ABSTRACT

Objective:

Relevant studies have suggested that the administration of convalescent plasma (CP) collected from COVID-19 patients who have recovered from the infection and whose plasma contains antibodies against SARS-CoV-2 is safe and may be effective in treating COVID-19 patients. The present study aimed to investigate whether the number of CP doses administered, the power of the IgG ratio and the time of CP administration following positive SARS-CoV-2 PCR had an impact on the 30-day in-hospital mortality.

Materials and Methods:

This single-center retrospective study was conducted with patients who were hospitalized and met the severe/critical COVID-19 disease criteria and received CP. Demographics, comorbidities, co-medications, onset of symptoms, duration between SARSCoV- 2 PCR testing and hospitalization, the time of the first CP administration, laboratory results, respiratory support needs, O2 saturation, fever at the baseline, APACHE II scores and SOFA scores were recorded.

Results:

Of the 224 patients with the mean age of 64.2±14.5 (19-91) years, 143 were male. The most common comorbidities were hypertension and congestive heart failure. Chronic renal failure, mechanical ventilation needs, PO2/FiO2 <300, clinically rapid progression, persistent fever, SOFA score increase and increased vasopressor need were associated with increased mortality. There was a statistically significant difference between the deceased (14.0±8.2) and survivor (8.74±5.28) groups in terms of APACHE II scores (p<0.001). The number of CP units administered, the power of the IgG ratio in the CP units and the timing of CP administration had no effect on the need for respiratory support and mortality rate. CP-associated complications were observed in 11 (0.5%) patients.

Conclusion:

In conclusion, CP therapy was not associated with improved survival or other positive clinical outcomes in severe/critical COVID-19 patients.

Keywords:

Severe/critical COVID-19, intensive care unit, convalescent plasma, the power of the IgG ratio, SOFA score, the APACHE II score, macrophage activation syndrome

Introduction

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection presents with a wide range of clinical symptoms, ranging from asymptomatic to severe pneumonia, multiple organ failure, and death (1-3). Although 80% of reported cases are estimated to have a mild or asymptomatic course of infection, approximately 5% are admitted to the intensive care unit (ICU) with acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure, or all three (4-6). Patients with a respiratory rate >30/min or SpO₂ in room air <90%, along with clinical signs of pneumonia, have been defined as severe coronavirus disease-2019 (COVID-19) cases, whereas those who have ARDS or respiratory failure requiring ventilation, sepsis, or septic shock are considered critical COVID-19 cases (7).

In the absence of other specific therapies, convalescent plasma (CP) has been used as either a preventive or therapeutic agent to provide immediate passive immunity, with variable success in various infectious diseases (8-10). In the early period of the COVID-19 pandemic, randomized controlled studies and case series have suggested that the administration of CP was collected from patients with COVID-19 who recovered from the infection and whose plasma contains antibodies against SARS-CoV-2, which is safe and may be effective in treating patients with COVID-19 (11-14). Concurrent with these studies, in August 2020, the American Food and Drug Administration (FDA) issued an Emergency Use Authorization for CP for the treatment of hospitalized patients with COVID-19 (15).

Our study aimed to evaluate the use of COVID-19 CP in patients with severe and critically hospitalized COVID-19 who lacked information regarding hospital mortality and changes in clinical and laboratory markers in the early course of the disease.

Materials and Methods

Patients

This single-center retrospective study was conducted at Ege University Hospital after receiving approval from the Clinical Research Ethics Committee (number: 20-5T/48).

Adult patients admitted to the COVID-19 ICU and services dedicated to treating patients with COVID-19 who met the severe/critical disease criteria and received COVID-19 CP between April 2020 and January 2021 were included in the study.

Study Protocol and Data Collection

CP collection and administration were performed according to the COVID-19 Immune (Convalescent) Plasma Supply and Clinical Use Guidelines of the Ministry of Health of Turkey (16).

Clinical and specific laboratory data were obtained from the electronic file records of the patients. The demographics, comorbidities, co-medications, onset of symptoms, time lag between SARS-CoV-2 polymerase chain reaction (PCR) testing and hospitalization, and time of first CP use were recorded. Laboratory assessments associated with the severity of COVID-19, including neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin, ferritin, D-dimer, and platelet values, were performed. Respiratory support needed, O₂ saturation, fever, and relevant laboratory parameters were determined at baseline, 48 and 72 hours, and 5 days after CP administration. Acute physiologic, chronic health evaluation II scores were obtained during hospitalization, and sequential organ failure assessment scores were recorded during hospitalization, baseline, and 5 days after CP administration. Immunoglobulin (Ig)A deficiency was excluded in all patients before CP transfusion. Adverse events occurred within the first 24 hours after CP infusion were noted.

All patients were transfused with one unit of COVID-19 CP. The 2^nd and 3^rd units of CP, at least 24 hours apart, were transfused based on the physician’s judgment of worsening the patients’ respiratory, hemodynamic, and laboratory parameters due to COVID-19.

The patients received corticosteroids, antiviral agents, anticytokines, and antiplatelet/anticoagulants by considering the current treatment protocols for COVID-19 (17-24) within the scope of the recommended basic treatments specific to the patient.

Production and Storage Conditions of COVID-19 CP

All plasma donors had confirmed COVID-19 by SARS-CoV-2 PCR test positivity and were donated at least 14 days after complete resolution of COVID-19 symptoms and negative PCR testing, or 28 days after well-being. Donors were approximately 18-55 years, and all provided written informed consent at the time of plasmapheresis. All donors met the standard blood donor criteria and were documented to be negative for hepatitis B, hepatitis C, HIV, and syphilis, per standards in Turkish regulations, and exhibited strong IgG positivity in the immunochromatographic fast test for IgM and IgG.

A total of 200-600 cc plasma was collected using the apheresis method using the Trima Accel^® Automated Blood Collection System (Terumo BCT) and divided into two or three bags of 200 mL each. CPs to be used in the first six hours were kept unfrozen, while the others were stored frozen. Those used as liquid plasma in the first six hours of the collection were subjected to 25 Gy Gamma irradiation.

Following the donation, all donor serum samples were tested with Euroimmune SARS-CoV-2 IgG ELISA (Euroimmun, Lübeck, Germany) to detect SARS-CoV-2 spike protein subunit 1 (S1). The results were expressed as the ratio of the optical density of the sample to that of the internal calibrator supplied with the kit. The threshold value for positive results was ≥1.1, and values between 0.8 and 1.0 were considered borderline positive.

We evaluated whether the number of CP doses administered (i.e., 1-3 units), power of the IgG ratio [i.e., low (1.1-2.0), moderate (2.1-4.0), and high (>4.1)], or the time of CP administration following positive SARS-CoV-2 PCR [i.e., very early (0-3 days), early (4-7 days), and late (>7 days)] had an impact on 30-day in-hospital mortality.

Statistical Analysis

The statistical analyses were performed using IBM SPSS Statistics 26 software (IBM Corp., Armonk, NY). Continuous variables with normal and non-normal distributions were summarized as mean ± standard deviation (SD) and median, respectively. Categorical variables are expressed as frequencies or percentages. Differences between the living and deceased groups were analyzed using the chi-square test. Mann-Whitney U test was used for continuous independent variables and the Wilcoxon signed-rank test for continuous dependent variables (in which the values were evaluated relative to the baseline value).

A One-Way ANOVA test was used for the independent evaluation of dependent variables in the CP subgroup analyses. The post hoc test (Tukey) was used to determine differences between the CP subgroups during follow-up.

All analyses were performed using the 95% confidence interval, and significance was assessed at the p<0.05 level.

Results

CP donations were made from the donors between 24 and 188 days (median: 80 days, SD: ±44.5 days) after the onset of their first symptoms. A total of 417 CP doses were used in 224 patients. Out of these 417 doses, 407 (97.6%) were IgG-positive, and strong positivity (IgG ratio >4) was detected in 58.3% of those.

When CP treatment was commenced, 173 of 224 patients (77%) were in the ICU. The demographic information and admission characteristics of the patients are presented in Table 1. The mean age of the patients was 64.2±14.5 (19-91) years, and 143 were males. The most common comorbidities were hypertension (HT) and congestive heart failure (CHF), whereas the presence of chronic renal failure (CRF) was found to be associated with increased mortality. MV needs, PO₂/FiO₂<300, clinically rapid progression, persistent fever, SOFA score increase of >2, and increased vasopressor need were detected to be linked to increased mortality. The mean CP administration time after positive SARS-CoV-2 PCR was 5.89±3.95 days, and after hospitalization was 4.09±3.39 days. Overall, the mean durations of stay in the ICU was 10.95±8.5 days, and in the hospital, 17.63±9.2 days. The APACHE score was 14.0±8.2 in the deceased group and 8.74±5.28 in the survivor group, and the difference was statistically significant (p<0.001). The SOFA scores were statistically higher on the day of hospitalization and on the first and the 5^th day of CP administration in the deceased group (p<0.001) (Table 1).

The macrophage activation syndrome (MAS)-like inflammation indicators, including baseline CRP, procalcitonin, D-dimer, ferritin, and NLR values, were significantly higher in the deceased group than in the survivor group. Comparing the baseline values, significant increases in the D-dimer and NLR values in the deceased group and the platelet count in the survivor group were observed during the sequential follow-up (Table 2). Although there was no significant difference between the baseline levels of the inflammation indicators between the groups that received low, moderate, and high IgG ratios in CPs, except for the platelet value change in high IgG ratios, no consistent changes were observed on those parameters during follow-up between the groups. It was statistically significant that the platelet value increased relative to the basal value during sequential follow-up in the group with a high Euroimmun IgG ratio (Table 3).

The number of CP units, power of the IgG ratio in the CP units, and timing of CP administration did not impact the need for respiratory support and mortality rate (Table 4). The SOFA score did not significantly differ between the groups receiving different power of IgG ratio (Table 5)

CP-associated adverse events were observed in 11 (0.5%) patients; the most common complication was fever in eight patients. In addition, two patients had transfusion-related acute lung injury (TRALI) and one patient had transfusion-associated circulatory overload (TACO); no mortality caused by complications was determined (Table 6).

Discussion

CP serum and immunoglobulin is a passive immunization method that has been used for approximately 100 years to prevent and treat outbreaks in which no vaccine or pharmacological intervention is available. The first CP administration was reported during the pandemic period of Spanish influenza A (H1N1) pneumonia (1918-1920); the meta-analysis of studies conducted during this pandemic revealed that CP reduces mortality (25). In recent years, CP has been used for Middle East respiratory syndrome, SARS caused by SARS-coronavirus-1 and Ebola (26, 27).

However, in many large-scale randomized controlled clinical trials, the results indicated that CP treatment does not contribute to disease progression or to mortality in patients with COVID-19 (28-32). Further, in May 2021, it was reported in the Cochrane Review that there is a high degree of certainty in the evidence that CP for the treatment of individuals with moderate to severe COVID-19 does not reduce mortality and has little or no effect on measurements of clinical improvement (33). On the other hand, Joyner et al. (34) reported in a retrospective analysis of 3,082 COVID-19 patients who were hospitalized and needed no mechanical ventilation that the transfusion of CP containing high anti-SARS-CoV-2 IgG antibody levels was associated with lower mortality (34). Other studies also support the use of CP to reduce in-hospital mortality and emphasize the need for relevant studies (35, 36). In December 2021, although World Health Organization revised the survival guide on COVID-19 treatments as “in addition to its high costs, CP does not improve survival or reduce the need for mechanical ventilation”, citing evidence that CP does not provide benefit to patients with non-severe COVID-19, it recommends that randomized clinical trials should continue in severe and critically ill patients (37). In this retrospective cohort study, we evaluated the impact of CP use on survival in patients with severe or critical COVID-19. Advanced age and male sex are associated with mortality as the most important risk factors for developing infection and progression to severe disease in COVID-19 patients (38). Other risk factors are cardiovascular disease, obesity, HT, diabetes mellitus (DM), chronic respiratory tract disease, CRF, cancer, and weakened immune status (5, 39-41). In our study, male sex was at the forefront, and the mean age was significantly higher in the deceased group. No significant difference was detected between genders regarding respiratory support, whereas the need for invasive and non-invasive respiratory support statistically increased with advanced age. The most common comorbid diseases in patients with critical and severe COVID-19 were HT/CHF, followed by DM.

In a meta-analysis evaluating the administration time of CP, patients who received CP in the first 10 days of hospitalization were compared with those who received it between 10 and 20 days. Mortality was found to be decreased in those who received CP in the first ten days, however this decrease was not statistically significant (42). However, Salazar et al. (43) showed that mortality in patients who received CP within 72 hours of hospital admission was lower than that in those who received it late. In our study, the mean time to CP administration after the first PCR positivity was 5.89±3.95 days, and no significant difference was detected between the survivor and deceased patient groups. Furthermore, in our cohort, CP administration within 72 hours of PCR positivity had no impact on mortality and the need for respiratory support.

The efficacy of passive antibody therapy was associated with the concentration of neutralizing antibodies in the plasma of recovered donors. The target titer recommendation of the European Commission for the neutralization test in COVID-19 CP is 1:320. Although the ability to demonstrate the neutralization performance of antibodies in SARS-CoV-2 CP is considered the gold standard, it is not easy to routinely perform tests intended for this purpose because they require a laboratory with a high biosafety level and experienced staff. Euroimmun IgG has been shown to correlate with neutralization assays (44-46). The FDA has stated that CP with a Euroimmun sample to the cutoff of ≥3.5 can be used to treat hospitalized patients (47).

It has been determined in many studies that the efficacy of CP treatment is linked to the SARS-CoV-2 antibody titer it contains (34, 48). In a multicenter study, administration of CP with a high antibody titer before seven days was associated with low mortality (49). A randomized controlled clinical study conducted with an outpatient elderly population indicated that CP with a high antibody titer administered within 72 hours of the onset of COVID-19 symptoms improves clinical outcomes compared with placebo (50). However, the RECOVERY study involving 11,558 inpatients showed no difference in mortality risk between patients who received high antibody titers and those who received standard CP treatment (30). We did not observe a difference in mortality and the need for respiratory support among patients who received CP with an IgG ratio >4.0. The optimal dose and timing of CP treatment remains unclear (51). On the other hand, although the dosage is not standardized in CP administration in clinical practice, administering 200-500 mL CP in one or two regimens is generally accepted approach (42). In our study, there was no significant difference between patients administered 1, 2, and 3 units of CP (200-400-600 mL) regarding mortality and the need for respiratory support.

In their retrospective study, which included 117 COVID-19 inpatients, Yang et al. (52) reported that the SOFA score can be an independent risk factor for in-hospital mortality and can be used to evaluate COVID-19 severity and prognosis. However, Raschke et al. (53) showed that the SOFA score has a low mortality predictive accuracy in ventilator triage among patients with COVID-19, and they associated this with the fact that severe single organ dysfunction causes only a minimal change in SOFA scores. In our study, the SOFA scores were significantly higher in the deceased group than in the survivor group. Nonetheless, there were no significant differences in SOFA scores at baseline and day 5 of CP administration between the groups based on the antibody ratio of CPs administered.

The hyperinflammation associated with COVID-19 is similar to the symptoms of MAS, the clinical features of which have been previously reported. Increased serum ferritin, CRP, and D-dimer levels and decreased fibrinogen and platelet counts in patients with COVID-19 indicate the development of severe MAS-like inflammation and fibrinolysis (41, 54). The inflammatory cascade, complement activation, and pro-inflammatory cytokines determine the course of the disease in COVID-19 patients. It has been stated that specific hematological and inflammatory biochemical laboratory parameters correlate with the severity of COVID-19 (55-57). Among the inflammatory markers, CRP has been found to increase significantly in the initial stages of infection in patients with COVID-19 and is considered an early marker for severe COVID-19 (58, 59). In a prospective study evaluating 267 patients with severe COVID-19 who received CP, a decrease in CRP, ferritin, and interleukin-6 levels was determined (60). Higher and persistent inflammation markers and lower platelet counts were also associated with a poor prognosis in our cohort. Nevertheless, there was no consistent effect of CP administration on hyperinflammatory markers during follow-up was not observed. No similar studies have investigated the relationship between the changes in the laboratory parameters evaluated in our study and the power of the IgG ratio. Therefore, our study is of importance.

Although CP administration is generally considered safe and effective, it can cause some adverse events. Limited information is available regarding the specific side effects of CP therapy. However, the reported symptoms, including fever, chills, allergic reactions, TRALI, and TACO, are similar to those of other types of plasma blood components (61, 25). The causes of the highest mortality risk following plasma transfusion are TRALI and TACO, possibly due to the sequelae of pulmonary complications (62). Theoretical concerns regarding the use of CP in patients with COVID-19 include a clinical condition that worsens after plasma transfusion due to antibody-dependent enhancement (ADE) or antibody-mediated pro-inflammatory effects. Joyner et al. (11) evaluated 5,000 patients with severe and critical COVID-19 regarding side effects after CP considering that respiratory problems due to COVID-19 may increase CP-associated complications. They detected less than 1% serious adverse events, 0.22% TRALI, 0.1% TACO, and 0.06% severe allergic reactions within the first 4 hours. Since the incidences of TRALI and TACO are expected to be approximately 10% in critically ill patients, the authors assessed CP treatment as reassuring due to their cohort’s lower TRALI and TACO incidence rates (11). The incidence of TRALI and TACO in our study is in line with the literature, and there was no mortality due to CP-induced complications. However, the presence of many comorbidities in the patient group and vascular and pulmonary involvement caused by COVID-19 made the differential diagnosis of CP-related TRALI and TACO difficult. The specific signs and symptoms of COVID-19-induced ADE are unknown, and clinical deterioration and worse outcomes following CP administration can be associated with ADE. In our study, ADE was not suspected.

Conclusion

The retrospective nature of our study and the use of multiple drugs (antibiotic, antiviral, corticosteroid, anti-cytokines, low molecular weight heparin) in the individualized treatment of patients are limiting factors, which make it difficult to differentiate the laboratory/clinical impact of CP in severe/critical COVID-19 patients.

In conclusion, under the conditions of this retrospective cohort study, CP treatment was not associated with improved survival or other positive clinical outcomes in patients with severe/critical COVID-19. There is a need for more comprehensive and prospective controlled studies that can demonstrate the efficacy of CP in patients with COVID-19.

Ethics

Ethics Committee Approval: This single-center retrospective study was conducted at Ege University Hospital after receiving approval from the Clinical Research Ethics Committee (number: 20-5T/48).

Informed Consent: Donors were approximately 18-55 years, and all provided written informed consent at the time of plasmapheresis.

Footnotes

Authorship Contributions

Surgical and Medical Practices: Ö.Ö., İ.Ç., A.T., M.S.T., H.A.E., K.D., M.U., Y.A., Concept: Ö.Ö., İ.Ç., H.A.E., K.D., M.U., Y.A., Design: Ö.Ö., İ.Ç., M.S.T., K.D., M.U., Y.A., Data Collection or Processing: Ö.Ö., İ.Ç., A.T., H.A.E., Y.A., Analysis or Interpretation: Ö.Ö., İ.Ç., A.T., M.S.T., H.A.E., P.K., K.D., M.U., T.Y., Y.A., Literature Search: Ö.Ö., İ.Ç., A.T., M.S.T., K.D., M.U., Y.A., Writing: Ö.Ö., İ.Ç., A.T., M.S.T., H.A.E., P.K., K.D., M.U., T.Y., Y.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270-3.

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.

World Health Organization, Coronavirus disease (COVID-19) Pandemic. Available from: https://www. who.int/emergencies/diseases/novel-coronavirus-2019. Accessed: 11 March 2020.

Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention. [The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 F;41:145-51. Chinese.

World Health Organization (WHO). Report of the WHO-China Joint Mission on coronavirus disease 2019 (COVID-19); February 2020. Available at: www.who.int/docs/default-source/ coronaviruse/who-china-joint-mission-on-covid-19-final-report.

Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324:782-93.

Alhazzani W, Evans L, Alshamsi F, Møller MH, Ostermann M, Prescott HC, et al. Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med. 2021;49:219-34.

Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24:44-6.

Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52:447-56.

Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. Antivir Ther. 2018;23:617-22.

Joyner MJ, Wright RS, Fairweather D, Senfeld JW, Burno KA, Klassen SA, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. J Clin Invest 2020;130:4791-7.

Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, 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;324:460-70. Erratum in: JAMA. 2020;324:519.

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.

Casadevall A, Pirofski LA. The convalescent sera option for contain - ing COVID-19. J Clin Invest. 2020;130:1545-8.

https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment https://www.fda.gov/media/141480/download

Turkish Republic Ministry of Health, General Directorate of Public Health, COVID-19 (SARS-CoV-2 Infection) Guide (Scientific com - mittee study), April 14, 2020. Available at: https://covid19bilgi.saglik. gov.tr.

Wong CKH, Lau KTK, Au ICH, Xiong X, Chung MSH, Lau EHY, et al. Optimal timing of remdesivir initiation in hospitalized patients with coronavirus disease 2019 (COVID-19) administered with dexamethasone. Clin Infect Dis. 2022;75:e499-e508.

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at: https://www.covid19treatmentguidelines.nih.gov/. Accessed: 03.03.2022

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397:1637-45.

Marconi VC, Ramanan AV, de Bono S, Kartman CE, Krishnan V, Liao R, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9:1407-18. Erratum in: Lancet Respir Med. 2021;9:e102.

Guimarães PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, et. al; STOP-COVID trial investigators. tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385:406-15.

REMAP-CAP Investigators; Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384:1491-502.

Centers for Disease Control and Prevention (CDC). Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Available at: www.cdc.gov/ coronavirus/2019-ncov/hcp/clinical-guidance-managementpatients.html (accessed: 22 March 2021)

World Health Organization (WHO). Clinical management of severe acute respiratory infection (SARI) when COVID19 disease is suspected: interim guidance. World Health Organization 2020;WHO/2019-nCoV/clinical/2020.4.

Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006;17;145:599-609.

Eibl MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am. 2008;28:737-64, viii.

Marson P, Cozza A, De Silvestro G. The true historical origin of convalescent plasma therapy. Transfus Apher Sci. 2020;59:102847.

Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.

Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med. 2021;384:619-29.

RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021;397:2049-59.

Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021;27:2012-24. doi: Erratum in: Nat Med. 2022;28:212.

Writing Committee for the REMAP-CAP Investigators; Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, et al. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2021;326:1690-702.

Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;5:CD013600.

Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021;384:1015-27.

O'Donnell MR, Grinsztejn B, Cummings MJ, Justman JE, Lamb MR, Eckhardt CM, et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J Clin Invest. 2021;131:e150646.

Arnold Egloff SA, Junglen A, Restivo JS, Wongskhaluang M, Martin C, Doshi P, et al. Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19. J Clin Invest. 2021;131:e151788.

7th update of WHO’s living guidelines on COVID-19 therapeutics. Available at: https://www.who.int/news/item/07-12-2021-who-recommends-against-the-use-of-convalescent-plasma-to-treat-covid-19

Palaiodimos L, Kokkinidis DG, Li W, Karamanis D, Ognibene J, Arora S, et al. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism. 2020;108:154262.

Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020;20:398-400.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:934-43.

Wang Y, Huo P, Dai R, Lv X, Yuan S, Zhang Y, et al. Convalescent plasma may be a possible treatment for COVID-19: A systematic review. Int Immunopharmacol. 2021;91:107262.

Salazar E, Christensen PA, Graviss EA, Nguyen DT, Castillo B, Chen J, et al. Treatment of Coronavirus Disease 2019 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality. Am J Pathol. 2020;190:2290-303.

Weidner L, Gänsdorfer S, Unterweger S, Weseslindtner L, Drexler C, Farcet M, et al. Quantification of SARS-CoV-2 antibodies with eight commercially available immunoassays. J Clin Virol. 2020;129:104540.

Patel EU, Bloch EM, Clarke W, Hsieh YH, Boon D, Eby Y, et al. Comparative Performance of Five Commercially Available Serologic Assays To Detect Antibodies to SARS-CoV-2 and Identify Individuals with High Neutralizing Titers. J Clin Microbiol. 2021;59:e02257-20.

Walker GJ, Naing Z, Ospina Stella A, Yeang M, Caguicla J, Ramachandran V, et al. SARS Coronavirus-2 Microneutralisation and Commercial Serological Assays Correlated Closely for Some but Not All Enzyme Immunoassays. Viruses. 2021;13:247.

US Department of Health and Human Services Food and Drug Administration Letter of Authorization, Reissuance of Convalescent Plasma EUA. 2021. Available at: https://www.fda.gov/media/141477/download

Rajendran K, Krishnasamy N, Rangarajan J, Rathinam J, Natarajan M, Ramachandran A. Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. J Med Virol. 2020;92:1475-83.

Joyner MJ, Senefeld JW, Klassen SA, Mills JR, Johnson PW, Theel ES, et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv [Preprint].

Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021;384:610-8.

Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, 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;211:80-90.

Yang Z, Hu Q, Huang F, Xiong S, Sun Y. The prognostic value of the SOFA score in patients with COVID-19: A retrospective, observational study. Medicine (Baltimore). 2021;100:e26900.

Raschke RA, Agarwal S, Rangan P, Heise CW, Curry SC. Discriminant Accuracy of the SOFA Score for Determining the Probable Mortality of Patients With COVID-19 Pneumonia Requiring Mechanical Ventilation. JAMA. 2021;325:1469-70.

Otsuka R, Seino KI. Macrophage activation syndrome and COVID-19. Inflamm Regen. 2020;40:19.

Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9:727-32.

Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.

Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020;506:145-8.

Tan C, Huang Y, Shi F, Tan K, Ma Q, Chen Y, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020;92:856-62.

Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020 ;58:1021-8.

Fodor E, Müller V, Iványi Z, Berki T, Kuten Pella O, et al. Early Transfusion of Convalescent Plasma Improves the Clinical Outcome in Severe SARS-CoV2 Infection. Infect Dis Ther. 2022;11:293-304. Erratum in: Infect Dis Ther. 2022;11:1767-8.

Chun S, Chung CR, Ha YE, Han TH, Ki CS, Kang ES, et al. Possible Transfusion-Related Acute Lung Injury Following Convalescent Plasma Transfusion in a Patient With Middle East Respiratory Syndrome. Ann Lab Med. 2016;36:393-5.

Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, et al. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol. 2020;75:2352-71.

Evaluation of the Effectiveness of Convalescent Plasma Therapy in Severe and Critical COVID-19