Convalescent plasma

Human convalescent plasma (CP) could be a rapidly available option for prevention and treatment of COVID-19 disease when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Passive immune therapy appears to be relatively safe. However, an unintended consequence of receiving CP may be that recipients won’t develop their own immunity, putting them at risk for re-infection. Other issues that have to be addressed in clinical practice (Kupferschmidt 2020) are plasma supply (regulatory conderations; logistical work flow may become a challenge) and rare but relevant risks (transfusion-related acute lung injury, in which transferred antibodies damage pulmonary blood vessels, or transfusion-associated circulatory overload). Fortunately, antibodies that are found in CP are very stable. Pathogen inactivation (using psoralen and UV light) did not impair the stability and neutralizing capacity of SARS-CoV-2-specific antibodies that was also preserved at 100% when the plasma was shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma for up to 9 days (Tonn 2020).

The major caveat of CP is consistency (concentration differs). In plasma from 149 patients collected on average 39 days after the onset of symptoms, neutralizing titers were extremely variable. Most plasmas did not contain high levels of neutralizing activity (Robbiani 2020). Pre-screening of CP may be necessary for selecting donors with high levels of neutralizing activity for infusion into patients with COVID-19 (Bradfute 2020). There seems to be a correlation between serum neutralizing capacity and disease severity, suggesting that the collection of CP should be restricted to those with moderate to severe symptoms (Chen 2020). Others have suggested more detailed selection criteria: 28 days after the onset of symptoms with a disease presentation of fever lasting longer than 3 days or a body temperature exceeding 38,5°C. Selection based on these criteria can ensure a high likelihood of achieving sufficiently high titers (Li 2020).

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AcalabrutinibAnticomplement therapiesAzithromycinCamostatChloroquineColchicineConvalescent plasmaCorticosteroidsCytokine blockersFamotidineFavipiravirG-CSFHuman recombinant soluble ACE2HydroxychloroquineIbrutinibIloprostInterferonsJAK inhibitorsLeflunomideLopinavirMonoclonal antibodiesN-acetylcysteineOseltamivir(other) Protease inhibitors(other) RdRp inhibitorsREGN-COV2Umifenovir

Outlook | References

On March 26, the FDA approved the use of plasma from recovered patients to treat people who are critically ill with COVID-19 (Tanne 2020). This was a remarkable decision, and the data is still scarce. Results are at least modest:

  • Two small pilot studies with 5 and 10 criticially ill patients, showing rapid improvement in their clinical status (Shen 2020, Duan 2020).
  • The first RCT was published in June (Li 2020). Unfortunately, the study was terminated prematurely (when the epidemic was under control in China, no more patients could be recruited) and, consequently, underpowered. Of 103 patients who were randomized, clinical improvement (on a 6-point disease severity scale) occurred within 28 days in 52% vs 43%. There was no significant difference in 28-day mortality (16% vs 24%) or time from randomization to discharge. Of note, CP treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87% of the CP group versus 38% (OR, 11.39). Main take-homes: CP is not a silver bullet and antiviral efficacy does not necessarily lead to better survival.
  • The second RCT came from India (Agarwal 2020). This open-label RCT investigated the effectiveness of CP in adults with moderate COVID-19, assigning 235 patients to two doses of 200 mL CP and 229 patients to a control arm. Progression to severe disease or all cause mortality at 28 days occurred in 44 (19%) and 41 (18%). Moreover, CP treatment did not show anti-inflammatory properties and there were no difference between patients with and without neutralizing antibodies at baseline. Main limitation: the antibody titres in CP before transfusion were not measured because validated, reliable commercial tests were not available when the trial started.
  • In a retrospective, propensity score–matched case–control study in 39 patients, those who received CP required somewhat less oxygen; preliminary data might suggest a mortality benefit (Liu 2020).
  • Compared to 20 matched controls with severe or life-threatening COVID-19 infection, laboratory and respiratory parameters were improved in 20 patients following CP infusion. The 7- and 14-day case fatality rate in CP patients compared favorably (Hegerova 2020). However, this small study was not randomized.
  • Don’t be too late: Of 6 patients with respiratory failure receiving convalescent plasma at a median of 21 days after first detection of viral shedding, all tested RNA negative by 3 days after infusion. However, 5 eventually died (Zeng 2020).
  • Uncontrolled, retrospective data on 1430 patients with severe COVID-19 who received standard treatment only, among them 138 patients who also received ABO-compatible CP (Xia 2020). Despite the higher severity level, only 3 CP patients (2.2%) died, compared to 4.1% patients without CP. However, confounding factors (i.e., biased patient assignments) in this retrospective study could not be ruled out. In addition, complete data on neutralizing antibody titers were unavailable.

COVID Reference chapters:

Epidemiology | Transmission | Prevention | Virology | Immunology | Diagnosis | Clinical Manifestations | Treatment | Severe COVID-19 | Comorbidities / Special Populations | Pediatrics| Timeline | Preface

By Christian Hoffmann