“All studies come with limits, and basically what we’re trying to do is provide a very high-level overview” of the data currently available, said author Dr. Michael Joyner, an anesthesiologist and physician-researcher at the Mayo Clinic in Rochester, Minnesota.
“The report provides a signal of hope that CP is beneficial, although unfortunately, it does not provide the confidence that is required to be able to responsibly recommend CP for the treatment of COVID-19,” Dr. Mila Ortigoza, an instructor in the Departments of Medicine and Microbiology at NYU Langone Health, who was not involved in the research, told Live Science in an email. Ortigoza, who is currently co-leading a clinical trial of CP therapy for COVID-19, noted that none of the randomized controlled trials included in the analysis “recruited a sufficient number of participants to be able to make conclusions about efficacy” on their own.
“What the current study really highlights is the need to continue supporting ongoing RCTs of CP” to ensure that they enroll enough patients to provide “indisputable evidence” that the therapy really works, she said.
As scientists design new medications for COVID-19, and clinicians repurpose existing drugs like remdesivir, doctors have also turned to CP therapy to treat the viral infection.
“If you look at convalescent plasma, specifically … [it’s] been applied to pandemics at least since the 1918 flu,” Joyner said. CP therapies were subsequently used during the 2003 SARS outbreak, caused by a coronavirus related to the one that causes COVID-19, and the 2009 H1N1 pandemic, Ortigoza added.
Because people who have recovered from a disease have mounted an effective immune response, CP therapy offers a way to treat infected patients by borrowing tools from the immune system itself — namely, antibodies that direct the immune system to attack a specific pathogen, or neutralize the bug directly, Live Science previously reported.
Although promising on paper, CP has been difficult to study in practice. Trials of CP conducted during past pandemics often lacked control groups for comparison, meaning the effects of CP could not be weighed against those of an alternate therapy, or the standard of care, Ortigoza said. But in the context of a pandemic, well-controlled trials can be difficult to execute at the scale and speed required to draw clear-cut conclusions for people who may need treatment right away.
“In a pandemic, you can’t always get a definitive ‘ah-ha’ study” that clearly demonstrates a therapy’s efficacy, Joyner said. Plasma therapies pose a particular challenge, given that they rely on blood donations from donors who are both eligible to donate plasma and test positive for antibodies, he added.
In addition, the number of COVID-19 patients at a given hospital fluctuates, making recruiting participants for RCTs even trickier.
But it’s important, because “it is very challenging to draw conclusions from non-RCT studies with confidence because they lack the randomization process,” and small RCTs, albeit randomized, don’t include enough patients to yield reliable statistics or be generalized to larger populations, Ortigoza said.
With these caveats in mind, Joyner said his team still felt it important to pool the available data and see what trends materialized; specifically, they wanted to know if COVID-19 patients who receive plasma die at lower rates than those who do not. In addition to three RCTs, the team analyzed four case series studies, which tracked the clinical outcomes of a small group of individuals given CP. The other five trials were matched-control studies, meaning each patient given CP was compared to a similar patient given a standard treatment, but these treatment assignments weren’t randomized.
In crunching all the numbers, “you start seeing this mortality benefit that’s substantial,” meaning CP patients do seem to die at significantly lower rates, Joyner said. However, more RCTs will be needed to nail down finer details, such as which patients benefit most from the treatment, or when the plasma should be given over the course of the infection to produce the best results, Joyner said. “You might see a more striking effect if [CP is] used optimally,” he said.
“When evidence with a high degree of confidence emerges, the data and safety monitoring board will make a joint recommendation to the leadership of all trials,” according to a statement on the COMPILE website.
Even if CP is proven effective one other obstacle stands in the way of its widespread use: the limited number of certified blood banks.
“Most hospitals across the United States are not equipped or certified to perform apheresis in-house,” meaning they cannot separate plasma from red blood cells and other components in donated blood, Ortigoza said. “Providing support to the certified blood banks … across the nation will be crucial for the success of this therapeutic strategy.”