By Vibhu Sharma, MD, MS

Assistant Professor of Medicine, University of Colorado, Denver

Dr. Sharma reports no financial relationships relevant to this field of study.

SYNOPSIS: This was a randomized, open-label, multicenter trial of intravenous convalescent plasma infusion (4 mL/kg to 13 mL/kg) therapy. Convalescent plasma therapy was not associated with improvements in mortality or time to clinical improvement.

SOURCE: Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA 2020;324:460-470.

This was an open-label, multicenter, randomized trial conducted in Wuhan, China, that started recruiting patients in February 2020. Patients with laboratory-confirmed COVID-19 infection with severe (defined as respiratory distress or hypoxemia) or life-threatening (mechanical ventilation, shock, or organ failure) disease were recruited. Patients with contraindications to plasma infusion, severe septic shock, PaO2/FiO2 < 100, severe congestive heart failure, immunoglobulin A (IgA) deficiency, and those who were pregnant/lactating were excluded. Additionally, patients with a positive antibody test to COVID-19 also were excluded. The trial enrolled 103 patients and had to be terminated prematurely in April 2020 at 50% of target recruitment because of a lack of patients with COVID-19.

Convalescent plasma (CVP) was collected from donors with prior COVID-19 infection with two negative nasopharyngeal polymerase chain reaction (PCR) tests. COVID-19 S-protein-receptor binding domain-specific immunoglobulin G (IgG) antibody levels were measured in the specimens, and only those units with a titer of at least 1:640 were used in the study. The volume of plasma transfused was 4 mL/kg to 13 mL/kg of actual patient body weight. Plasma was infused with usual precautions for transfusion-related reactions. The majority of those enrolled (101/103, 98%) were included in the per-protocol analysis.

The primary outcome was clinical improvement within a 28-day period after randomization. Multiple secondary outcomes were assessed, including 28-day mortality, duration of hospitalization, and proportion of nasopharyngeal swab conversion to negative. A post-hoc analysis was added to assess rates of improvement at one and two weeks as well. A six-point disease severity scale was used to assess clinical improvement (described as a two-point or greater reduction in the disease severity scale). The scale awarded points according to disease severity: death (6 points), extracorporeal membrane oxygenation (ECMO) or invasive mechanical ventilation (5 points), noninvasive ventilation or high-flow oxygen (4 points), nasal cannula oxygen (3 points), hospitalization (2 points), and discharge from the hospital (1 point). This scale was adapted from and has been used previously in patients studied in an influenza-related plasma infusion trial.1

For all patients, no differences were found in the primary outcome. More importantly, for those with severe disease, the primary outcome (two-point improvement in severity score) occurred in 20.7% who received CVP, and 24% in those who did not (P = 0.83). Secondary clinical outcomes were no different between groups except that those individuals receiving CVP had a higher rate of nasopharyngeal PCR conversion to negative at 24-72 hours. Two transfusion-related adverse effects were observed with the use of CVP: One patient developed a rash and another developed severe dyspnea six hours after transfusion of plasma.

COMMENTARY

This study concludes that CVP therapy does not affect relevant outcomes among hospitalized patients with COVID-19 infection. The rates of death were equivalent among groups. Although a higher proportion of patients receiving CVP therapy converted nasopharyngeal swabs to negative, the clinical relevance of this finding is not clear.

Several limitations deserve to be highlighted. First, the study was underpowered for the primary outcome because of a small number of patients enrolled. Second, the median time between onset of symptoms and randomization was 30 days. Studies published after this trial was published suggest a benefit for infusion of monoclonal antibodies early (as early as outpatient status) in the course of illness.2 Another assessed transfusion of CVP with high titer of anti-spike protein receptor binding domain antibodies (≥ 1:1350) and found a significant reduction in 28-day mortality when transfused within 72 hours of admission.3 Third, standard therapy for severe COVID-19 infection was used in all patients but was not protocolized. Most importantly, the group that was randomized to receive CVP had a higher proportion of patients receiving steroids (46% vs. 33%, respectively), and dexamethasone has been shown to reduce mortality in COVID-19 patients.4 Finally, although the inclusion criterion was “severe or life-threatening COVID-19 infection,” 32/103 (31%) of patients randomized had a disease severity score of 2 or 3 and were either not on oxygen or were on supplemental oxygen alone (not high-flow or noninvasive ventilation). The definition of severe disease was a respiratory rate of ≥ 30/minute at rest, an O2 saturation of 93% or less on room air, or a PaO2/FiO2 < 300; debatably, these are a broad set of descriptors. CVP therapy is safe for the most part, with one patient developing a severe transfusion reaction in this study. A larger study of 20,000 patients had similar findings, with a rate of transfusion reactions of < 1%.5 In the study reviewed here, patients with PaO2/FiO< 100 were excluded, so there remains the concern that a severe transfusion reaction in this group may be fatal.

In conclusion, based on the results of this study, CVP therapy is unlikely to be of benefit late in the course of the disease, and CVP with higher titer antibodies may be more effective. Enrolling patients early in a high-titer antibody plasma infusion trial remains the most plausible recommendation currently. Further data should be forthcoming given ongoing trials (NCT04372979, NCT04513158, NCT04412846).

REFERENCES

  1. Beigel JH, Tebas P, Elie-Turenne MC, et al. Immune plasma for the treatment of severe influenza: An open-label, multicentre, phase 2 randomised study. Lancet Respir Med 2017;5:500-511.
  2. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med 2020; Oct 28. doi: 10.1056/NEJMoa2029849. [Online ahead of print].
  3. Salazar E, Perez KK, Ashraf M, et al. Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma. Am J Pathol 2020;190:1680-1690.
  4. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19 - Preliminary report. N Engl J Med 2020; Jul 17. doi: 10.1056/NEJMoa2021436. [Online ahead of print].
  5. Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc 2020;95:1888-1897.