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Rethinking the role of COVID-19 convalescent plasma in the critically ill

      Abbreviations:

      convalescent (convalescent), coronavirus (coronavirus), plasma (plasma), antibody (antibody)

      Keywords

      An axiom of antibody therapy for infectious diseases that dates to the early 20th century is that efficacy requires treatment early in the course of disease with preparations that contain sufficient quantities of specific immunoglobulins to mediate a biological effect [
      • Casadevall A.
      • Pirofski L.A.
      • Joyner M.J.
      The principles of antibody therapy for infectious diseases with relevance for COVID-19.
      ]. This principle was validated during the COVID-19 pandemic with COVID-19 convalescent plasma (CCP) and monoclonal antibodies to SARS-CoV-2, which were found to be more effective in ambulatory patients [
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • et al.
      Early high-titer plasma therapy to prevent severe covid-19 in older adults.
      ,
      • Sullivan D.J.
      • Gebo K.A.
      • Shoham S.
      • et al.
      Early outpatient treatment for covid-19 with convalescent plasma.
      ] than inpatients [
      • Ortigoza M.B.
      • Yoon H.
      • Goldfeld K.S.
      • et al.
      Efficacy and safety of COVID-19 convalescent plasma in hospitalized patients: a randomized clinical trial.
      ]. Hence, the report of Chowdhry et al. [
      • Chowdhry M.
      • Hussain M.
      • Singh P.
      • et al.
      Convalescent plasma – an insight into a novel treatment of covid-19 ICU patients.
      ], which suggests that some patients in intensive care units may benefit from CCP, runs counter to considerable evidence that CCP is not effective in critically ill patients. However, before going further, we must note that the Chowdhry et. al., report is an observational study in which all patients received CCP, some of which was low quality, and the data were not adjusted for other medications (e.g., corticosteroids) or patient factors. Nonetheless, the possibility that CCP could be beneficial in some critically ill patients is intriguing, because it challenges current dogma that CCP efficacy is limited to the early phase of COVID-19, and hypothesis generating, because the therapeutic armamentarium for such patients remains limited. With these caveats in mind, we consider mechanisms by which CCP could be beneficial in critically ill patients.
      COVID-19 pathogenesis is characterized by an early virologic phase that results from viral infection with replication in multiple tissues, including the lungs, followed by an inflammatory phase during which the immune response to the virus can damage tissues and impair function, e.g., pulmonary inflammation that interferes with gas exchange. CCP contains antibodies to SARS-CoV-2, which are responsible for its biological activity. Its ability to neutralize SARS-CoV-2 has been known since early in the pandemic when multiple studies showed a reduction in the viral loads of patients treated with CCP, even critically ill patients in whom it did not improve outcomes or affect survival. The ability of CCP to improve patient outcomes was firmly established when knowledge of COVID-19 pathogenesis was used to select patients with short symptom durations as a proxy for the viral phase for therapy [
      • Libster R.
      • Perez Marc G.
      • Wappner D.
      • et al.
      Early high-titer plasma therapy to prevent severe covid-19 in older adults.
      ,
      • Sullivan D.J.
      • Gebo K.A.
      • Shoham S.
      • et al.
      Early outpatient treatment for covid-19 with convalescent plasma.
      ]. Antiviral effects of CCP are observed in patients with and without their own antibody responses [
      • Marconato M.
      • Abela I.A.
      • Hauser A.
      • et al.
      Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.
      ] and its clinical efficacy has been demonstrated in patients who do not produce their own SARS-CoV-2 antibodies, such as those with hematological malignancy [
      • Thompson M.A.
      • Henderson J.P.
      • Shah P.K.
      • et al.
      Association of convalescent plasma therapy with survival in patients with hematologic cancers and COVID-19.
      ]. However, the benefit of CCP may not be limited to antibody neutralization as it also contains non-neutralizing antibodies and cytokines and exosomes that can mediate immunomodulatory properties [
      • Focosi D.
      • Franchini M.
      • Pirofski L.A.
      • et al.
      COVID-19 convalescent plasma is more than neutralizing antibodies: a narrative review of potential beneficial and detrimental co-factors.
      ]. Thus, it is not surprising that CCP therapy also associates with a reduction in serum markers of inflammation [
      • Bandopadhyay P.
      • Rozario R.
      • Lahiri A.
      • et al.
      Nature and dimensions of the systemic hyper-inflammation and its attenuation by convalescent plasma in severe COVID-19.
      ] and anti-inflammatory signatures [
      • Beraud M.
      • Hashami S.A.
      • Lozano M.
      • Bah A.
      • Keith P.
      Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome.
      ] in critically ill patients. Hence, based on its ability to exert antiviral as well as anti-inflammatory activity [
      • Herman J.D.
      • Wang C.
      • Loos C.
      • et al.
      Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response.
      ], CCP could conceivably improve patient outcomes by neutralizing residual virus and reducing inflammation through a reduction in viral load and/or by dampening inflammation via anti-inflammatory cytokines or Fc-mediated antibody functional activity. While its neutralizing activity may be most prominent in the viral phase, CCP Fc-mediated antibody functions, which can dampen inflammation and enhance clearance of infected cells, could be beneficial in the viral as well as the inflammatory phase if virus is present.
      A review of published clinical evidence supports the hypothesis that CCP can be beneficial in some critically ill patients with COVID-19. A propensity score-matched study that investigated CCP efficacy in patients who were treated before or after 6 days of hospital admission found a benefit of CCP in the early group, in which 40 % were mechanically ventilated [
      • Briggs N.
      • Gormally M.V.
      • Li F.
      • et al.
      Early but not late convalescent plasma is associated with better survival in moderate-to-severe COVID-19.
      ]. In a subgroup analysis of a small (74 patient) randomized controlled (RCT) trial that used 4:1 randomization to CCP or standard plasma, there was a statistically significant reduction in mortality of patients treated with CCP who were intubated at baseline, although there were only 5 CCP- and 3 standard plasma-treated patients in this analysis [
      • Bennett-Guerrero E.
      • Romeiser J.L.
      • Talbot L.R.
      • et al.
      Severe acute respiratory syndrome coronavirus 2 convalescent plasma versus standard plasma in coronavirus disease 2019 infected hospitalized patients in New York: a double-blind randomized trial.
      ]. Another RCT that showed an overall reduction in mortality for CCP-treated patients also included a large proportion of critically ill patients in the intensive care unit [
      • O'Donnell M.R.
      • Grinsztejn B.
      • Cummings M.J.
      • et al.
      A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19.
      ]. However, larger RCTs have shown no mortality benefit in mechanically ventilated or non-ventilated critically ill patients [
      • Horby P.W.
      • Estcourt L.
      • Peto L.
      • et al.
      Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ].
      Given hints of efficacy in some studies of critically ill patients and evidence that CCP can have antiviral and anti-inflammatory effects, it is logical to posit that some patients may benefit from CCP even if they are outside the ‘early’ viral phase and have clinical manifestations of the inflammatory phase of COVID-19. In support of this hypothesis, a machine learning-based model (Treatment Benefit index (TBI)) that was designed to predict which patients might benefit from CCP based on their oxygen requirement and COVID-19 risk factors, identified profiles of critically ill patients in whom CCP may be beneficial [
      • Park H.
      • Tarpey T.
      • Liu M.
      • et al.
      Development and validation of a treatment benefit index to identify hospitalized patients with COVID-19 who may benefit from convalescent plasma.
      ]. Blood type, which was found to associate with CCP benefit in the Chowdhry study [
      • Chowdhry M.
      • Hussain M.
      • Singh P.
      • et al.
      Convalescent plasma – an insight into a novel treatment of covid-19 ICU patients.
      ], is an optional component of the TBI. Patient heterogeneity and the many factors that affect the course of COVID-19 make the design of a prospective study of CCP in this population challenging. Nonetheless, given its excellent safety profile, such an endeavor may be worthy of consideration if disease courses like those observed at the onset of the pandemic occur again. We note that while the TBI suggests CCP may be detrimental in some critically ill patients [
      • Park H.
      • Tarpey T.
      • Liu M.
      • et al.
      Development and validation of a treatment benefit index to identify hospitalized patients with COVID-19 who may benefit from convalescent plasma.
      ], it could be used to select patients who are likely to benefit for a study.
      The study of Chowdhry et al. [
      • Chowdhry M.
      • Hussain M.
      • Singh P.
      • et al.
      Convalescent plasma – an insight into a novel treatment of covid-19 ICU patients.
      ] reminds us that we should not automatically dismiss the possible benefit of CCP in critically ill patients or neglect its likely anti-inflammatory activity. The latter is deserving of consideration given increasing evidence that corticosteroid therapy can be detrimental in some patients with COVID-19 [
      • Crothers K.
      • DeFaccio R.
      • Tate J.
      • et al.
      Dexamethasone in hospitalised COVID-19 patients not on intensive respiratory support.
      ]. The ample hints in the literature that some critically ill patients benefit from CCP, combined with biological plausibility that it mediates antiviral activity [
      • Marconato M.
      • Abela I.A.
      • Hauser A.
      • et al.
      Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.
      ], including via Fc mediated functions [
      • Herman J.D.
      • Wang C.
      • Loos C.
      • et al.
      Functional convalescent plasma antibodies and pre-infusion titers shape the early severe COVID-19 immune response.
      ,
      • Natarajan H.
      • Crowley A.R.
      • Butler S.E.
      • et al.
      Markers of polyfunctional SARS-CoV-2 antibodies in convalescent plasma.
      ], and dampens the inflammatory response [
      • Bandopadhyay P.
      • Rozario R.
      • Lahiri A.
      • et al.
      Nature and dimensions of the systemic hyper-inflammation and its attenuation by convalescent plasma in severe COVID-19.
      ], suggests that further studies of CCP in critically ill patients are warranted. However, we note that our understanding of the conditions in which CCP could be effective remains limited because our knowledge of SARS-CoV-2 pathogenesis is still evolving. Nonetheless, despite the tremendous therapeutic advances during the pandemic, the mortality of critically ill COVID-19 patients remains unacceptably high. Consequently, the identification of critically ill patients who could benefit from CCP would provide an opportunity to further reduce mortality with an agent that to date has a stellar safety profile. Although extensive real world data has identified the early phase of COVID-19 as a time when CCP is beneficial, data mining to identify patients who benefit despite being critically ill may provide clues to populations in which CCP could be formally tested in an RCT.

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