Lessons learned from the use of convalescent plasma for the treatment of COVID-19 and specific considerations for immunocompromised patients

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.


Introduction
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]. The emergence of new variants highlights the importance of surveillance systems to update vaccination strategies and treatment approaches [3]. These variants cause particular concern as many world areas struggle to vaccinate their citizens due to the lack of infrastructure for production and deployment at scale, affordability, and timely allocation [4]. Moreover, some vaccines may offer suboptimal protection against new variants [5].
Patients with COVID-19 are often asymptomatic or present with mild respiratory symptoms [6]. However, SARS-CoV-2 can also lead to severe complications caused by mechanisms other than the direct viral infection, such as acute respiratory distress syndrome, coagulation disorders, multi-organ dysfunction syndrome, or septic shock. In some patients, adaptive immunity is suppressed, leading to delayed clearance of the virus, hyperactivation of the innate immune response, overproduction of various inflammatory factors, and increases in the number of active immune cells at the inflammation sites [7]. This imbalance in the immune system resulting in a cytokine storm is a major cause of disease exacerbation and death in patients with COVID-19 [7].
Even though several pharmacological agents have been developed or repurposed for the treatment of COVID-19 and monoclonal antibodies are now available, approved treatment options remain limited globally [8]. COVID-19 convalescent plasma (CovCP) is one treatment that has been extensively used in hospitalized patients with COVID-19 since the first months after the pandemic start [9]. CovCP is obtained from patients who have fully recovered from the infection and ideally contains high titers of virus neutralizing antibodies (NAbs) [10]. Convalescent plasma (CP) infusion is a method of passive immunization that was also previously used during the Spanish influenza pandemic in 1918 [11,12] and later for the treatment of other severe viral infections (severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS], H1N1 influenza, and Ebola virus) [13][14][15].
Despite the high level of investment and the numerous studies that evaluated the use of CovCP to treat COVID-19, inconsistencies in study design, efficacy endpoints, and reported data have limited the ability to compare results among trials [16]. The objectives of this narrative review are to analyze available data on the safety and efficacy of CovCP infusions for the treatment of COVID-19, to evaluate whether CovCP could be useful for specific subpopulations of patients with COVID-19, and to identify the lessons learned concerning the use of CP to inform future treatment and investigations for emerging viruses.

Material and methods
Systematic searches of PubMed, Scopus, and the Dialog database "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 to treat patients with COVID-19. The searches were performed with the following terms: ("convalescent plasma" OR "convalescent sera") AND ("covid-19" OR "novel coronavirus" OR ("wuhan" AND "virus") OR "SARS-CoV-2" OR "coronavirus 2019" OR "2019-nCoV" OR "coronavirus disease 2019" OR "novel coronavirus pneumonia"). The systematic literature search was initially performed on May 4, 2020, and weekly updates using the established criteria were conducted until May 1, 2021.
Screening of the retrieved articles was performed by an independent reviewer to identify (i) robust studies evaluating the efficacy and/or safety of CovCP in patients with COVID-19 versus control patients with COVID-19 who did not receive CovCP (screening 1), and (ii) all studies evaluating the use of CovCP in immunocompromised patients with COVID-19 who were identified as a specific subpopulation potentially benefiting from CovCP treatment (screening 2). During screening 1, eligible robust studies included randomized controlled trials (RCTs), prospective controlled clinical trials, and matched case-control studies. During screening 2, eligible immunocompromised patients included organ transplant recipients or patients with primary or secondary immunodeficiency, B-cell depletion, hematological cancers/malignancies, lymphomas, or other cancers. During both screenings, systematic and narrative literature reviews and meta-analyses were excluded, but their reference lists were checked for relevant articles that might have been overlooked. Reference lists of selected articles were also checked for relevant articles.
Data were extracted from the selected articles. Methodological classification was performed using the Oxford Centre for Evidence-Based Medicine levels by two independent assessors with differences resolved by consensus [17]. As decided a priori, any article published on a pre-print server was downgraded to the lower Oxford level of evidence (LoE). The other downgrading criteria included early study termination, small sample size, absence of systematic measurements of NAb levels in CovCP, and inclusion of CovCP units with low NAb levels.

General information on search results
The systematic literature search identified 1708 peer-reviewed articles, pre-prints and abstracts, of which 261 were selected for further screening.
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).

Safety
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 COVID-19, which was similar to that of standard plasma infusions. The potentially CovCPrelated 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 nonhemolytic, 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].
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 CovCPtreated 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].
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].

Safety
Among nine articles identified during screening 2, safety was evaluated in one non-matched case-control 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.

Efficacy
Because screening 2 identified only two controlled studies in        immunocompromised patients with COVID-19, conclusions about efficacy were difficult to draw in this subpopulation (Table 4). Nevertheless, the only matched case-control study showed that CovCP treatment was associated with significantly improved 30-day mortality (13.3 % versus 24.8 %) in patients with COVID-19 and hematologic malignancies [43].
In the non-matched case-control series, a significantly reduced mortality rate (13 % versus 41 %) following CovCP treatment was observed in patients with hematologic malignancies [57]. In this study, CovCP-treated patients showed a significantly milder course of infection, less severe symptoms, and faster recovery. In the uncontrolled case series conducted in immunocompromised patients with COVID-19, mortality rates and lengths of hospital stay were highly variable, and conclusions were difficult to draw. Improvements in clinical symptoms were reported in 8 of 14 patients within 5 days in one case series [59], in three of four patients in another case series [62], and in all patients in three other case series [61,63,64]. A recently published RCT suggested that CovCP with high NAb levels in addition to high IgG levels should be used if further studies evaluate its use in patients with an impaired humoral immunity [65].

Why was CovCP broadly used at the early stages of the pandemic?
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 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 transfusion-related 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.

How was CovCP implemented during the COVID-19 pandemic?
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][33][34][35][36][37]39,41,[43][44][45]47,49,[51][52][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]. The facts that the plasma of many patients who recovered from COVID-19 does not contain sufficient NAb levels to provide therapeutic benefit and that NAb titers decrease with time highlight the importance of determining NAb titers with reliable and consistent testing methods in CovCP before infusion [65,67]. A consensus concerning the choice of the assay to measure antibody levels in CovCP in clinical trials is critical to allow comparisons among studies. Several assays are currently used, such as viral plaque neutralization tests and binding antibody surrogate immunoassays (enzyme-linked immunosorbent assay [ELISA] and chemiluminescent immunoassays [CLIA]), of which 12 are considered acceptable by the US FDA to qualify CovCP units for clinical use in hospitalized patients [84].
The timing of CovCP infusion was also highly variable among the studies evaluating CovCP in patients with COVID-19. Early in the pandemic, CovCP was mainly given to severe or critically-ill patients, who were often in the ICU units and/or mechanically ventilated [20,[22][23][24][29][30][31][32]35,36,[38][39][40]44,46,47,49,[51][52][53][54][55][56]. While CP infusions may be an effective treatment option in severely ill patients suffering from other diseases, no positive effect of CovCP was observed in patients with COVID-19 at a late disease stage who were at high risk of mortality mainly from hyperinflammation (cytokine storm) or secondary infections and less from the SARS-CoV-2 infection itself [25,79]. A few studies suggested that CovCP might be beneficial when administered to patients at an earlier stage of disease [25,85,86], 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, well-defined 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 post-hospital 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 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 significantly improved survival rates [43,57], and uncontrolled case series suggested that CovCP infusions resulted in clinical improvements [60,61,63,64]. A pilot study suggested that immunosuppressed patients with COVID-19 at an early disease stage and without detectable anti-SARS-CoV-2 antibodies are potential candidates for CovCP treatment, and patients with high post-transfusion antibody titers have the highest chance of treatment success [59]. A recent review has also suggested that CovCP with high NAb titers is a safe and effective treatment for immunocompromised patients [90]. The observed benefits of CovCP in these patients could potentially be explained by their lower risk for hyperinflammation and cytokine storm and their higher risk for chronic SARS-CoV-2 infections that can be treated with CovCP infusions [59,88]. Of note, the available results in this subpopulation should be interpreted with caution because potential confounding factors, such as co-administered treatments (e.g., steroids), were not considered in the analyses. Additional studies are needed to determine whether CovCP administration prevents or favors the development of viral mutations, which were previously reported in immunocompromised patients with chronic SARS-CoV-2 infections [91,92].
The above-mentioned observations are in line with the revisions made by the FDA in March 2021 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.

What are the lessons learned for the next pandemic?
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. Fig. 1 provides a list of elements that should be considered during the implementation of a CP program for emerging viruses.
During the first months of the COVID-19 pandemic, NAb levels were not measured in CovCP units due to the clinical urgency-even if existing literature based on previous epidemics had shown that CP is beneficial only if antibody levels are high in infused units-and the disease pathophysiology was not sufficiently understood to determine the optimal treatment strategies. The first lesson that we have learned is † All publications were from 2020 or 2021.
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 of plasma collected after vaccination could play a role in case of emergence of a more aggressive variant or during the existing vaccination gap in some countries and can be helpful to be better prepared for a next wave of infections.
A second lesson learned is that early understanding of disease pathophysiology is necessary to identify target populations optimally benefiting from any treatment, including NAb-containing CP infusions. Previous studies have suggested with a low LoE that CP infusions might be beneficial in critically-ill patients affected by some respiratory viruses, such as SARS or MERS [13,[73][74][75][76][77]. For other viral infections whose life-threatening effects are not the direct result of viral cellular damage, such as COVID-19, CP infusions do not seem effective in critically-ill patients but might improve clinical outcome in specific subpopulations. For COVID-19, additional studies are needed to determine whether CovCP infusions may be beneficial at early disease stages in immunocompromised patients. These observations highlight the importance of the early characterization of the disease pathophysiology to determine the optimal timing and schedule of CP infusions and to design narrow clinical trials in targeted subpopulations. Since the disease pathophysiology is always unknown during the first months of new epidemics/pandemics, safe and broadly available approaches, such as CP infusions, remain valuable treatment options during the emerging phase. CP treatment may stop infections and should not be restricted to critically-ill patients but should be used at earlier disease stages for all patients or specific subpopulations of vulnerable patients in future pandemics/epidemics.
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 essential. Ideally, a standard protocol for RCTs evaluating CP safety and efficacy should be drafted and made publicly available and ready to be Fig. 1. Key elements that should be considered during the implementation of a CP program for emerging viruses. Footnote: Ab, antibody; CP, convalescent plasma; NAb, neutralizing antibody; RCT, randomized controlled trial. 1. Negative for antihuman leukocyte antigen or no history of pregnancy/transfusion; 2. E.g., antibodydependent enhancement of infection, transfusion-associated circulatory overload or transfusion-related acute lung injury.
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 low-income countries should also be established.

Conclusion
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 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 coadministered 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.

Data availability
No data was used for the research described in the article. Data will be made available on request.

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

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

Declaration of Competing Interest
MB, EG and AB are employees of Terumo Blood and Cell 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).