Plasma therapy: the Covid success story that wasn't

• Since the very beginning of the coronavirus pandemic, medical professionals in Hungary have been experimenting with plasma extracted from the blood of recovered patients. The treatment is still included in the official therapeutic protocol and is usually presented as a Hungarian success story in official communications and the media.
• However, international scientific evidence now suggests that the effectiveness of plasma therapy against COVID-19 is at the very least questionable, and perception of it is mixed. After initial high hopes, most guidelines no longer recommend its use, at least not on a large scale.
• It may still prove to be beneficial among more restricted patient groups and in certain circumstances, but as the very pioneer of Covid plasma therapy in Hungary acknowledged to Telex, even domestically, researchers are still trying to figure out how to best apply it.
• Even Hungary's official guidelines state that the treatment might only have a meaningful effect in a narrow group of patients, and yet it doesn't recommend the treatment to the patients who stand to benefit from it according to the latest research.
• Domestic research is still ongoing: the hope is to refine plasma therapy and produce an effective medicine from the plasma of those who have recovered.

The coronavirus pandemic blindsided the world in early 2020, and since no treatment existed for this previously unknown disease, naturally there couldn't have been one that was proven to be effective. Doctors and researchers first began experimenting with existing drugs and treatments. Some worked and are still being used successfully in COVID-19 therapy. Others, however, quickly proved to lead to dead ends. There are some treatments that are still controversial because, despite initial hopes, they have yet to be linked to any results that clearly demonstrate their effectiveness.

Still, this fact on its own is not problematic. It's merely a part of science's healthy functioning that as data accumulates, the picture becomes clearer, and new studies can shed light on a possible cure, even completely overturning earlier practices. A problem is more likely to arise if fine-tuning is not carried out, because this intuitive self-examination is being phased out of the system – or even being sanctioned, as we have seen in Hungary with favipiravir.

One of the controversial treatments is plasma therapy, which is worth exploring in more detail if only for one reason: while its international reputation is significantly less positive than at the beginning of the pandemic, in Hungary, this shift has received less recognition, and the treatment is still being used in COVID-19 therapy, albeit in a much more limited range of cases than initially.

Hungarian plasma for Hungarian blood

Plasma is the yellowish liquid portion of the blood that remains after the blood cells have been removed, and it makes up over half of the total blood volume. Treatment of COVID-19 makes use of so-called reconvalescence plasma, which means that it is extracted from the blood of those who have recovered from the disease. (The term is often shortened to convalescent plasma, but the meaning is the same.)

The idea is that if recovered patients have produced enough antibodies against the virus, these antibodies can be passed on to active patients via their plasma and help them overcome the virus. While vaccination is usually referred to as active immunization because it induces the immune system itself to produce antibodies, plasma therapy is passive immunization because it simply delivers the finished product for immediate use.

The application of convalescent plasma has a history that goes back more than a century. For example, it was used in treating the Spanish flu. In the 1930s and 40s, however, the widespread availability of antibiotics rendered its application against bacterial infections obsolete. And thanks to vaccines, we have been able to prevent the spread of a number of viral diseases. As a result, plasma therapy was practically abandoned and only used on a case-by-case basis, typically during viral outbreaks.

However, the last decade has seen an increase in its experimentation: it was tested against SARS, MERS, and even the H1N1 influenza virus, which was responsible for the last pandemic. This gave reason to hope that it could work in the treatment of COVID-19. There were high expectations in the first year of the pandemic, although even then the results were not so favorable. We'll come back to its efficacy in a moment, but we can say right off the bat that it is considered safe. The risks are the same as for any treatment involving blood transfusions, and research shows that Covid patients who received the plasma do not have more frequent serious side effects.

In Hungary, the use of convalescent plasma had already begun in the spring of 2020. The University of Physical Education, the University of Pécs, Semmelweis University, and OrthoSera Ltd. participated in the development and launch of the therapy, with the latter having been involved in the production of plasma serum even before the pandemic.

Even today, the treatments are administered only in the context of clinical trials. Although a list of the clinical trials that were authorized in Hungary can be downloaded from the website of the National Institute of Pharmacy and Nutrition (OGYÉI), no plasma therapy trial is mentioned for 2020 or 2021. Even Zsombor Lacza, CEO of OrthoSera and vice-rector of science and innovation at the University of Physical Education, did not know the reason for this, but he told Telex that three such trials had been authorized.

The first one had been applied for by OrthoSera at the beginning of the pandemic, and it was the first clinical trial of any therapy against COVID-19 in Hungary. The second was initiated by the National Public Health Center and the South Pest Central Hospital. A third trial was proposed last autumn by the Hungarian National Blood Transfusion Service (OVSZ) on behalf of a consortium of several universities.

The government supported the launch of plasma therapy even financially: the Ministry of Innovation and Technology and the National Research, Development and Innovation Office (NKFIH) allocated roughly 133 million forints (~300,000 euros) for the project. Zsombor Lacza had said earlier that the therapy would cost 200,000 forints (~530 euros) per patient, and the initial funding ran out by November 2020. In March of last year, the consortium led by OVSZ (including Semmelweis University, the University of Physical Education, and Eötvös Loránd University) was awarded a 400 million forint (over 1 million euro) grant by the NKFIH for the project "Investigation and application of natural immunizing factors against coronavirus infection in plasma therapy".

Figures on how many patients have received plasma treatment against COVID-19 in Hungary are issued sporadically. The last time it was reported was in a statement made by OVSZ at the end of last June, which said that the therapy "had been applied in over 60 hospitals a total of more than 4000 times." We asked OVSZ for the exact figures, but they replied that plasma "is issued according to the needs of medical institutions and that OVSZ does not keep records of its use." However, they did disclose that about 5,500 people had applied to donate plasma, of whom 1,500 were found to be suitable donors, and given that a person can donate more than once, a total of 1,800 plasma donations had been made.

The version of Hungary's Covid treatment manual that is still available on the official epidemiological information page doesn't even mention plasma therapy. Of course, given that it hasn't been updated since June 2020, this isn't that surprising. Among its recommended treatments, for example, you can still find chloroquine and hydroxychloroquine, which have long been contraindicated elsewhere in the world. The December 2020 version of the handbook, on the other hand, can be found in a far more obscure place: the website of the College of Health Professions. This version refers to chloroquine and hydroxychloroquine as being contraindicated. It also mentions plasma therapy, but only as an experimental option – it is still not included in the therapeutic protocol.

The most important chapter of the manual, the protocol for the treatment of confirmed infections, is even made available as a separate file. Nor in this version is plasma therapy included – supposedly, it was first included in the March 2021 version. In other words, it seems that although plasma therapy was already being used in practice starting from spring 2020, it did not appear in the official protocol until a year later. The latest edition of the protocol, published last November, contains the following recommendation:

• for mild cases it is not recommended under any circumstances;
• for moderate cases in their early stages, it "can be suggested" in a hospital setting if the patient has other risk factors;
• for severe cases, it "can be suggested" for patients who are immunosuppressed (i.e. have reduced immunity due to an illness or treatment) or have protracted viraemia (viraemia means that the virus is present in the bloodstream);
• for critical cases, it "can be considered" for patients who are likewise immunosuppressed and viraemic.

So in practice, the therapy can only be administered in a hospital setting, and only to some patients suffering from at least a moderately severe case of the disease. We'll be comparing this later with the recommendations from other countries around the world.

An unproven success story

To assess the current state of the science on plasma therapy, it is worth first reviewing the most recent meta-analyses. They summarize and analyze the results of published clinical trials according to a common set of criteria to reconcile the many varied results and thus give a more comprehensive picture. This, in turn, presents the evidence in its entirety, and thereby, possibly even our complete knowledge of the matter. As more and more new results come in, so too are new meta-analyses regularly being published. Let's take a look at those published since last summer.

We start things off with a rather peculiar case: the meta-analysis of the Cochrane collaboration. Although it was last updated in May of last year, the review is worth mentioning because of its authority. It concludes with a high level of certainty that plasma therapy does not reduce mortality in moderate or severe cases and has almost no effect on their recovery. There was no clear conclusion for mild cases because there had not been enough studies of such patients.

We found seven meta-analyses published thereafter that also concluded – based on studies involving cases of varying levels of severity – that there was no significant benefit to be gained from plasma therapy:

• One analysis in September found that there is no substantive benefit for either serious or non-serious cases.
• An October study found that hospitalized patients didn't experience any significant clinical or mortality benefit. The result seemed so definitive that the authors considered it futile to investigate the matter further, or instead of determining its effectiveness in general, further research should be directed in highly select patient groups, such as immunocompromised patients.
• A November meta-analysis found that it did not reduce mortality in moderate-to-severe cases.
• A December analysis found no evidence of a reduction in mortality risk. Nor did it find evidence that plasma therapy for mild patients prevented the need for mechanical ventilation or intensive care.
• Another study in December concluded that while supplementing standard hospital care with plasma therapy can be regarded as safe, it does not provide any significant benefit in terms of clinical improvement or reduction in mortality.
• The authors of a January meta-analysis found no association between plasma therapy and clinical outcomes for hospitalized patients.
• The latest analysis, published in February, found that plasma therapy did not increase the chance of improvement or reduce mortality risk in severe and critically ill patients.

All in all, we could only find one relatively recent meta-analysis suggesting that plasma therapy may be of some benefit. Published in August, it concluded that plasma therapy can reduce the mortality risk in severely and critically ill patients, but available findings were both limited and mixed, so the analysis recommends further research.

Early last year, two large trials – one in the UK focusing on hospital patients and one in the US on outpatients – were terminated because the results indicated that there was no point in continuing.

All this is not to say that plasma therapy in Hungary is necessarily pointless, but for some reason these international doubts are even less present in Hungary's public discourse than in the case of favipiravir. This is in stark contrast to the fact that plasma therapies in Hungary are often reported as being incredibly successful. Plasma therapy is still being administered to this day in Hungary. The most recent donor recruitments were held this past November and December on the official epidemiological information site and OrthoSera's site, respectively. OrthoSera's November call for donors contained the following message: "As is well known, the most reliable therapy in the fight against coronavirus infection is blood plasma therapy."

Sacrificing the desire for knowledge

In Hungary's media, the most common declarations made about the effectiveness of plasma therapy are similar to those mentioned above. With that said, a study on Hungary's experiences with the treatment was made available as a preprint (i.e. prior to peer review) last May. The paper was subsequently published this past November in Infectious Diseases and Therapy, a renowned international journal.

The study involved 267 hospitalized patients with severe cases of the illness. According to the main findings: patients who eventually died from COVID-19 received plasma treatment later than those who survived the disease; regardless of outcome, plasma treatment caused a significant reduction in the overall inflammatory status of patients; for these reasons, the authors concluded that plasma therapy is a safe and effective supplementary treatment for hospitalized patients if administered as early as possible. However, the effect of treatment on mortality is less clear:

"We found that severe patients had significantly reduced inflammation levels after treatment. Their condition was steadily deteriorating. Then they got the plasma, and they were getting better by the next day. But this was not enough to markedly improve mortality in the long term,"

one of the study's authors, the leader of the development of Covid plasma therapy in Hungary, Zsombor Lacza told Telex.

Tamás Ferenci, biostatistician and associate professor at Óbuda University, applauded the fact that research on the topic is also being conducted in Hungary, but he said the study raises several methodological concerns, which call into question the relevance of the results. The main problem is that there was no control group, i.e. participants who did not receive plasma treatment but were similar in all other respects to the plasma-treated group.

"Without a control group, it's impossible to appraise the main result. After all, the fact that the mortality of those who receive plasma later is higher could very well mean that giving it earlier is helpful just as giving it later is harmful. This research design is simply not able to distinguish these two possibilities. But the real problem is that we have no idea how these mortality rates compare to those without plasma therapy, i.e. the effect of the therapy on mortality, whether given early or late. All we know is that the mortality rate was 31.5%, which at first glance seems catastrophic (more than ten times the national average), but we can't forget that these were hospitalized patients, and in more severe conditions at that. So it may well be that the therapy works – it just isn't necessary to measure it against all patients. But that is the problem: we do not know what to benchmark against. It was not a randomized trial, which is justifiable, but there still should have been at least what's known as a historical control, i.e. to select similar patients from a database and match them statistically to the patients in the study. Without this, we do not know whether a 31.5% mortality rate is good or bad, or whether this treatment has any sort of effect," Ferenci told Telex.

He considers the improvement in inflammatory parameters to be more reliable, but in the absence of a control group, he thinks plasma therapy's role in this is unclear. "This is because the condition following administration of the treatment differs not only in that the patient has already received treatment but also in that time has passed – and there's a dynamic to these parameters. The passage of time in itself can have an effect on them. Without a control group, how do we know how much of the change is due to the plasma treatment and how much is due to time passing? Inflammation may have decreased, but we can't know whether it would have decreased less, the same amount, or more on its own. Nevertheless, I think this is a rather conclusive result because we are talking about big improvements over a short period of time," said Ferenci.

As early as 2020, Zsombor Lacza said that he thought that placebo-controlled trials in a pandemic situation are ethically questionable (and he's not alone – Hungary's trials of favipiravir were discontinued for similar reasons). He new made a similar, albeit slightly more permissive statement to Telex: “The world is changing, and we're learning more and more. Even now I still question it, but when a new epidemic breaks out, and we have in our hands a therapy that, based on the historical data and literature, has a realistic chance of working, it is simply not acceptable to flip a coin to determine whether a patient gets it or not – everyone needs to get it. Sacrificing our desire for knowledge to potentially improve patient outcomes is, I think, the right thing to do as doctors. And then later, once we have observed that the therapy is not very risky and identified the patients for whom it will likely be ineffective, then we can revisit this question.”

When asked about the extent to which statistically relevant conclusions can be drawn from the results of their research if there was no control group, he said that researchers have to ask the question in a different way. "There are studies where there are no control groups, and if I ask the question the right way, the results are still valid. There is a wide range of scientific research methods, and only one of them is this randomized, controlled clinical trial. There is an ongoing debate in the literature – completely independent of Covid – as to whether it is justified to rank it above the other methods."

We should add that in other parts of the world, there have been and are still many randomized, controlled-group clinical trials on the efficacy of plasma therapy against COVID-19 – with the approval of ethics committees, of course. The study of Lacza's team itself notes at the end that the "limitations of the current study include its non-controlled design", so "our observations should rather be viewed as an indicator prompting further studies with improved design."

In search of a narrower target group

Even Zsombor Lacza acknowledged that instead of hoping for a wider application, it now seems that plasma therapy against COVID-19 might be used to treat a much narrower range of patients. However, he believes that this was to be expected. The task is to identify this particular restricted group. "The fact that the plasma of those who have recovered is effective against the virus is obvious, as they are full of antibodies. These inhibit the virus from replicating, spreading and attaching to cells. The key question is how can we turn this into a treatment. That is, according to what protocol, to which patients, at what time, and in what quantity should we administer it so that it will have a therapeutic effect. That's what everyone is searching for, including us."

"With any pandemic outbreak like this, the first thought is to give patients fresh plasma from those who have recovered and see what happens. This is how we started, as people did everywhere else in the world. Then, the therapy needs to be refined based on the outcome. We are now at the stage where it definitely needs to be refined. One reason is that it is not worth taking plasma from every recovered patient because they each produce antibodies of varying quantity and quality. Especially at the beginning of the pandemic we were hard-pressed to find any recovered patients with antibodies of sufficient quality and quantity. Secondly, the initial results showed that giving plasma to everyone is definitely not a good idea. It was very often given to people who were in a very late stage of the disease – when they were no longer fighting the virus but rather their immune system's response to the virus. In such cases, you can't expect a miracle from administering antibodies that target the virus."

There are two main directions in the search for the ideal target group: those who can still be treated in time because their condition is not yet serious and those who are at higher risk of developing a serious case of the illness, for example, because of an immunodeficiency disease. The results on the benefits of early treatment are mixed. Several of the above meta-analyses looked at whether the trials they reviewed showed a positive additional effect in people who received plasma earlier but found none. However, there have been more recent studies – apart from the Hungarian study above – that have come to a different conclusion.

The one that got the most attention was a US study released late last year as a preprint. Science magazine wrote a piece on the study with the title, "Convalescent plasma shows renewed promise for COVID-19 in outpatient trial". The research found that treatment halved the risk of hospitalization among outpatients in an early stage of the disease – something that is in line with the picture sketched by Zsombor Lacza. According to the researchers, as the effectiveness of monoclonal antibodies at this stage of the disease is undermined by newer variants, and such treatment is more expensive than plasma therapy, the latter may serve as an alternative in outpatient care in poorer countries.

There are two other studies that have looked specifically at the effectiveness of plasma therapy in outpatients – with mixed results. A US study last February investigated the treatment's effectiveness in 160 elderly patients with mild conditions and also found that plasma therapy halved the risk of developing a serious case of the disease. But yet another US study last November of 511 high-risk outpatients found no significant effect.

The other direction – which is also included in the Hungarian recommendation – is the treatment of immunocompromised patients. There have been encouraging results on this before: a US study published last May, which was not a clinical trial but a review of previous case reports. It found that these reports might suggest a benefit of plasma therapy in immunocompromised and immunosuppressed patients. But research on this is still ongoing.

For example, an international review article published this past January found that while the benefit of plasma therapy cannot be established for severe cases in general, some results suggest that it may help immunocompromised patients, although the evidence is still weak. And a French study published in February found that plasma therapy improved overall survival in Covid patients with B-cell lymphoma compared with patients who did not receive plasma.

These approaches can of course be combined: it is possible to give plasma to people in the early stages of infection whose condition is not yet serious, but there is a high risk of it becoming so. A US study in January, for example, even proposed the development of a numerical treatment benefit index to help decide whether plasma therapy might make sense for a particular patient. Of course, the more restricted and specific the group, the smaller the overall therapeutic benefit of the treatment.

"The debate now is whether we have found a protocol, or whether a protocol even exists that could put this therapeutic option to good use. We have identified a few things not to do, and we have a rough idea of which direction to go, but we don't have a really good protocol yet,"

said Zsombor Lacza.

"The doctors working at patients' bedside who deal with this already perceive and intuit it – they have experience of who to give it to and when in order to obtain a significant response. This benefit dissipates in large numbers when everyone receives the treatment, but there is already empirical evidence to show who it is worth giving to. I think the pieces are starting to fall into place for this treatment," he added.

Recent scientific findings, as we have seen above, have cast considerable doubt on the efficacy and benefits of plasma therapy against COVID-19, and it is clear that research is now also being directed towards smaller patient groups. It is worth revisiting what Hungary's current therapeutic protocol says about this treatment and comparing it with how plasma therapy is perceived in other countries – where it is recommended and in what manner.

A reminder: Hungary's protocol recommends plasma therapy only for hospitalized patients, in particular, those with risk factors of moderate severity and immunosuppressed patients with severe cases (for immunosuppressed patients in a critical condition, the treatment can be considered but it is not explicitly recommended). It is worth taking a closer look at the United States, where much of the major research on the subject has been carried out and where several reputable professional organizations have issued guidelines on the use of plasma therapy.

The US National Institutes of Health (NIH) issued a recommendation, which was most recently updated in mid-December, according to which plasma therapy is contraindicated in hospitalized, immunocompetent patients. Further, it states that there is insufficient evidence for or against the treatment's recommendation in other patients (e.g. immunocompetent outpatients or immunocompromised patients in general).

The changes in the US Food and Drug Administration's (FDA) position illustrate how the perception of plasma therapy has evolved and also what it is like when an authority tries to keep up with new findings. In August 2020, the FDA issued an Emergency Use Authorization for convalescent plasma for the treatment of hospitalized patients with COVID-19. (The decision, announced personally by then President Donald Trump, was criticized by multiple scientists who said there was not enough evidence to support it at the time.)

However, the authorization has been revised several times since then. The updates first saw the removal of immunocompetent patients from the list of those recommended for plasma therapy and then the addition of immunocompromised outpatients alongside immunocompromised inpatients. Under the current version, issued at the end of December, only plasma with high antibody levels can be used under the authorization, and only in patients (hospitalized or otherwise) with reduced immunity due to disease or treatment. But they note that even in such patients, there is little evidence of benefit from plasma treatment against COVID-19, so further studies are needed.

The Infectious Diseases Society of America (IDSA) last updated its recommendation in early February. It excludes hospitalized patients from plasma therapy altogether and only recommends it for outpatients with mild to moderate cases that are at high risk of becoming more severe, and even then, only if no other treatment is available for them.

So to summarize, among professional organizations in the US:

• The NIH does not recommend but leaves open the possibility of administering the treatment in the case included in Hungary's recommendation (immunosuppressed inpatients), but it also includes one that Hungary rules out (outpatients);
• The FDA permits treatment for those who are also included in Hungary's recommendation (immunosuppressed inpatients) as well as for some that Hungary leaves out (immunosuppressed outpatients);
• IDSA only recommends the treatment for those who are excluded by the Hungarian recommendation (outpatients).

It is clear that the regularly updated US recommendations are moving in the same direction as the research, and in doing so, they are diverging further and further from the Hungarian recommendation, which also suggests the treatment for the immunosuppressed but continues to focus only on inpatients, while excluding outpatients from the treatment.

The World Health Organization (WHO) also maintains a "live", i.e. regularly updated, guideline on drugs that can be used against COVID-19. The part pertaining to plasma therapy was last updated in early December and takes a slightly different approach as compared to the US recommendations: similarly, it does not recommend plasma therapy to anyone, and it considers the therapy strongly contraindicated for patients with non-severe cases.

Further, it finds the evidence to be weaker for severe and critical patients and therefore warrants further clinical trials. They add, however, that the available literature found no substantive difference in any of the important areas (mortality, mechanical ventilation, acute lung injury, time to symptom improvement, length of hospital stay, number of ventilator-free days) between the severely ill patients receiving plasma therapy and those receiving standard care.

Let us also briefly mention Britain's recommendation, which does not even bring up plasma therapy; Australia's, which gave the treatment a red "not recommended" stamp; and Germany's, which only permits it in the context of clinical trials.

If not now, then next time

It is worth separating the changes in the scientific assessment of plasma therapy for COVID-19 from the efficiency with which it was launched in this country at the beginning of the epidemic, when hopes were high everywhere. Indeed, Hungary was at the forefront in developing the infrastructure for plasma therapy at a time when it was still seen as having potential for wider use in the fight against the pandemic worldwide.

As Zsombor Lacza has repeatedly told the media, this was partly made possible by the fact that authorities acted swiftly at the beginning of the pandemic. A few weeks following the start of the initiative, they enabled the work to get started, and backed it financially too. And all this will not have been for naught even if plasma therapy ends up being downgraded to a stratified treatment in light of the more recent findings. The question is where to go from here.

"One of the research directions is not to inject the entire plasma, but to extract from it the active substances that are needed – and these aren't just antibodies. It's a relatively trivial process: I recover from the disease, I produce antibodies against the virus, I pass those on to another patient who has just caught the virus, and those antibodies have some sort of effect. Sure, but plasma also contains a multitude of other substances: anti- and pro-inflammatory substances and cytokines – and these have an effect on the body. They too can improve or worsen the patient's condition. Many studies are no longer looking at the plasma itself, but at the effects of the substances extracted from it."

"Our research teams, in collaboration with the National Blood Transfusion Service, Semmelweis University and ELTE, are working with this sort of selective method to find a type of plasma that is even more effective. We are not only looking at what effect the antibodies have, but also at what molecules have a further effect and how they can be used to inhibit inflammation. It's not a quick process. When you switch from using fresh, frozen plasma to pharmaceutical manufacturing, it's a different ball game," said Zsombor Lacza, referring to the project with the 400 million forint research grant mentioned earlier on in the article.

"The major advantage of fresh plasma therapy is that it's readily available. We went from the idea to treating the first patient in four weeks, and that includes all the permits. For medicines, this is unrealistic. It requires much more data and testing, it costs more, and there's more to be done. For example, we are currently building a production facility where this type of plasma drug can be produced in the appropriate quantity because there is no such facility in the country. In order to move forward at all, we need to develop these as well, to create infrastructure," he added.

"We have a lot of work ahead of us, but I think there is a pretty good chance that we will find a solution that will work – if not during this pandemic, then perhaps maybe in response to the next challenge that we'll face."