Highlights

The World Health Organization (WHO) no longer recommends the use of convalescent plasma in the treatment of COVID-19 infection caused by the new coronavirus SARS-CoV-2.

Experts from the world’s leading medical agency agree that prescribing convalescent plasma for non-serious COVID-19 does not improve clinical outcomes in patients, and therefore strongly discourage its use because of both its very low effectiveness and substantial infrastructural cost.

In the case of severe or critical COVID-19, convalescent plasma has similarly had no significant effect on improving clinical outcomes. However, since the evidence collected is not unequivocally reliable, the WHO is not against conducting additional clinical trials. Well, in the meantime, the use of convalescent plasma in clinical practice is unlikely to be justified.

On August 23, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the use of convalescent plasma for the treatment of hospitalized patients with COVID-19. On February 4, 2021, the FDA updated the EUA to allow only plasma with high antibody titers and to treat COVID-19 in the early stages of the disease course and to those hospitalized patients who have impaired humoral immunity and cannot produce an adequate antibody response.

It is currently unknown how the WHO recommendations will affect the status of the use of convalescent plasma in the treatment of American patients.

 

What Is Convalescent Plasma

Convalescent plasma, also called immune plasma or hyperimmune plasma, is blood plasma obtained from individuals who have recovered from infection and whose immune system has generated a humoral response against the infectious pathogen. The main active component of the plasma of the recovered patients are neutralizing antibodies and other immune mediators that can confer short-term passive immunity to the recipients.

The plasma antibodies infused into the patient bind to the virus, inhibiting cellular entry and enhancing the clearance of viral particles through antibody-dependent cellular phagocytosis (ADCP) or antibody-dependent cell-mediated cytotoxicity (ADCC). In those who have not been previously infected or vaccinated, it takes two to three weeks to initiate an antibody response. Ready neutralizing antibodies greatly accelerate this process: they can prevent the disease, shorten its duration or reduce its severity, thereby preventing the development of serious or life-threatening complications.

Convalescent plasma is thought to be more effective in the earliest stages of the disease. Once the infection has progressed to the point where organ damage has occurred and there are other consequences of massive inflammation, it cannot be said with certainty that plasma is useful because it works against the infectious pathogen rather than the complications it causes.

Evidence suggests that convalescent plasma collected from survivors of COVID-19 infection contains specific receptor-binding domain (RBD) antibodies with potent antiviral activity. Meanwhile, issues related to effective titers of neutralizing antibodies against the new coronavirus SARS-CoV-2, the optimal time period for the donation of convalescent plasma, and the severity class of COVID-19 patients who could benefit most from its use remain unexplored to the end.

In the pre-vaccine era, convalescent plasma was used in the prevention and treatment of both bacterial and viral diseases, such as respiratory infections (Streptococcus pneumoniae, Neisseria meningitis, Haemophilus influenzae), diphtheria, tetanus, clostridial infections (Clostridium botulinum, C. difficile), viral infections (hepatitis A, hepatitis B, cytomegalovirus, rabies, measles, tick-borne encephalitis, etc.).

 

Convalescent Plasma: Discouraging Conclusions

WHO’s conclusions come from a meta-analysis covering data from 16 randomized clinical trials (RCTs) involving more than 16 000 patients with non-serious, severe, or critical COVID-19 infection.

 

Patients With Non-Severe COVID-19

According to a meta-analysis of pooled data from 4 RCTs (n=1602), administration of convalescent plasma had no significant effect on mortality compared with standard COVID-19 treatment: odds ratio (OR) 0.83 (95% CI: 0.43–1.46), the absolute difference was 1 fewer death per 1000 patients.

Convalescent plasma did not reduce the likelihood of needing mechanical ventilation: OR 0.71 (95% CI: 0.18–1.77), the absolute difference was 2 fewer patients needing mechanical ventilation per 1000 patients.

The evidence certainty was rated as moderate because of concerns about the serious risk of bias in the included studies.

 

Patients With Severe COVID-19

Data from a meta-analysis pooling the results of 10 RCTs (n=14 366) showed that convalescent plasma had little or no effect on mortality compared with standard COVID-19 treatment: OR 0.92 (95% CI: 0.70–1.12), the absolute difference was 9 fewer deaths per 1000 patients.

The evidence certainty was rated as low because of indirectness, risk of bias, and imprecision.

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Convalescent plasma also had no effect on the following outcomes:

  • Reduced likelihood of mechanical ventilation: OR 0.92 (95% CI: 0.70–1.12) [5 RCTs, n=623]
  • Shortened time to symptom resolution: 0 fewer days (3 RCTs, n=472)
  • Shortened duration of hospital stay: 0.7 fewer days (7 RCTs, n=1015)
  • Decreased number of ventilator-free days: 0.7 fewer days (3 RCTs, n=2859).

All evidence with low certainty.

 

Patients With Any COVID-19 Severity

According to a meta-analysis, the addition of plasma from donors who recovered from a COVID-19 infection to standard therapy was not associated with an increase in the following risks, as follows:

  • Transfusion-associated acute lung injury (TRALI): risk difference (RD) of 0 fewer per 1000 patients (4 RCTs, n=1365)
  • Transfusion-associated circulatory overload (TACO): RD of 5 more per 1000 patients (4 RCTs, n=1442)
  • Allergic reactions: OR 3.25 (95% 1.27–9.30) [8 RCTs, n=15 243].

All evidence with moderate certainty.

Researchers predefined three patient subgroups of interest for the meta-analysis: age (less than 70 years —versus over 70 years), severity of COVID-19 at the time of treatment initiation (non-serious vs. severe and critical), and therapeutic dose (higher donor antibody titer vs. lower titer). In most subgroups, insufficient data were collected for subgroup analysis. In those subgroups where data did exist, significant subgroup effects were not found for criteria such as disease severity (p=0.80) or age (p=0.84) for fatal outcomes, disease severity (p=0.17) for mechanical ventilation.

 

Conclusions

WHO experts strongly do not recommend the use of convalescent plasma for the treatment of patients with non-severe COVID-19 infection.

Convalescent plasma has not demonstrated a positive effect on any important clinical outcome in non-severe COVID-19. Given that convalescent plasma requires substantial resources (including time and cost) associated with identifying potential donors and testing them to establish an adequate antibody titer against SARS-CoV-2, collecting donor plasma, storing, transporting, and transfusing to patients, there is currently no justification for its use. Given the huge number of patients with non-severe COVID-19 and the low frequency of clinically important events among these patients, the use of convalescent plasma on a large scale would be questionable.

WHO experts do not recommend the use of convalescent plasma for the treatment of patients with severe or critical COVID-19 infection — except for its study in clinical trials.

Convalescent plasma has had no beneficial effects on important clinical outcomes in severe or critical COVID-19. Although it is significantly more convenient to administer convalescent plasma in an inpatient setting than in an outpatient one, its use still requires significant resources and time. Since the evidence is of low certainty, WHO believes that additional clinical trials of convalescent plasma would be appropriate to remove uncertainty about its efficacy.

 

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Why Convalescent Plasma Doesn’t Work

Convalescent plasma might work, were it not for a number of circumstances that make it decisively difficult to accurately establish the limits of its effectiveness.

First, the procedure for obtaining plasma is very labor-intensive, as it requires blood to be donated by recovered donors, processed, appropriate pools of plasma to be formed, distributed by dose, and finally administered to patients. None of the above steps are inherently burdensome, but cumulatively aggravating.

Second, given how much convalescent plasma is required to be administered to patients, a large number of suitable donors are needed.

Third, and perhaps most importantly, the levels of neutralizing antibodies in the plasma taken from donors varies enormously. And therefore its pools are formed when, for example, plasma with a high concentration of antibodies is diluted with plasma with a low concentration. And it is not a fact that every donor is screened for the appropriate level of antibodies. As a result, it is quite possible that there are not enough antibodies in any dose of convalescent plasma.

Fourthly, there are quite a few complaints about the clinical trials themselves, which evaluated the effectiveness of convalescent plasma.


Be that as it may, given the many practical and methodological issues outlined above, the following picture emerges. Instead of studying convalescent plasma, industry efforts should be directed toward developing both new monoclonal antibodies specifically designed against SARS-CoV-2 and new small-molecule drugs effective in treating COVID-19, inexpensive to produce, and convenient to administer.

 

Extras

A living WHO guideline on drugs for COVID-19. BMJ 2020;370:m3379. [source] [PDF]

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