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====== Convalescent Plasma Therapy ======

===== Introduction =====

Convalescent plasma therapy, often referred to as passive antibody therapy, constitutes a therapeutic intervention wherein blood plasma derived from individuals convalescing from a specific infectious ailment is employed to treat contemporaneously afflicted patients. The principal objective of this therapy lies in conferring immediate passive immunity to the recipient by means of preformed antibodies against the causative pathogen, thereby potentially ameliorating the course of the ongoing malady. 

===== Historical Background =====

The genesis of convalescent plasma therapy can be traced to the latter part of the 19th century, finding its inaugural application during the ravages of the Spanish flu pandemic in 1918. Since its inception, this therapeutic modality has been invoked in a spectrum of infectious disease outbreaks, encompassing the H1N1 influenza pandemic of 2009, the Ebola virus scourge in West Africa in 2014, and most recently, amidst the global COVID-19 pandemic.

===== Mechanism of Action =====

Convalescent plasma is culled from individuals convalescent from the targeted infectious malady. This plasma component is enriched with antibodies, specialized proteins elicited by the immune system in response to the presence of a particular pathogenic entity. When introduced into a patient harboring an active infection, these antibodies function as vigilant sentinels, effecting the neutralization of the pathogen, impeding its replicative capacity, and buttressing the host's immune riposte.

===== Collection and Processing =====

The acquisition of convalescent plasma entails a methodical procedure. Convalescent individuals are subjected to stringent screening criteria to ensure eligibility, encompassing requisite antibody titers and the absence of concurrent infectious agents. Subsequently, plasma is garnered through the process of plasmapheresis, wherein blood is drawn, plasma is segregated from cellular constituents, and the latter are subsequently returned to the donor.

===== Indications =====

Convalescent plasma therapy finds its principal application in the combat against viral infections, typically resorted to when alternative therapeutic modalities are constrained or unavailable. It has garnered notable successes in the context of influenza, Ebola, and most prominently, amidst the formidable COVID-19 pandemic.

===== Efficacy and Contentions =====

The efficacy of convalescent plasma therapy remains a subject of sustained scientific inquiry and discourse. Its potency is contingent upon multifarious factors, including the specific infectious agent, the temporality of administration, and the quality of the procured plasma.

===== COVID-19 and Hyperimmune Convalescent Plasma Therapy =====

In 2019, a new type of coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to the outbreak of coronavirus disease 2019 (COVID-19), rapidly spreading worldwide after its initial identification in Wuhan, China. In the early months of 2020, the application of convalescent plasma began in specific cases and small-scale instances in both China and Italy. [(RefNumber1>>
authors: Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al.
title: Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial
url: https://doi.org/10.1001/jama.2020.10044
published: August 2020
journal: JAMA. 324 (5): 460–470.
)]
[(RefNumber2>>
authors: Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al.
title: Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma
url: https://doi.org/10.1001/jama.2020.4783
published: April 2020
journal: JAMA. 323 (16): 1582–1589.
)]
[(RefNumber3>>
authors: Perotti C, Baldanti F, Bruno R, Del Fante C, Seminari E, Casari S, et al.
title: Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial
url: https://doi.org/10.3324/haematol.2020.261784
published: December 2020
journal: Haematologica. 105 (12): 2834–2840.
)]
The broader implementation of convalescent plasma therapy in the United States was facilitated through a Mayo Clinic-led Expanded Access Program for convalescent plasma, [(RefNumber4>>
authors: Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, et al.
title: Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study
url: https://doi.org/10.1371/journal.pmed.1003872
published: December 2021
journal: PLOS Medicine. 18 (12): e1003872.
)]
followed by an Emergency Use Authorization granted by the United States Food & Drug Administration. [(RefNumber5>>
title: FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment
published: August 23, 2020
publisher: Food and Drug Administration.
url: https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
)]
Data derived from the Expanded Access Program indicated that patients not requiring mechanical ventilation who received high-titer convalescent plasma exhibited lower mortality rates compared to those administered low-titer convalescent plasma (14.2% vs. 22.2%). [(RefNumber15>>
authors: Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al.
title: Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19
url: https://doi.org/10.1056/NEJMoa2031893
published: March 2021
journal: The New England Journal of Medicine. 384 (11): 1015–1027.
)]

During the initial stages of the pandemic, several randomized controlled trials concluded that convalescent plasma therapy was not effective for COVID-19. Notably, most of these trials focused on patients who were already seropositive or in the advanced stages of the disease and/or used plasma units with inadequate antibody levels. [(RefNumber6>>
authors: Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al.
title: A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia
url: https://doi.org/10.1056/NEJMoa2031304
published: February 2021
journal: The New England Journal of Medicine. 384 (7): 619–629.
)]
[(RefNumber7>>
authors: Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. (RECOVERY Collaborative Group)
title: Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial
url: https://doi.org/10.1016/S0140-6736(21)00897-7
published: May 2021
journal: Lancet. 397 (10289): 2049–2059.
)]
[(RefNumber8>>
authors: Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P
title: Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)
url: https://doi.org/10.1136/bmj.m3939
published: October 2020
journal: BMJ. 371: m3939.
)]
[(RefNumber9>>
authors: Bégin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, et al.
title: Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial
url: https://doi.org/10.1186/s13063-021-05235-3
published: May 2021
journal: Trials. 22 (1): 323.
)]
[(RefNumber10>>
authors: Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, et al.
title: Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial
url: https://doi.org/10.1001/jama.2021.18178
published: November 2021
journal: JAMA. 326 (17): 1690–1702.
)] 
[(RefNumber11>>
authors: Focosi D, Franchini M, Pirofski LA, Burnouf T, Paneth N, Joyner MJ, Casadevall A
title: COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes
url: https://doi.org/10.1128/cmr.00200-21
published: March 2022
journal: Clinical Microbiology Reviews. 35 (3): e0020021.
)]
Conversely, randomized controlled trials that directed their attention towards the early administration of high-titer convalescent plasma following diagnosis demonstrated a substantial reduction in hospital admissions, ranging from approximately 50-80%. [(RefNumber16>>
authors: Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al.
title: Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults
url: https://doi.org/10.1056/NEJMoa2033700
published: February 2021
journal: The New England Journal of Medicine. 384 (7): 610–618.
)]
[(RefNumber12>>
authors: Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, et al.
title: Early Outpatient Treatment for Covid-19 with Convalescent Plasma
url: https://doi.org/10.1056/NEJMoa2119657
published: May 2022
journal: The New England Journal of Medicine. 386 (18): 1700–1711.
)]
This outcome aligns with the effectiveness achieved with monoclonal antibodies and small-molecule antiviral agents. [(RefNumber13>>
authors: Sullivan DJ, Focosi D, Hanley D, Franchini M, Ou J, Casadevall A, Paneth N
title: Effective antiviral regimens to reduce COVID-19 hospitalizations: a systematic comparison of randomized controlled trials
url: https://doi.org/10.1101/2022.05.24.22275478
published: May 2022
journal: medRxiv.
)]

An epidemiological analysis examining the utilization of convalescent plasma and subsequent mortality rates in the United States revealed a robust inverse correlation, presenting compelling evidence of its effectiveness at a population-wide level. Based on this data, it was estimated that the deployment of convalescent plasma potentially averted roughly 100,000 fatalities in the United States. [(RefNumber14>>
authors: Casadevall A, Dragotakes Q, Johnson PW, Senefeld JW, Klassen SA, Wright RS, et al.
title: Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality
url: https://doi.org/10.7554/eLife.69866
published: June 2021
journal: eLife. 10: e69866.
)]


===== Riferimenti =====

~~REFNOTES~~