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Does convalescent plasma improve 7-day or 30-day mortality in hospitalized patients with Corona Virus Disease 2019 (COVID-19)?

Comment by InpharmD Researcher

The use of convalescent plasma in hospitalized COVID-19 patients may reduce mortality. However, it is not recommended unless in a clinical-trial setting and/or other treatment options have been exhausted.
Background

The National Institute of Health COVID-19 Treatment Guidelines states that there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19. Convalescent plasma should not be considered the standard of care for the treatment of patients
with COVID-19. Prospective, well-controlled, adequately powered randomized trials are needed to determine whether convalescent plasma is effective and safe for the treatment of COVID-19. [1]

The Food and Drug Administration issued an Emergency Use Authorization (EUA) for COVID-19
convalescent plasma for the treatment of hospitalized patients with COVID-19. [2]

The Infectious Diseases Society of America (IDSA) COVID-19 Guidelines state that among patients who have been admitted to the hospital with COVID-19, convalescent plasma should be used only in the context of a clinical trial. [3]

A review article stated that human plasma from recovered COVID-19 patients is projected to be a safe and potentially effective therapy for treatment and post-exposure prophylaxis. Substantial evidence of benefit with prior use for viral infections offers strong precedent for such an approach. However, well-controlled clinical trials need to be performed to confirm efficacy. [4]

A review article assessed that the number of COVID-19 patients with known outcomes of convalescent plasma administration is limited, stemming from 6 case series. The follow-up of cases reaching hospitalizations of 51 days and 60 days after onset of symptoms highlights the need for adequate observation, but also underlines the time needed from the early, sizable Chinese cohorts to provide robust results in relevant scientific publications. The formulation, namely convalescent plasma or hyperimmune globulin, as well as the optimal time frame, remain to be identified in the future. [5]

A review article states that convalescent plasma from donors who have recovered from COVID-19 may be most promising when used as prophylaxis or when administered shortly after symptom onset (within 14 days). Given the lack of information around the natural history of this COVID-19 virus, pathogen reduction technology (PRT) should be considered to add a layer of safety to protect recipients of convalescent plasma.[6]

A review of articles published in PubMed was performed in July 2020 to summarize the currently available evidence in human studies for convalescent plasma as a treatment for coronaviruses. The review included sixteen COVID-19, four Middle East respiratory syndrome (MERS), and five Severe acute respiratory syndrome (SARS) reports describing convalescent plasma use in humans. There were two randomized control trials, both of which were for COVID-19 and were terminated early. Most COVID-19 reports described a potential benefit of convalescent plasma on clinical outcomes in severe or critically ill patients with few immediate adverse events. However, there were a number of limitations, including the concurrent use of antivirals, steroids and other treatments, small sample sizes, lack of randomization or control groups, and short follow-up time. [7]

A meta-analyses and systematic review of convalescent plasma in COVID-19 and other severe respiratory viral infections was performed. Included were studies of patients infected with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza virus with severe respiratory infection, and Ebola virus infection. However, no eligible studies of COVID-19 were identified. The authors concluded that studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events. [8]

An on-going/living systematic review included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. While still being updated, it is currently uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. Additionally, there is low-certainty evidence for safety of convalescent plasma for COVID-19. [9]

References:

[1] COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of
Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [09/08/20].

[2] Investigational COVID-19 Convalescent Plasma; Guidance for ... https://www.fda.gov/media/136798/download. Accessed September 8, 2020.

[3] Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With Coronavirus Disease 2019 (COVID-19). Clinical Infectious Diseases. 2020. doi:10.1093/cid/ciaa478

[4] Bloch EM, Shoham S, Casadevall A, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020;130(6):2757-2765. doi:10.1172/JCI138745

[5] Psaltopoulou T, Sergentanis TN, Pappa V, et al. The Emerging Role of Convalescent Plasma in the Treatment of COVID-19. Hemasphere. 2020;4(3):e409. Published 2020 May 21. doi:10.1097/HS9.0000000000000409

[6] Brown BL, McCullough J. Treatment for emerging viruses: Convalescent plasma and COVID-19. Transfus Apher Sci. 2020;59(3):102790. doi:10.1016/j.transci.2020.102790

[7] Wooding DJ, Bach H. Treatment of COVID-19 with convalescent plasma: lessons from past coronavirus outbreaks [published online ahead of print, 2020 Aug 11]. Clin Microbiol Infect. 2020;S1198-743X(20)30482-1. doi:10.1016/j.cmi.2020.08.005

[8] Devasenapathy N, Ye Z, Loeb M, et al. Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis. CMAJ. 2020;192(27):E745-E755. doi:10.1503/cmaj.200642

[9] Piechotta V, Chai KL, Valk SJ, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2020;7(7):CD013600. Published 2020 Jul 10. doi:10.1002/14651858.CD013600.pub2

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Does convalescent plasma improve 7-day or 30-day mortality in hospitalized patients with Corona Virus Disease 2019 (COVID-19)?

Please see Table 1 for your response.


Effect of Convalescent Plasma on Mortality among hospitalized Patients with COVID-19: Initial Three Month Experience

 

Design

Open-label, non-randomized, single-arm, Expanded Access Program (EAP) trial

 

EAP:  A US government-sponsored, national, pragmatic intervention conducted as a multicenter, open-label protocol in hospitalized adults with COVID-19

 

N= 35,322

Objective

To explore potential signals of efficacy of COVID-19 convalescent plasma

Methods

Eligible patients were aged 18 years or older, hospitalized with a laboratory confirmed diagnosis of infection with severe acute respiratory syndrome coronavirus 2 (SARS138 CoV-2), and had or were at high-risk for severe or life-threatening COVID-19.

 

Convalescent plasma was obtained from a registered or licensed blood collector, and COVID-19 antibody levels were unknown at the time of plasma collection. Convalescent plasma was donated by COVID-19 survivors with confirmed diagnosis via clinical laboratory tests and whom were symptom free for 14 days.

 

Compatible COVID-19 convalescent plasma was administered intravenously at a transfusion dose of at least one unit (approximately 200 mL), with the option to administer additional doses if clinically justified.

 

Binding antibody levels from sera were tested using the Ortho-Clinical Diagnostics VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (CLIA). The Ortho-Clinical IgG CLIA is a qualitative assay based on a recombinant form of the SARS-CoV-2 spike subunit 1 protein.

 

Study Groups/Patients

Between April 4th and July 4th, 47,047 patients were enrolled in the EAP, of whom 36,226 were transfused with COVID-19 convalescent plasma.

 

Data were included for 35,322 transfused patients with 7-day and 30-day follow-up.

Duration

April 4th to July 4th, 2020

Outcome Measures

7-day and 30-day mortality in patients transfused with convalescent plasma

 

7-day and 30-day adjusted mortality stratified by antibody groupings in patients transfused with COVID-19 convalescent plasma

Results

 

 

Crude Mortality (7 and 30 day) of patients transfused with COVID-10 Convalescent Plasma

 

 

7-Day Mortality

30-Day Mortality

Sample number

Events number

Estimate

p-value

Sample number

Events Number

Estimate 95% confidence interval

p-value

Overall Mortality

35,322

3,706

10.5%

--

35, 322

8,652

24.5% (24.0%, 24.9%)

--

Age:

<0.001

 

<0.001

18-39 y

3,472

109

3.1%

3,472

261

7.5%

40-59 y

12,168

662

5.4%

12,168

1,837

15.1%

60-69 y

8,968

897

10.0%

8,968

2,431

27.1%

70-79 y

6,704

1,023

15.3%

6,704

2,367

35.3%

80 y or older

4,010

1,025

25.3%

4,010

1,756

43.8%

On Ventilator prior to Infusion:

<0.001

 

<0.001

No

25,205

1,932

7.7%

25,205

4,523

17.9%

Yes

9,573

1,685

17.6%

9,573

3,924

41.0%

Missing

544

89

16.4%

544

205

37.7%

Days to Transfusion:

<0.001

 

<0.001

<3 days

15,407

1,340

8.7%

15,407

3,329

21.6%

4+ days

19,915

2,366

11.9%

19,915

5,323

26.7%

 

Ortho IgG data were stratified by groupings of antibody levels into low (<4.62 S/Co), medium (4.62 to 18.45), and high (>18.45 S/Co).

 

7-day and 30-day adjusted mortality stratified by antibody groupings in patients transfused with COVID-19 convalescent plasma

 

7-Day Mortality

30-Day Mortality

Sample number

Events number

Estimate

p-value

Sample number

Events Number

Estimate 95% confidence interval

p-value

Ortho IgG:

 

0.0483

 

0.0208

Low

561

77

13.7%

561

166

29.6%

Medium

2006

233

11.6%

2006

549

27.4%

High

515

46

8.0%

515

115

22.3%

Study Author Conclusions

The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma.

 

InpharmD Researcher Critique

The sample size for the EAP was not determined a priori and patient accrual has not concluded at the time of this writing. The sample sizes for these analyses could be missing data. Additionally, the degree of immune activity within the units of convalescent plasma (i.e. specific IgG levels) was not known. Further limitations include the study being a non-randomized, single arm trial published in pre-print form. There is no peer-review of this study currently and information may change upon formal publication. 

 

 

 

References:

Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv. https://www.medrxiv.org/content/10.1101/2020.08.12.20169359v1. Published January 1, 2020. Accessed September 3, 2020.