DHM COVID-19 Clinical Dispatch

Bite-sized, weekly clinical updates

Issue #6: Convalescent Plasma

This week we bring you another potential treatment for COVID...

Convalescent Plasma! This not-so-new treatment has recently been getting a lot of press for COVID-19, and so we start with the big question: “What is convalescent plasma and how does it work?”

We explore how convalescent plasma been used as a treatment for more than 100 years, look at some of the evidence in other viral infections before highlighting our Paper of the Week (a study of 10 patients in COVID-19).

Our Big Take-away for the week?
Convalescent Plasma has been used to treat a variety of severe respiratory viral illnesses (including SARS and influenza) with promising results and a good safety profile. There is good reason to think that it may benefit COVID-19 patients, but randomized trial data are lacking and much more study is warranted before we can say whether this is an effective therapy.

Also, be sure to check our "What We're Reading," our weekly literature round-up at the end. Happy Thursday!

- The COVID Clinical Working Group

Spaced Learning Corner: Quiz Yourself!

In the Wang et al randomized control trial investigating remdesivir use in patients with severe COVID-19, which of the following outcomes was the only one that showed improvement (though not statistically significant) in patients who received remdesivir within 10 days of symptom onset?

SARS-CoV2 viral load
Mortality at 28 days
Time to clinical improvement
CRP level
Lymphopenia

Find the answer here!

Introduction to Convalescent Plasma

Schematic representation of convalescent plasma components and mechanisms of action, Rojas et al.

What is convalescent plasma and how does it work?
In the absence of a vaccine that allows the body to generate its own immune response against SARS-CoV-2, convalescent plasma is a way to provide passive immunity against the virus. When previously infected donors undergo apheresis, the resulting product contains antibodies which are specific to SARS-CoV-2 and function to neutralize the virus. This could result in a reduction in viral load in the recipient. Convalescent plasma also likely contributes to immunomodulation through a number of other mechanisms, including inhibition of the complement cascade, transfer of anti-inflammatory cytokines and modulation of T cell responses, which limit the hyperinflammatory response to viral infection.

How long has this idea been around?
Convalescent plasma gained traction initially in the 1890s when a German scientist reported on the treatment of diphtheria in humans with the serum of immunized animals. It has subsequently been used in a variety of viral infections including the 1918 influenza pandemic, measles, SARS, MERS-CoV, Ebola and more. These data, consisting of primarily observational studies, are summarized in the table below!

I want convalescent plasma! How do I get it?
Infectious Disease is actively screening our COVID patients for all investigational therapies but welcome us reaching out if you feel that a patient could benefit from convalescent plasma. If any questions, page the COVID-ID attending!

Quick Lit - One-Page Literature Review

For our Patients... Convalescent Plasma FAQ

What does it mean to get convalescent plasma?
Patients are transfused 200-500mL of plasma, from a SARS-COV2 antibody positive donor, over 1-2 hours. Patients typically get one to two units of plasma while donors typically donate two to three. The potential adverse reactions are still being studied but are likely similar to those of other transfusions: allergic reactions, transfusion-associated heart or lung damage, and transmission of infections.

When is the best time to get convalescent plasma? And how long will it take to see benefits?
Plasma is being studied at all stages of disease, though the general thought has been that prophylactic or early use (within 2 weeks) would be most beneficial. Further studies are underway to clarify timing of use and when and what improvements to expect.

What are the ways to get convalescent plasma?

A physician can apply for FDA approval with a Single Patient Emergency Investigational New Drug application.
Expanded Access Program: Compassionate use for patients without alternative access to plasma.
Randomized Clinical Trials: Currently there are at least 13 FDA approved trials studying the use of convalescent plasma across the country.

Click here for more information!

Where can you get convalescent plasma in San Francisco?
Via the expanded access pathway, convalescent plasma is available at UCSF, St. Mary’s, San Francisco VA, Zuckerberg General, St Francis, and CPMC.

I had COVID-19. How can I donate plasma?
People with confirmed COVID-19, who qualify to donate blood and are symptom free for at least 2 weeks could potentially qualify to donate plasma. If interested, check out a list of donor sites here.

What We're Reading

Here are the articles that our team is reading this week, which are particularly relevant to this issue. To see these and all of our literature summaries please check out our Literature Database!

Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. (Shen et al. JAMA, March 27): This uncontrolled case series included 5 patients in Shenzhen, China with severe COVID associated ARDS who received convalescent plasma. Four of the 5 patients experienced clinical improvement, viral load reduction and resolution of ARDS within 12 days of convalescent plasma transfusion, and all patients were either discharged or were in stable condition 37 days after transfusion.
Convalescent plasma in COVID-19: Possible mechanisms of action. (Rojas et al, Autoimmun. Rev., April 11): This review article provides the historical background for the use of convalescent plasma in viral disease, highlighting the cellular mechanisms by which antibodies directly neutralize viruses and contribute to immunomodulation in the recipient, making this an often effective form of passive immunity in the absence of a vaccine.
Use of Convalescent Plasma Therapy in SARS Patients in Hong Kong. (Cheng et al, Eur J Clin Microbiol Infect Dis, Jan 2005): This prospective study administered convalescent plasma (CP) to 80 patients with SARS-CoV-1 infection (original SARS) with worsening disease despite treatment ribavirin and steroids. Overall mortality in all patients who received CP was ~12% (SARS mortality overall ~17%) and better clinical outcomes were seen in patients who received CP before infection day 14d (58.3% vs 15.6%; P<0.001).
Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. (Valk et al, Cochrane Database Syst Rev, May 14): This Cochrane systematic review evaluated eight completed studies including 32 participants (7 case series, 1 prospective uncontrolled trial). High risk of bias and poor precision result in “very low certainty” regarding outcomes. Of the total 32 participants, two adverse events were identified, including one case of anaphylactic shock. 48 further ongoing studies on convalescent plasma (47) or hyperimmune immunoglobulin (1) were identified but not summarized; 22 are RCTs.
COVID-19 convalescent plasma: phase 2. (Knudson et al, Transfusion. May 06): This commentary is an interim report of an ongoing phase 2 trial at the University of Iowa. Donors had been asymptomatic for 14 days and since confirmed COVID-negative. Donations were solicited from 36 subjects, and 20 patients have been treated thus far. They do not report on preliminary results, but raise several implementation issues such as how much plasma to give and how to account for ABO compatibility.

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