key: cord-0803668-4lla0th3
authors: Beraud, Mickael; Goodhue Meyer, Erin; Lozano, Miquel; Bah, Aicha; Vassallo, Ralph; Brown, Bethany L.
title: Lessons learned from the use of convalescent plasma for the treatment of COVID-19 and specific considerations for immunocompromised patients
date: 2022-01-13
journal: Transfus Apher Sci
DOI: 10.1016/j.transci.2022.103355
sha: f1009f12c3985409437f39ee4cb0a29c58b9bd70
doc_id: 803668
cord_uid: 4lla0th3

Coronavirus disease 2019 (COVID-19) convalescent plasma (CovCP) infusions have been widely used for the treatment of hospitalized patients with COVID-19. The aims of this narrative review were to analyze the safety and efficacy of CovCP infusions in the overall population and in immunocompromised patients with COVID-19 and to identify the lessons learned concerning the use of convalescent plasma (CP) to fill treatment gaps for emerging viruses. Systematic searches (PubMed, Scopus, and COVID-19 Research) were conducted to identify peer-reviewed articles and pre-prints published between March 1, 2020 and May 1, 2021 on the use of CovCP for the treatment of patients with COVID-19. From 261 retrieved articles, 37 articles reporting robust controlled studies in the overall population of patients with COVID-19 and 9 articles in immunocompromised patients with COVID-19 were selected. While CovCP infusions are well tolerated in both populations, they do not seem to improve clinical outcomes in critically-ill patients with COVID-19 and no conclusion could be drawn concerning their potential benefits in immunocompromised patients with COVID-19. To be better prepared for future epidemics/pandemics and to evaluate potential benefits of CP treatment, only CP units with high neutralizing antibodies (NAbs) titers should be infused in patients with low NAb titers, patient eligibility criteria should be based on the disease pathophysiology, and measured clinical outcomes and methods should be comparable across studies. Even if CovCP infusions did not improve clinical outcomes in patients with COVID-19, NAb-containing CP infusions remain a safe, widely available and potentially beneficial treatment option for future epidemics/pandemics.

The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for more than 240 million infections and more than 4.8 million deaths up to October 17, 2021 [1] . While the number of people fully vaccinated against COVID-19 is globally increasing as several vaccines are available, there are still many active infections and the infectivity, transmission, and lethality of SARS-CoV-2 are evolving [2] .

Besides differences in study design and LoEs between studies, characteristics of patients (disease severity and duration, mechanical ventilation [MV] status, NAb titers, and concomitant treatment) and of CovCP (timing of CovCP collection and infusion, NAb titers, and volume) were also highly variable (Tables 1 and 2) .

Additionally, the results of seven RCTs evaluating the use of CovCP to treat COVID-19 published after May 2021, hence not identified by the systematic literature search, are also briefly discussed [65-71].

Among 37 articles identified during screening 1, safety was evaluated in 24 studies ( Table 3) . They confirmed that CovCP treatment has a clinically acceptable safety profile in patients with  which was similar to that of standard plasma infusions. The potentially CovCP-related reactions included local reactions at the injection site (pain, chills, rash, redness, and itching); intravenous catheter blockage; transfusion-related acute lung injury (TRALI); transfusion-associated circulatory overload (TACO); pulmonary, allergic, febrile non-hemolytic, and hypotensive reactions; anemia; urticaria; nausea; dyspnea; bradycardia; and tachycardia. No case of antibody-dependent enhancement of infection, listed as a theoretical risk of CovCP administrations by the United States (US) Food and Drug Administration (FDA) [72] , was reported.

While the results of most of the seven recently published RCTs support the reassuring safety profile of CovCP [65] [66] [67] [68] [69] , patients receiving CovCP experienced more serious adverse events than control patients in two of these RCTs [70, 71] .

There have been inconsistencies and significant biases in efficacy evaluations performed during this global pandemic. Estimations of the direct impact of CovCP infusions and comparisons among studies J o u r n a l P r e -p r o o f have been prevented by differences in study design, methods, analyses, and standard practices. Early in this pandemic, standard practices were heavily influenced by clinical observations and variability in clinical judgement by geographies.

In 25 of 37 articles identified during screening 1, mortality rates were significantly lower [20, 29, 34, 40, 41, 43, 47-49, 54, 55] or tended to be lower [25, 27, 30, 32, 35, 37, 38, 42, 44, [50] [51] [52] [53] 56] in all patients or specific subpopulations of patients with COVID-19 who received CovCP compared with control patients ( Table 3) . In other studies, no positive impact of CovCP infusions on mortality rates was detected [21-24, 26, 28, 31, 33, 36, 39, 45, 46] .

Duration of hospitalization and length of stay in intensive care unit (ICU) were difficult to compare among studies due to the variability in the evaluated parameters. While some studies assessed the total duration of hospitalization or length of ICU stay, others evaluated the duration of hospitalization or length of ICU stay after CovCP administration. The duration of hospitalization tended to be longer in CovCP-treated patients in some studies [26, 28, 29, 32, 33, 35, 36, 40, 42, 44, 45, 49, 52, 53] , but the opposite was observed in others [22, 24, 27, 30, 46, 47, 50, 51] (Table 3 ). In two studies, similar lengths of stay were observed in both groups [20, 56] .

The impact of CovCP on the clinical status of patients with COVID-19 was also difficult to assess because the parameters evaluated in the studies with available results were inconsistent ( Table 3) . In some studies, no statistically significant improvements in clinical outcomes were observed [21, 22, 26, 28, 29, 31, 33, 37, 39, 40, 42, 44, 46, 49, 52, 53] [51] , rate of transfer to MV [41] , and clinical status [38] in the overall study population or specific subgroups of patients with COVID-19.

Among the seven recently published RCTS, the use of CovCP seemed associated with improved outcomes in one study in 20 patients with COVID-19 [66] . Another study showed no improvements in survival and outcomes in 53 patients who received CovCP infusions versus 52 control patients, but a significant benefit of CovCP was observed in the subgroup of patients who received larger amount of NAbs [67] . The importance of high NAb levels rather than high IgG levels to select appropriate CovCP samples was also highlighted in another RCT [65] . In contrast, a large RCT in 940 patients with COVID-19 showed that CovCP did not reduce the risk of intubation or death and that CovCP infusions with unfavorable antibody profile were even associated with a worsening of clinical outcomes [70] . Other RCTs also showed that CovCP did not improve clinical outcomes in 1084 critically-ill patients with COVID-19 versus 916 controls [71] , early administration of CovCP did not prevent disease progression in 257 high-risk patients versus 254 controls [69] , and CovCP was associated with increased antibody levels but not with improved outcomes in 59 patients versus 15 controls [68] .

Among nine articles identified during screening 2, safety was evaluated in one non-matched casecontrol study and three single-group case series in immunocompromised patients with COVID-19 (Table 4 ). These studies showed that CovCP infusions were well tolerated in this subpopulation. No transfusion-related reactions were reported.

Because screening 2 identified only two controlled studies in immunocompromised patients with COVID-19, conclusions about efficacy were difficult to draw in this subpopulation ( 

Before the COVID-19 pandemic, CP was used during previous epidemics or outbreaks caused by other coronaviruses (MERS and SARS) and emerging viruses [11] [12] [13] [14] [15] [73] [74] [75] [76] [77] . While data on CP use were scarce for MERS [73, 74] , studies in a limited number of patients with SARS suggested that CP might improve clinical outcomes when administered at an early disease stage or in patients with severe disease [13, 75, 76] . A meta-analysis on the use of CP for the treatment of severe acute respiratory infections caused by SARS and influenza showed consistent evidence for a reduction in mortality when CP was administered early after the onset of symptoms [77] . Although the LoE was low for CP efficacy against other coronaviruses, these results suggested that CovCP could be a potentially effective treatment for patients with COVID-19. Therefore, CovCP treatment was initiated during the early months of the pandemic as a short-term strategy for conferring immediate passive immunity to susceptible individuals and to manage the disease before effective and targeted pharmacotherapy was found [78] . CovCP was used in various countries because passive antibody administration was the only immediately available therapy J o u r n a l P r e -p r o o f potentially able to prevent cellular infection by SARS-CoV-2, block viral replication, and treat COVID-19 [78, 79] .

In high-income countries, CovCP could be rapidly obtained using established blood collection and transfusion infrastructures as the number of patients who recovered from the disease had been increasing [78] . In low-and middle-income countries, CovCP was less frequently used in the early stages of the pandemic due to the challenges related to donor recruitment, blood collection, capacity to procure CovCP, and characterization of CovCP units [80] .

The safety profile of CovCP was considered comparable to that of standard plasma infusions since the only difference was the presence of anti-SARS-CoV-2 antibodies in CovCP. In high-income countries, the risk of transfusion-transmitted infections is very low and the safety profile of CovCP infusions is considered as clinically acceptable [81] . In these countries, the main CovCP transfusionrelated risks include allergic transfusion reactions, TRALIs, and TACOs, which are manageable reactions. The other theoretical risk of CovCP infusions was antibody-dependent enhancement of infection, a process whereby non-neutralizing antibodies, sometimes developed during a prior infection with a different viral serotype, enhance viral cellular entry, exacerbating the severity of symptoms [72, 82, 83] . This theoretical risk has not been observed with CovCP infusions.

At the onset of the COVID-19 pandemic, the decision to implement CovCP was guided by urgency, and the lessons learned from CP use in previous epidemics with respiratory viruses were initially difficult to apply [77] . Several studies were conducted before routine assays were available to determine NAb titers in CovCP units [23, 28, 30, 32-37, 39, 41, 43-45, 47, 49, 51-53] . Therefore, CovCP with low NAb titers was infused during the early months of the pandemic, which may have led to negative or inconclusive results. The variability in NAb quantity in CovCP was further amplified by the differences in treatment protocols, including timing and volume of CovCP infusions [81] 85, 86] , but these results were not confirmed in more recent RCTS [69, 70] . At the early disease stages, the blocking of viral entry and intracellular replication by the CovCP NAbs might help prevent disease progression and activation of the inflammatory cascade leading to cytokine storm [25, 79] . For any future use of CP in the setting of an emerging infectious pandemic/epidemic, welldefined patient grading scales are needed, which should be based on additional factors beyond the time since symptom onset or admission to hospital or ICU. Standardized definitions should be based on viral physiopathology, disease severity (e.g., with or without MV) and number of days posthospital admission (correlated to disease severity) in addition to symptom duration (though disease progression varies from patient to patient). Antibody testing later in the disease course may also be J o u r n a l P r e -p r o o f important to identify patients who have not yet formed sufficient levels of antibodies and may benefit from CP. Moreover, binding antibody signal in patients with early infection may not accurately reflect NAb levels and should not be the only criterion used to initiate CP infusions [65, 67] . Another option to describe disease stages is the consistent use of the WHO clinical progression scale [87] .

In this narrative review, we discussed whether clinical outcomes could be improved with CovCP in specific subpopulations of patients with COVID-19 since its use in the general population does not seem beneficial. Based on published studies, our experience, and the pathophysiology of COVID-19, we identified immunocompromised patients (e.g., organ transplant recipients, or patients with primary or secondary immunodeficiency, B-cell depletion, or cancers), who are at increased risk for mortality, as a potential target population who might benefit more from CovCP therapy [59, 88, 89] .

In this population, two controlled studies showed that CovCP treatment was associated with concerning the Emergency Use Authorization (EUA) of CovCP initially issued on August 23, 2020 to facilitate access for hospitalized patients in the US [93] . In the revised EUA, CovCP use was limited to units with high anti-SARS-CoV-2 antibody titers for the treatment of hospitalized patients with COVID-19 early in the course of disease (even if there is currently no consensus concerning the definition of early disease stage) and hospitalized patients with COVID-19 and impaired humoral immunity [84] . This updated EUA is also in line with the interim recommendations of the Association for the Advancement of Blood and Biotherapies (AABB, formerly the American Association of Blood Banks) mentioning that the risks of CovCP are comparable to those of standard plasma, CovCP is optimally effective when transfused as close to symptom onset as possible, and CovCP effectiveness is related to the anti-SARS-CoV-2 antibody quantity within a unit [81] . In the US, the FDA requirement for higher NAb titers has complicated the collection of CovCP meeting the various binding NAb titer criteria. These complexities and data inconsistencies have resulted in a halt to reimbursement for CovCP treatment and a decrease in demand in the US.

CP is a potentially useful treatment, but data reported to date on its efficacy do not provide rigorously evaluated and consistent conclusions. There are currently no guidelines for its collection and administration during pandemics. Major problems are the difficulties to collect enough CP with high NAb titers to treat large numbers of patients and to rapidly and timely implement RCTs with reduced risks of biases during a pandemic. More than 1.5 year after the onset of the COVID-19 pandemic, we have more insight on how to be better prepared for a next epidemic or pandemic. sufficiently understood to determine the optimal treatment strategies. The first lesson that we have learned is that it is essential to rapidly develop standardized quantitative methods with capacity for high throughput (preferably neutralization tests or validated surrogates) and to define optimal criteria for the selection of CP units with high antibody titers in the early stages of pandemics. A clear strategy should be established for the identification of potential donors who recovered from the disease. Therefore, standardized viral nucleic acid tests and antibody assays should be rapidly developed for screening. Because eligible donors should be negative for anti-human leukocyte antigen [80] , only men or nulliparous women with no history of transfusion should be considered as donors in the absence of testing. The establishment of a CP donor registry may be useful to identify eligible candidates for possible future donations. A plasma bank of frozen and ready-to-use CP could also be built by collecting plasma once or twice from all potential donors, especially in the early stages of a pandemic. Of note, it is important to determine whether the virus can be transmitted by transfusion and pathogen inactivation methods should be considered until this is confirmed, especially if prophylactic CP infusion post-potential exposure is considered. Moreover, the identification of CP recipients lacking high existing antibody levels is also essential to establish an efficient CP strategy in epidemics/pandemics.

While several studies have shown that CovCP infusions are not effective to treat patients suffering from COVID-19, a question that still needs to be addressed is whether plasma from vaccinated individuals might be beneficial. It has been recently shown that the in vitro neutralization activity induced by vaccination was lower against some variants, but that vaccinated individuals retained neutralization capability against most emerging variants [94] . Another study has shown that antibody responses to the first dose of mRNA vaccines (BNT162b2/Pfizer; mRNA-1273/Moderna) in individuals with pre-existing immunity from infection were equal to and frequently exceeded the titers found in naïve individuals after their second dose [95] . Thus, the collection of CovCP from vaccinated individuals who have recovered from primary infection is an area of interest [96] . Storage A third lesson learned is that there is a need for increased rigor and consistency in terms of treatment protocols and testing methodologies in studies evaluating the use of CP. At the onset of a pandemic, high-quality RCTs should be rapidly implemented and a consensus concerning key clinical outcomes to assess should be established to allow for comparisons between studies. The evaluation of confounding variables, such as concomitant treatments, and the monitoring of safety are also J o u r n a l P r e -p r o o f essential. Ideally, a standard protocol for RCTs evaluating CP safety and efficacy should be drafted and made publicly available and ready to be implemented worldwide.

A fourth lesson learned is that CP treatment implementation and use in later stages of pandemics may vary from one country to another. The implementation of CP treatment at the early stages may be more complicated and require adapted strategies in developing countries due to operational considerations [80] . However, CP treatment may be useful in the longer term in countries with limited resources owing to its low cost, wide availability, and clinically acceptable safety profile, assuming infectious disease safety is ensured by testing or inexpensive plasma pathogen reduction, and cold chain can be maintained [97] . In countries with limited resources where the determination of NAb titers in CP is complicated, the identification of clinical predictors of high NAb titers is also critical. For CovCP, a previous study has shown that male sex, older age, and hospitalization for COVID-19 were associated with increased antibody levels [98] . In countries with limited resources, collection and storage of CP could be another option to improve preparedness for a next wave of infections or the emergence of new variants. If feasible, CP sharing programs between high-and lowincome countries should also be established.

The evidence of benefit of NAb-containing CP infusions observed during previous epidemics and the reassuring safety profile of plasma treatment led to the widespread use of CovCP at the onset of the COVID-19 pandemic. While CovCP was used to fill a gap in the treatment for this new emerging virus, it was not intended for long-term use and was never considered as the ultimate therapy for COVID-19 since the eventual goals were to find effective targeted therapies and prevention measures through vaccination.

With the insights that we have more than 1.5 year after the onset of the pandemic, we realize that the implementation of CovCP infusions for the treatment of COVID-19 was suboptimal. To be better J o u r n a l P r e -p r o o f prepared for future epidemics or pandemics and to evaluate the potential benefits of CP treatment, we should ensure that only CP with high NAb titers is infused in patients with low NAb titers, patient eligibility criteria are based on the pathophysiology of the targeted disease, and measured clinical outcomes and methods are comparable across studies. Future research on the use of CP should focus on increasing scientific rigor for consistency in study design, test methods, and data analyses to allow for improved data interpretation and evidence-based clinical decisions. A standard protocol accounting for confounding variables, such as co-administered drugs and patients' confounding clinical variables, could be developed for the implementation of RCTs.

While CovCP infusions seem ineffective for the treatment of critically-ill patients with COVID-19, additional studies are needed to evaluate their potential benefits in immunocompromised patients.

Even if CovCP infusions do not improve clinical outcome in patients with COVID-19, NAb-containing CP infusions remain a safe, widely available and potentially beneficial treatment option to fill treatment gaps for emerging viruses. An early characterization of the disease pathophysiology will be essential to determine the optimal timing and schedule of CP infusions and to design narrow clinical trials in targeted subpopulations for future global pandemics or local epidemics.

Technologies. BB is an employee of the American Red Cross. RV is an employee of Vitalant.

ML on behalf of his institution, Clinic Research Foundation, received research support (Terumo Blood and Cell Technologies, Sanofi-Genzyme) and speaker honoraria (Grífols). ( J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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This work was supported by Terumo Blood and Cell Technologies, which was involved in all stages of the literature review and manuscript development.

All authors contributed to the literature review interpretation, critically revised the manuscript, and approved the final version.

CovCP, COVID-19 convalescent plasma; n, number of patients; NR, not reported; PaO2/FiO2, ratio of arterial oxygen partial pressure to fractional inspired oxygen; SD, standard deviation; US, United States; WHO, World Health Organization. * Type of publication at the time of writing of this review. † All publications were from 2020 or 2021.J o u r n a l P r e -p r o o f