troponin, which have been associated with mortality in other work. (The 10 predictors in the tool are found below!)
Issue 3 - Hypercoagulability in COVID-19
In our third issue we reviewed a retrospective study (Tang et al. 2020) showing that in COVID-19 non-survivors, when compared with survivors, had:
A) Elevated Fibrinogen
B) Elevated D-dimer
C) Normal PT/INR
D) Elevated Fibrin Degradation Products
E) A and D
One-line update: Hypercoagulability is still a concern, CHEST guidelines recommends universal pharmacologic VTE prophylaxis.
In late April we presented some of the emerging data regarding coagulopathy in patients with COVID-19, and this continues to be a common theme in larger datasets that have been generated since.
Frequent laboratory findings in these patients include elevated PT, aPTT, and markedly elevated D-dimer levels. D-dimer in particular seems to be correlated with both coagulopathy and more severe disease.
Initial reports suggested a significantly elevated VTE risk in all COVID-19 patients, though VTE PPx was variable, and newer reports have called this into question. However, analysis of datasets generated from COVID-19 patients requiring ICU-level care has demonstrated a widely variable VTE rate of 0-54%(!). Based on these data, VTE prophylaxis with LMWH or UFH is recommended in all patients who do not have specific contraindications. (Connors and Levy 2020) but therapeutic-dose anticoagulation is NOT yet recommended given concerns for higher bleeding risk and unclear benefit.
Additionally, NEW GUIDELINES from Chest were released and are summarized below!
Issue 5 - Remdesivir
In our Remdesivir issue, we noted that this drug has been studied for the treatment of many prior viral outbreaks. Which of these diseases has NOT been tested for treatment with Remdesivir (as far as we know)?
A) SARS-1-CoV (original SARS)
B) MERS
C) Ebola
D) HBV
E) HCV
One-line update: It’s all about ACTT-1, which found a significant association between remdesivir use and time to clinical improvement - possibly only in those requiring supplemental O2 and not more intensive oxygenation or ventilatory support.
In early-May, our remdesivir issue highlighted a RCT from Wuhan that hinted at a possible benefit to remdesivir, though was underpowered to show a significant effect.
A week after that dispatch (naturally), preliminary results from the ACTT-1 trial were published. This multi-country RCT remains the most impactful study of remdesivir in humans to date. It demonstrated that patients who received remdesivir had a shorter time to recovery (median 11 days vs. 15 days, p < 0.001) than those who received placebo.
There was also a non-significant trend toward improved mortality (7.1% vs 11.9% - 95% CI 0.47 to 1.04).
In a subgroup analysis looking at severity of illness, there was significant benefit to remdesivir in those requiring supplemental oxygen, though no significant effect in patients receiving HFNC, NIPPV, mechanical ventilation, or ECMO (possibly due to low enrollment from these subgroups). It remains unclear whether remdesivir would be beneficial in these patient populations.
How else is Remdesivir being explored?
- ACTT is now beginning its second trial (aptly named ACTT-2) that will randomize patients to remdesivir alone vs. remdesivir plus baricitinib - an oral treatment for RA that interferes with cytokine signaling and might theoretically might mitigate the inflammatory response induced by SARS-CoV-2.
- SIMPLE, A randomized, non-controlled trial published in NEJM compared 5- and 10-day regimens of remdesivir, found no significant difference in clinical improvement of severely ill, non-ventilated patients.
In the spirit of interesting team-ups, some researchers are even calling for clinical trials to explore a combination of remdesivir plus vitamin D.
Issue 6 - Convalescent Plasma
Our sixth issue detailed several potential mechanisms of action for convalescent plasma in the treatment of viral infections. Which one of the following is NOT a possible mechanism from that list?
A) Reduction in viral load
B) Transfer of anti-inflammatory cytokines
C) Inhibition of the complement cascade
D) Modulation of T cell response
E) Addition of clotting and anti-clotting factors
One-line update: While convalescent plasma (CP) has shown benefit in other viral infections, there is no conclusive evidence regarding the use of CP as a significant therapy against COVID-19.
In this issue from mid-May, we focused on convalescent plasma, a treatment with proven benefit in other viral infections. So far, much of the published data has been in retrospective studies or case series.
Recently, a randomized control trial studying the use of convalescent plasma in SARS-CoV2 infection was published. In this multi center, randomized, open-label trial, 103 patients in seven medical centers in Wuhan China were randomized to receive convalescent plasma + standard of care vs. standard of care alone. Trial participants had laboratory confirmed, severe or life-threatening COVID-19. The primary outcome was time to clinical improvement within 28 days (discharged alive or reduction of 2 points in a disease severity scale).
Unfortunately, the trial was terminated early because of under-enrollment, as the caseload in China had dramatically decreased. There was no difference in the primary outcome (and a number of the secondary outcomes) between the two groups, though the study was underpowered.
So is convalescent plasma the answer we have been waiting for? The jury is still out. Currently, there are several active RCTs (including one in Stony Brook) that will hopefully provide further clarification about the efficacy of convalescent plasma.
Links
Questions, thoughts, insights? Share them on our Clinical Knowledge Portal!
Prior Dispatches:
Issue 1: GI symptoms in COVID
Issue 2: Predictors of Severe COVID Disease
Issue 3: Hypercoagulability in COVID-19
Issue 4: SARS-CoV-2 and the Inflammatory Response
Issue 5: Remdesivir for COVID-19
Issue 6: Convalescent Plasma
Issue 7: ARDS
Issue 8: Post-infectious Immunity
Issue 9: Racial Disparities in COVID-19
Issue 10: Transmission
Questions from our Readers
submitted via the Clinical Knowledge Portal
“A patient previously on a checkpoint inhibitor is persistently covid+ x 8 weeks - why?”
“A prospective study of 137 patients (J Clin Inf Dis) reported a median duration of viral positivity of 12 days. The longest duration was 45 days. A pre-print report in March (medrxiv) describes a case of viral positivity up to 49 days, “...the longest duration of nasopharyngeal viral shedding in a symptomatic person, as far as we know.” Stool viral positivity has been reported up to 56 days post-infection, though the clinical significance of this remains unknown.
This means your patient’s long viral positivity is likely quite unique - you might consider writing a case report!
Unfortunately, reports on checkpoint inhibitor use during viral infection vary widely. There are some reports that concurrent use of checkpoint inhibitors during viral infection may impair viral clearance, while others suggest that they may expedite it. They may also facilitate a more effective antiviral response by delaying T cell exhaustion. Of particular interest in the case of COVID-19, and depending on the patient's baseline immune state, this modulation of the immune response in the setting of checkpoint inhibitors may be beneficial, or may result in an excessive response that triggers the cytokine storm syndromes observed in a subset of patients.
