Convalescent Plasma Could Reduce Death From Covid-19

September 7, 2020

Patients with COVID-19 treated with blood that had recovered from infection had significantly lower mortality rates than those given standard therapy alone, according to a preliminary analysis.

In the analysis, which was posted to the preprint database bioRxiv on July 30, researchers examined more than a dozen trials in which hospitalized COVID-19 patients received convalescent plasma (CP) therapy – a treatment that involves drawing plasma from recovered patients and injecting the antibody-rich fluid into sick patients. According to the report, the 12 trials were conducted at different sites around the world and included more than 800 participants in total, and combined, patients given the plasma were less than half as likely to die as those given the other treatments.

Specifically, patients given plasma had a mortality rate of 13 percent, compared to 25 percent for those given standard treatment. While this is a correct trend, the new analysis was not peer-reviewed, and the data from some of the trials studied in the analysis were not peer-reviewed either. What’s more, only three of the 12 studies were randomized controlled trials (RCTs) in which patients were randomly assigned to receive treatment or standard care, the gold standard for evaluating medical care.

“All of the studies have limitations, and basically what we’re trying to do is provide a very high-level overview,” said author Dr. Michael Joyner, an anesthesiologist and physician fellow at the Mayo Clinic in Rochester, Minnesota.

“The report provides a hopeful signal that CP is beneficial, although unfortunately it does not provide the confidence needed to be able to responsibly recommend CP for COVID-19,” Dr. Mila Ortigoza, a lecturer in the department of medicine and microbiology at Langone Health at New York University, told Live Science in an email. He was not involved in the study.Ortigoza, who is currently co-leading a clinical trial of a CP therapy for COVID-19, noted that none of the randomized controlled trials included in the analysis had “recruited a sufficient number of participants to be able to draw their own conclusions about efficacy.”

“What the current study really highlights is the need to continue to support ongoing CP RCTs” to ensure they recruit enough patients to provide “incontrovertible evidence” that the therapy does work, she said.

A positive sign
As scientists devise new drugs for COVID-19 and clinicians repurpose existing drugs, such as remdesivir, doctors are turning to CP therapies to treat viral infections.

“If you look at healing plasma, in particular … [it] has been used for pandemics since at least the 1918 flu,” Joyner says. CP therapy was then used during the 2003 SARS outbreak, caused by a coronavirus related to the coronavirus that causes COVID-19, as well as the 2009 H1N1 pandemic, Ortigoza added.

Because people recovering from the disease have built up an effective immune response, CP therapy offers a way to treat infected patients by borrowing tools from the immune system itself – that is, by directing the immune system to attack antibodies to specific pathogens, or by directly neutralizing the bugs, Live Science has reported.

While promising on paper, CP has been difficult to study in practice. CP trials conducted during past pandemics have often lacked control groups for comparison, meaning that the effects of CP cannot be compared to those of alternative therapies or standard care, Ortigoza said. But in the context of a pandemic, well-controlled trials can be difficult to execute at the scale and speed needed to draw definitive conclusions for people who may need immediate treatment.

Joyner said, “In a pandemic, you can’t always get an ‘aha’ study” that clearly demonstrates the efficacy of a therapy. Plasma therapies pose a particular challenge, he adds, because they rely on blood donations from donors who are both eligible for plasma donation and who test positive in antibody tests.

A typical donation yields about 20 to 27 ounces (600 to 800 milliliters) of plasma, which can then be used for several doses of CP at 6.7 to 10.1 ounces (200 to 300 milliliters) each, Joyner said. For example, patients in the NYU trial received one or two 8.4-ounce (250-milliliter) doses of plasma. Plasma can be stored at below-freezing temperatures for years, which means it’s possible for hospitals to build up supplies for COVID-19 patients. But organizing a trial in which a large number of patients are randomized to receive plasma or standard therapy becomes difficult, given that hospitals will only accept CP if there is a suitable plasma donation, which may depend on donation rates and the prevalence of COVID-19 in the region.

In addition, the number of COVID-19 patients in a given hospital can fluctuate, which makes participant recruitment for RCTs even trickier.

But that’s important because “drawing confident conclusions from non-RCT studies is very challenging because they lack a randomization process” and small RCTs, while randomized, don’t include enough patients to generate reliable statistics or be generalized to a larger population, Ortigoza said.

With these caveats in mind, Joyner said his team still felt it was important to pool the available data to see what trends emerged; in particular, they wanted to know if COVID-19 patients who received plasma had a lower mortality rate than those who did not. In addition to the three RCTs, the team also analyzed four case series that followed the clinical outcomes of a small group of individuals who were given CP. The other five trials were matched-control studies, meaning that each patient given CP was compared to similar patients given standard treatment, but these treatment assignments were not randomized.

In tightening up all the numbers, “you start to see this mortality benefit, which is quite large,” meaning that CP patients do seem to die at a significantly lower rate, Joyner said. However, more RCTs will be needed to determine finer details, such as which patients benefit most from treatment or when plasma should be given during infection to produce the best results, Joyner said.” If [CP] is used optimally, you may see a more dramatic effect,” he said.

Joyner and his colleagues will add more trials to their meta-analysis as they emerge and will conduct similar analyses of how CP treatment affects patients’ length of stay, their intensive care unit (ICU) status and symptom severity, such as whether they need supplemental oxygen. NYU is also leading an initiative to pool data from ongoing RCTs, called COMPILE, which could “provide faster, more reliable answers related to the effectiveness of convalescent plasma before many of the ongoing RCTs are over,” says Ortigoza. The analysis is similar to Joyner’s, but will only include RCTs that meet specific criteria.

According to a statement on the COMPILE website, “the Data and Safety Monitoring Committee will make joint recommendations to the leadership of all trials when evidence with a high degree of confidence emerges.”

Even if CP is proven effective, there is one barrier to its widespread use: the limited number of certified blood banks.

“Most hospitals in the U.S. are not equipped or certified to perform pheresis in-house,” meaning they can’t separate plasma from red blood cells and other components of donated blood, Ortigoza says.” Providing support to certified blood banks across the country…. . will be key to the success of this treatment strategy.”