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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 26-32

Is convalescent plasma therapy effective for COVID-19? Our initial experience at tertiary care center


Department of Transfusion Medicine, Blood Bank, Yashoda Hospital, Secunderabad, Telangana, India

Date of Submission28-Nov-2020
Date of Decision12-Feb-2021
Date of Acceptance05-May-2021
Date of Web Publication29-May-2021

Correspondence Address:
Dr. Neha Jayant Hurkat
Department of Transfusion Medicine, Blood Bank, Yashoda Hospital, Secunderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_111_20

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  Abstract 


Background and Objectives: Previous studies suggest that convalescent plasma (CP) may be effective in improving survival rates in COVID-19 patients. But still there is uncertainty regarding effectiveness of CP in improving mortality or clinical improvement in COVID-19 patient as randomized studies were short of statistical significance. We aim to report our initial experience with CP transfusions for COVID 19 patients at a tertiary care set up with regard to its efficacy and safety in patients at various stages of disease. Methods: This is an observational study which includes 324 patients who have received convalescent plasma from 1st July to 31st August 2020 in a tertiary care set up. The outcome of the study was measured by recovery of the patient and discharge from hospital in stable condition. Recovery was defined as no fever for 3 consecutive days, respiratory rate and oxygen saturation returning to normal at room air and patient being hemodynamically stable. Results: The overall recovery was attained in 249/324 patients (76.9%) and 75/324 patients (23.1%) died in hospital. In moderate disease patients the recovery rate was found to be 96.1%. In Severe disease patients, 38.8% recovered and in critically ill patients, 23.4% recovered. 80.6% patients recovered who received plasma within 5 days of hospitalization where as only 67.4% patients recovered who received plasma after 5 days of hospitalisation indicating earlier administration of CP in disease course has better outcomes. SARS-CoV 2 IgG ab levels of CP units correlated with outcome. The recovery was significantly higher in patients who received CP with higher IgG values (>12) as compared to patients who received CP with lower IgG values (<12). No adverse effects of CP transfusion were reported. Conclusion: This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes. Thus it is reasonable to consider CP therapy as an effective, safe and feasible therapeutic option for COVID-19 in the early course of disease.

Keywords: Convalescent plasma, COVID-19, clinical outcome, recovery, mortality


How to cite this article:
Hurkat NJ, Ramulu V, Gurram S. Is convalescent plasma therapy effective for COVID-19? Our initial experience at tertiary care center. Glob J Transfus Med 2021;6:26-32

How to cite this URL:
Hurkat NJ, Ramulu V, Gurram S. Is convalescent plasma therapy effective for COVID-19? Our initial experience at tertiary care center. Glob J Transfus Med [serial online] 2021 [cited 2021 Dec 7];6:26-32. Available from: https://www.gjtmonline.com/text.asp?2021/6/1/26/317121




  Introduction And Background Top


The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in December 2019, causes a respiratory illness known as COVID-19. Clinical manifestations of COVID-19 range from mild, self-limiting respiratory tract illness to severe progressive pneumonia, multiorgan failure, and death.[1],[2]

A variety of therapeutics has been proposed or is currently under clinical investigation including immunomodulatory agents and other antiviral agents, yet there is no approved treatment for COVID-19. Additional treatment consists largely of supportive care. Among the experimental treatment modalities are the use of immune convalescent plasma (CP) and similarly, hyperimmune globulin from recovered COVID-19 patients.[3]

This treatment entails the administration of plasma from individuals following resolution of infection under the rationale that antibodies in the plasma that is transferred to recipients (frequently described as passive antibody therapy) are able to neutralize the virus and protect recipients from infection or prevent or mitigate progression of existing infection.

Since the publication of the first case series from China, multiple observational studies have been published, some on preprint servers, highlighting the usefulness of CP in reducing mortality, hospital stay, and viral load in COVID-19 patients.[4],[5],[6],[7] A recent Cochrane review, including 20 studies [1 RCT, 3 controlled nonrandomized study of intervention (NRSI), 16 noncontrolled NRSIs], concluded that there is uncertainty regarding effectiveness of CP in improving mortality or clinical improvement in COVID-19 patients.[8]

Despite some methodological limitations of these previous reports, the data suggest the possibility of clinical benefit related to CP therapy with further well-designed quality research.

With this background, we aim to report our initial experience with CP transfusions for COVID-19 patients at a tertiary care setup with regard to its efficacy and safety.

The objective of this work is to describe the clinical outcome associated with CP transfusions for patients with moderate, severe, and critically-ill COVID-19 patients at our center.


  Methods Top


This was an observational study which includes initial 324 patients who have received CP between July 1 and August 31, 2020.

Inclusion criteria for CP therapy were as follows

  • Diagnosis of COVID-19 confirmed by detection of SARS-CoV-2.


  • RNA by real-time (RT) polymerase chain reaction (PCR) obtained from the nasopharyngeal swab.

  • Moderate or severe COVID-19
  • Informed consent.


Exclusion criteria

  • Age <18 years
  • Patients with known hypersensitivity to blood products.


Severity of disease is defined as follows:

  • Moderate disease: This is defined by patients who either have PaO2/FiO2 ratio between 200 and 300 or are tachypnea to more than 24 breaths/min and have SpO2 < 93%


  • Severe disease: Patients with severe COVID-19 pneumonia, P/F ratio <200 (moderate acute respiratory distress syndrome [ARDS]) requiring noninvasive mechanical ventilation and/or oxygen saturation at room air <90%
  • Critically ill: Patients with PaO2/FiO2 <200 (severe ARDS) and/or in shock and/or requiring hemodynamic support and requiring invasive mechanical ventilation.


Eligibility of donor for convalescent plasma donation is followed as per the ICMR guidelines

  • 18 years to 65 years of age
  • Males or nulliparous female donors of weight >50 Kg
  • Prior diagnosis of COVID-19 documented by a laboratory test (RT-PCR) with symptomatic disease with at least fever and cough and
  • Complete resolution of symptoms at least 28 days before donation


  • OR

  • Complete resolution of symptoms at least 14 days before donation and two negative real-time PCR test for COVID-19 from nasopharyngeal swab, collected 24 h apart
  • Anti-SARS CoV-2 immunoglobulin G (IgG) S/CO value above 6 by orthoclinical diagnostics VITROS chemiluminescent immunoassay (CLIA)
  • In addition, donor eligibility criteria for whole blood donation will be followed in accordance to the Drugs and Cosmetics Act 1940 and rules 1945 therein (as amended till March 2020).[9]


All routine screening tests including ABO blood grouping, Rh phenotype, complete blood counts, screening for HIV, HBV, HCV, syphilis, malaria, and total serum protein were conducted as per the drugs and cosmetics rules (second amendment), 2020.[10]

Antibody testing: The levels of serum IgG were tested using the Ortho Clinical Diagnostics VITROS anti-SARS-CoV-2 IgG CLIA in accordance with manufacturer instructions. This is a qualitative assay based on a recombinant form of the SARS-CoV-2 spike subunit 1 protein (RBD). Results of this assay are based on the sample signal-to-cutoff (S/Co) ratio, with values <1.0 and ≥1.00 corresponding to negative and positive results.

Measuring neutralizing IgG against S1 in CP against SARS-CoV-2 requires a biosafety level 3 laboratory and is cumbersome, and thus, it is not feasible in most settings. Considering the fact that S/Co values reflect relative levels of anti-SARS-CoV-2 antibodies, a signal to cutoff (S/Co) of ≥6 was kept to accept all the donors for CP donation assuming it to have good titer neutralizing antibodies.

Thus, all the donors with SARS-CoV-2 IgG antibody level <6 were deferred for CP donation.

Plasmapheresis of donors

Plasma was collected by apheresis procedure using a TRIMA Accel Automated Blood Collection System (Terumo Penpol Pvt Ltd).

A 400 ml plasma volume was collected from each donor, which was further divided into two 200 ml plasma units and immediately stored at −30°C.

Treatment protocol

The transfusion dose of CP was at least one unit of 200 ml with the option to administer additional doses if clinically justified.

The first dose of 200 ml CP was transfused on the day of request, and if it was well tolerated, as per the treating physicians' request, it was followed by an additional unit of 200 ml after 24 h of first infusion. The additional plasma unit was preferably from a different donor depending on the availability of another ABO compatible plasma unit or else plasma unit from the same donor was issued.

Main outcome measure

Recovered and discharged from hospital in a stable condition.

(Recovery and Hospital Discharge criteria: no fever for 3 consecutive days, respiratory rate and oxygen saturation return to normal at room air, and patient hemodynamically stable).

Statistical analysis

Analysis was performed using SPSS software version 20.0. Descriptive statistics are presented as frequencies and percentages. Mean, median, and standard deviation were used as appropriate. We calculated the antibody mean of CP units given to patients by calculating the S/Co values of IgG in the number of CP units given to each patient. Categorical data were compared using Chi square test. P <0.05 was considered statistically significant.


  Results Top


A total of 324 patients who were transfused with COVID-19 CP between the time period of July 1 and August 31, 2020 are included in this analysis. Demographic and baseline characteristics of patients are presented in [Table 1]. About 65% patients had some or the other comorbidities at the time of presentation to hospital. 77 (23.8%) patients had both diabetes mellitus (DM) and hypertension (HTN). 52 (16%) patients had only diabetes, 51 (15.7%) patients had only hypertension, 17 (5.2%) patients were having multiple comorbidities like along with DM and HTN; they were having either coronary artery disease (CAD) or chronic kidney disease (CKD) or chronic liver disease (CLD). Two patients were having chronic obstructive lung disease and two were the known case of pulmonary tuberculosis.
Table 1: Demographic and baseline characteristics of patients

Click here to view


Ten (3%) patients had either of CAD or CKD or CLD. Seventy percent patients had moderate disease who required oxygen support in the form of either nasal cannula, face mask, or nonrebreathing face mask, and 30% patients had severe disease or were critically ill who required noninvasive or invasive mechanical ventilation at the time of hospital admission.

CP was collected from 344 donors. Each donor donated 400 ml of plasma by apheresis which was divided into two aliquots of 200 ml each. 98.5% were male donors, and all the criteria for eligibility of donor selection were strictly followed as described above. In all the CP units, IgG levels were above 6. In 74 of 344 donors (21.5%), IgG antibody value was between 6 and 12; in 148 out of 344 donors (43%), IgG antibody value was between 12 and 18; and in 122 out of 344 donors (35.4%), IgG antibody value was above 18.

Clinical outcome measures

The overall survival (defined as recovered and discharged from hospital) was attained in 249/324 patients (76.9%) and 75/324 patients (23.1%) died in hospital [Table 2]. Of these, 75 patients who died, 36 patients were critically ill, and 30 patients were having severe disease at the time of hospital admission, and they were on invasive and noninvasive ventilation, respectively, before CP therapy.
Table 2: Outcome measures

Click here to view


In moderate disease patients, the recovery rate is 96.1%, i.e. 219/228 patients recovered and discharged whereas 9/228 patients (3.9%) died in due course of admission. In this group, all patients were hypoxic and required oxygen support ranging from moderate to high flow oxygen therapy to maintain normal saturation at initial presentation.

In severe disease patients, 19/49 (38.8%) improved whereas 30/49 (61.2%) patients deteriorated and could not be revived as all these patients presented very late in the hospital and all required ventilatory support at initial presentation.

All critically ill patients were mechanically intubated before plasma therapy was given. Of 47 such patients, 11 (23.4%) got extubated and recovered after plasma therapy whereas 36/47 (76.6) patients died.

Nearly 80.6% patients who received plasma within 5 days of hospitalization got recovered whereas only 67.4% patients recovered who received plasma after 5 days of hospital admission which is statistically significant indicating earlier administration of CP in disease course has better outcomes.

With respect to plasma volume, patients received from minimum 1 unit, i.e. 200 ml to maximum of 4 units, i.e. 800 ml, but no statistically significant difference was found for survival benefit between those who have received either one or four units. Notably, it is seen that 77.8% and 78.3% patients recovered who received 1 and 2 units, respectively, whereas 61.1% and 73.9% patients recovered who received 3 and 4 units, respectively, which indicates that higher volumes do not have any additional impact on survival (See [Table 2]).

Correlation of antibody levels and outcome

In the group of patients who received CP with mean antibody level <12, 34 of 55 (61.8%) patients recovered versus 215 of 269 patients (79.9%) in the group of patients that received CP with a mean antibody level >12 [Table 3].
Table 3: Correlation of antibody levels and outcome

Click here to view


There was an association between patients' improvement and antibody levels in correlation to the days that elapsed before transfusion. In patients that received CP transfusion within 5 days of hospitalization, 71.1% improved with antibody level of <12 versus 82.5% improved with antibody level >12, whereas in patients that received CP after 5 days of hospitalization, 7 of 17 (41.2%) recovered in the group with low antibody levels versus 55 of 75 (73.3%) patients recovered in the group that received CP with high antibody levels.

Similarly, in critically ill patients, those who received as seen in [Table 3] CP with mean antibody level >12, 11/35 patients recovered versus 0 out of 12 patients who received CP with mean antibody level <12, P = 0.026.


  Discussion Top


Based on results of this single-centered clinical study, administration of CP to COVID-19 infected patients resulted in significant improvements of their clinical outcomes.

This study supports the beneficial effect of CP plasma for treatment of COVID-19 patients at various disease stages. The overall rate of improvement was 76.9% (249/324), and all-cause mortality rate was 23.1%. Our center being tertiary care and referral center, majority of patients presented very late in their disease course and in critical condition.

In recent publications describing outcomes for hospitalized COVID-19 patients, mortality ranged between 26% and 88%.[11],[12],[13],[14],[15],[16],[17]

In this cohort of patients, the mean age was 56.96 ± 12.03 (range from 25 to 92), and 65% patients had comorbidities which were statistically significant showing higher risk of mortality in patients having comorbidities.

In our study, the recovery rate in moderate disease patients is 96.1%, in severe disease patients, 19/49 (38.8%) recovered whereas in critically ill patients, 11 out of 47 (23.4%) got extubated and recovered after plasma therapy. Of note, it is evident from this study that there was significantly improved survival in nonintubated patients than in intubated patients which may help in patient selection for CP therapy. Furthermore, this is in alignment with the general principle that CP is more effective when administered early in the disease course.[18] Many prior studies demonstrated that CP is more effective when administered early during the disease course for optimal effect.[19],[20]

Our study also demonstrates that early administration of CP in COVID-19 patients is a critical step as 80.6% patients who received plasma within 5 days of hospitalization got recovered whereas only 67.4% patients recovered who received plasma after 5 days of hospital admission.

Similarly, a large observational study advocated the usefulness of CP in COVID-19, stating that the 7-day and 30-day mortality were lower in those who received CP within 3 days of symptom onset.[21]

We demonstrated that the recovery rate of those who received CP with IgG above 12 was significantly higher than compared to patients that received CP with lower IgG levels which is in accordance with other similar type of studies.[21]

Even though beneficial effect of CP was seen more in moderate disease patients, our results of improved outcome in patients with severe and critically ill COVID-19 following CP transfusion suggest that CP therapy, particularly when antibody levels are high, may be beneficial even beyond the earlier stages of disease.

In this study, no adverse effects of plasma transfusion were observed, and thus, it is remarkable that CP therapy is a safe treatment option for COVID-19.

Study limitation

This study has several limitations. The study lacks a control group. Due to ethical consideration, responsible physicians were reluctant to deprive COVID-19 patients from CP therapy, and thus, randomized controlled clinical study design was not possible. Furthermore, other treatment regimens including steroids, antivirals, immunomodulators, and other supportive medications along with CP transfusion were used. As a result, the possibility that these agents could contribute to the recovery of patients, or synergize with the therapeutic effect of CP, could not be ruled out.


  Conclusion Top


CP therapy, in addition to concomitant drug therapy and other supportive therapies, has shown superior evidence in clinical improvement. Thus, it is reasonable to consider CP therapy as an effective, safe, and feasible therapeutic option for COVID-19 in the early course of the disease.

Measuring IgG antibody levels against the spike protein which serves as a surrogate marker for neutralizing antibodies in CP units before transfusion to ensure adequate antibody level are indeed crucial. Nevertheless, further well-designed randomized controlled studies are required to establish the definite role of CP in COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.  Back to cited text no. 1
    
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4.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9.  Back to cited text no. 4
    
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Abolghasemi H, Eshghi P, Cheraghali AM, Imani Fooladi AA, Bolouki Moghaddam F, Imanizadeh S, et al. Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: Results of a multicenter clinical study. Transfus Apher Sci 2020;59:102875.  Back to cited text no. 5
    
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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:CD013600.  Back to cited text no. 8
    
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Government of India. Drugs and Cosmetics Act 1940 and Rules 1945, Amended. 2020. Available from: https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NTc2MQ.  Back to cited text no. 9
    
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Department of Health and Family Welfare, Ministry of Health and Family Welfare; Government of India. Gazette of India. Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdfdocuments/NewDrugs_CTRules_2019.pdf.  Back to cited text no. 10
    
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Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-9.  Back to cited text no. 17
    
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Casadevall A, Scharff MD. Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis 1995;21:150-61.  Back to cited text no. 18
    
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Casadevall A, Joyner MJ, Pirofski LA. SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy. J Clin Invest 2020;130:5112-4.  Back to cited text no. 19
    
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Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005;24:44-6.  Back to cited text no. 20
    
21.
Joyner, Michael J et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv: the preprint server for health sciences 2020.08.12.20169359.2020.08.12.20169359.  Back to cited text no. 21
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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