Convalescent plasma therapy for COVID-19

Simon Collins, HIV i-Base

Several papers have reviewed the potential benefits of using convalescent plasma therapy with immunoglobulins to treat COVID-19.

Although data is currently very limited, many more studies are already underway including in the UK RECOVERY study.

The first report of convalescent plasma to successfully treat five people critically ill with COVID-19 was published in JAMA. [1]

All participants (aged 36 to 73 years, 2/5 were women) had severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment, methylprednisolone and mechanical ventilation. None were smokers and none had pre-existing comorbidities. Convalescent plasma was given between 10 and 22 days after admission with a SARS-CoV-2–specific antibody (IgG) binding titre greater than 1:1000 and a neutralisation titre >40 that had been obtained from five patients (aged 18 to 60) who recovered from COVID-19 approximately 11 days after discharge.

In 4/5 patients, body temperature normalised within three days, the SOFA score decreased, and P/F oxygen ratio increased within 12 days (range, 172-276 before and 284-366 after). Viral load also became negative within 12 days of the transfusion. SARS-CoV-2–specific ELISA and neutralising antibody titres increased following the transfusion (range, 40-60 before and 80-320 on day 7). Acute respiratory distress syndrome (ARDS) resolved in 4/5 patients at 12 days, and 3/5 were weaned from mechanical ventilation within 2 weeks of treatment.

At last follow-up, 3/5 have been discharged from hospital (after 53, 51, and 55 days), and two are in stable condition at 37 days after transfusion.

Kai Duan and colleagues also published outcomes from six men and four women with severe COVID-19 treated with a single infusion (200 mL) of convalescent plasma. [3] The primary endpoint was safety with secondary endpoints of clinical improvement and laboratory parameters within 3 days after transfusion. [2]

Median age was 52 years old (IQR: 45 to 59) and median time from symptoms to hospitalisation and transfusion was 6 days (IQR: 2.5 to 8.5) and 16.5 days (IQR:11.0 to 19.3), respectively.

After transfusion, neutralising antibody levels increased rapidly up to 1:640 in five cases, and was maintained at a high level (1:640) in four others. The clinical symptoms significantly improved within three days. Other improvements included increased lymphocyte counts (0.65 × 10⁹/L vs. 0.76 × 10⁹/L) and reduced C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Viral load in seven participants become undetectable.

However, nine patients received the antiviral treatment, mainly umifenovir in combination with remdesivir, ribavirin, or peramivir. Antibacterial or antifungal treatment was used when patients had coinfection. Six patients received IV methylprednisolone.

Another paper from Korea included two cases (a 71 year old man and a 67 year old woman) who used convalescent plasma (from donors in their 20s), who were admitted for tertiary care, were unresponsive to lopinavir/r, hydroxychloroquine and antibiotics and who had progressed to intubation. [3]

Both had improvements in fever and need for oxygen decreased following convalescent plasma and were successfully weaned off intubation. Both showed an increasing trend in viral load that began to decrease right after the use of convalescent plasma, but because neither were in early phase infection (22 and 7 days after onset of symptoms) this cannot be ruled out as part of natural pathology.

Unfortunately, less successful outcomes were reported by Qing-Lee Zeng and colleagues for six patients with COVID-19 and respiratory failure who received convalescent plasma for a median of 21.5 days after viral shedding was first detected. Although all tested negative for SARS-CoV-2 RNA within three days after infusion, 5/6 people eventually died. [4]

This led the researchers to conclude that convalescent plasma treatment can stop SARS-CoV-2 shedding but cannot reduce the mortality rate in critically ill patients with end-stage COVID-19, and treatment should be initiated earlier.

Many other papers have discussed use of convalescent plasma for COVID-19 including a recent paper in Lancet Infectious Diseases by Chen and colleagues, who reviewed historical use to treat SARS-1, MERS, H1N1 and related viral infections and on possible use to treat SARS-CoV-2. [5] Earlier reviews have also reported potential benefits with few risks but are based on small low-quality studies without control groups. [6]

A useful review of 10 ongoing studies in Nature, mostly controlled, including with placebos, and ranging from 60 to over 420 participants and due to end from May to December 2020, will produce stronger evidence. [7]

However, this doesn’t include the UK RECOVERY study initially randomised more than 9000 participants (2:1 control:active arm) to standard of care defined at no treatment or to one of several active arms including lopinavir/r (Kaletra), low-dose dexamethasone, hydroxychloroquine (related to an anti-malarial drug), azithromycin, tocilizumab or convalescent plasma. It is unclear whether all these arms are still ongoing. [8]

Finally, the UK has also already launched a campaign to collect convalescent plasma. [9]

In the US, a large-scale open-label study had registered more than 2000 sites by 30 April 2020, enrolled 7,774 patients and provided transfusion to 3,809 of them. [10]

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These papers show the potential for both successful and unsuccessful outcomes from use of convalescent plasma and without controls is it difficult to evaluate the impact of treatment.

Despite critical illness the initial case study included younger patients who did not have comorbidities that predict worse outcomes and they also received other antiviral treatment.

In other papers, convalescent plasma is used with other potential treatments, and combination therapy is increasingly thought to be more effective than monotherapy with any single treatment.

Most also comment, either in the original paper or in correspondence that optimal timing for plasma infusion still needs to be determined but earlier use might be important.

It is similarly important for ongoing studies now responding to use multiple treatments, even if the UK is currently hopefully coming to the end of the initial first wave of COVID-19.

STOP PRESS: Results from a Chinese that randomised 103 participants with severe or life-saving COVID-19 to either open-label convalescent plasma or standard of care reported no difference in clinical recovery or PCR changes by day 28. Evolving standard of care during the study included antiviral medications, antibacterial medications, steroids, human immunoglobulin, Chinese herbal medicines, and other medications. However, this study was original planned to include 200 participants but was closed early due to lack of new cases after COVID-19 was contained in China. [11]

This report was first published on 23 May 2020 and was updated on 3 June 2020 to include the STOP PRESS report on the JAMA paper.

References

Shen C et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020 323(16): 1582–1589. doi: 10.1001/jama.2020.4783. (27 Mar 2020).
https://jamanetwork.com/journals/jama/fullarticle/2763983
Duan et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS, PNAS 117 (17) 9490-9496; DOI: 10.1073/pnas.2004168117. (6 April 2020).
https://www.pnas.org/content/117/17/9490
Ahn JY et al. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020;35:e.149. doi: 10.3346/jkms.2020.35.e149.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152526
Zeng Q-L. Effect of convalescent plasma therapy on viral shedding and survival in COVID-19 patients. Journal of Infectious Diseases, jiaa228, DOI: 10.1093/infdis/jiaa228. (29 April 2020)
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa228/5826985
Chen L et al. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis 2020; 20:398–400. doi: 10.1016/S1473-3099(20)30141-9. (20 April 2020).
https://www.thelancet.com/article/S1473-3099(20)30141-9/fulltext
Mair-Jenkins J et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015 Jan 1; 211(1): 80–90. doi: 10.1093/infdis/jiu396.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264590
Sheridan C. Convalescent serum lines up as first-choice treatment for coronavirus. Nature Biotechnology. doi: 10.1038/d41587-020-00011-1. (7 May 2020).
https://www.nature.com/articles/d41587-020-00011-1
The UK RECOVERY study.
https://www.recoverytrial.net
https://www.recoverytrial.net/files/recovery-protocol-v6-0-2020-05-14.pdf (protocol PDF)
NHS. Convalescent plasma programme.
https://www.nhsbt.nhs.uk/covid-19-research/plasma-programme
Expanded access to convalescent plasma for the treatment of patients with COVID-19. (15 May 2020).
https://www.uscovidplasma.org/pdf/COVID-19 Plasma EAP.pdf (protocol PDF)
https://clinicaltrials.gov/ct2/show/NCT04338360 (trial listing).
Li L 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. DOI:10.1001/jama.2020.10044. (3 June 2020).
https://jamanetwork.com/journals/jama/fullarticle/2766943