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Il Plasma convalescente e' il plasma raccolto da un sopravvissuto ad una malattia infettiva. La raccolta e'tipicamente ottenuta attraverso la plasmaferesi, ma nei Paesi a reddito medio-basso, la terapia puo' essere somministrata anche come sangue intero convalescente. Questo plasma contiene anticorpi specifici contro un patogeno e puo' essere usato come terapia per fornire immunita' passiva quando trasfuso ad un paziente appena infettatosi con lo stesso microorganismo. Il plasma convalescente puo'essere trasfuso cosi' come e'stato raccolto o rappresentare il materiale di partenza per il siero iperimmune o per anticorpi monoclonali contr il patogeno; e'importante notare come, mentre questi ultimi consistono esclusivamente di IgG, il plasma include anche IgA ed IgM, il che ha rilevanza per la penetrazione degli anticorpi nei tessuti.

Come funziona

Gli anticorpi

Gli anticorpi specifici contro un patogeno sono ritenuti il fattore principale nel plasma che induce beneficio clinico.^[1] Nel caso dei virus, la sottoclasse di anticorpi che contiene la maggior parte di questa attivita'e'quella che induce la neutralizzazione del virus, ovvero gli anticorpi neutralizzanti, che puo'essere quantificata nelle prove di neutralizzazione. Questa idea si basa su studi clinic di dose-risposta che hanno dimostrato come il beneficio clinico sia correlato direttamente al contenuto di anticorpo neutralizzante,^[2]^[3]^[4]^[5] and mechanistic studies that have established the antiviral activity of antibodies in convalescent plasma.^[6]^[7] In aggiunta alle alte concentrazioni di anticorpi, er l'efficacia e'essenziale anche la tempestivita' di somministrazione; il plasma e'in generale piu'efficace quando somministrato come profilassi o precocemente nel corso della malattia (ovvero fino a quando persiste la replicazioene del patogeno o fino a quando si sviluppa la rispsota immunitaria endogena nel paziente)).^[8]

Altri componenti del plasma convalescente

In aggiunta agli anticorpi, il plasma convalescente include una miscela di molte proteine diverse e fattori che occorrono in individui sani o che si sviluppano in parallelo durante la convalescenza. Questi composti influenzano l'infezione, la coagulazione e l'infiammazione indipendentemente dall'effetto degli anticorpi anti-patogeno.^[1] Poiche'l a terapia col plasma convalescente e'in genere molto sicura,^[9] e gli effetti degli anticorpi neutralizzanti dominano la risposta terapeutica, la comprensioe attuale di questi potenziali effetti aggiuntivi e'limitata e costituisce un'area di ricerca tutt'ora in corso.^[1]

Usi storici del plasma convalescente

Nel 1890, Emil von Behring e Shibasaburo Kitasato usarono il siero convalescente ottenuto da grandi mammiferi per trattare le malattie infettive e trovarono che era particolarmente efficace nel prevenire e trattare la difterite.^[10] Il siero e il plasma convalescente differiscono perce' il primo include i fattori della coagulazion ma sono entrambi confrontabili per quel che riguarda il contenuto anticorpale. In generale, gli studi iniziali erano incentrati sul siero mentre quelli odierni sul plasma. A seguito della scoperta di von Behring e Kitasato, la terapia anticorpale ottenne un supporto mondiale come trattamento contro i microorganismi.Von Behring e' stato premiato per le sue scoperte col primo Premio Nobel per la Fisiologia o Medicina nel 1901.^[10]

Prima dello sviluppo dgli antibiotici negli anni 30, la terapia antc

the development of antimicrobial treatment in the 1930s, antibody therapy in the form of serum therapy was the primary means of treating many bacterial and viral infections.^[11] This treatment appears to have reduced the mortality of meningococcal meningitis,^[12] pneumonia,^[13] and erysipelas.^[14]  Additionally, antibody therapy seems to have been used successfully to prevent infection after exposure to measles,^[15]^[16]^[17] mumps,^[18] and chickenpox.^[19]

1918 Influenza pandemic

The 1918 Spanish influenza pandemic was caused by an H1N1 influenza virus of avian origin, and around 500 million people, or one-third of the world’s population, became infected with this virus.^[20] The Spanish influenza pandemic was the first pandemic in which convalescent plasma was used as a therapy. A 2006 meta-analysis of eight studies from the Spanish influenza pandemic, including 1,703 patients, found that infected patients who received convalescent plasma had a 21% lower absolute mortality risk than patients not treated with convalescent plasma (16% vs. 37%).^[21] Consistent with the general treatment principles of antiviral therapy, the most significant clinical and mortality benefits were noted among patients receiving convalescent serum in the early stages of the disease course.^[21]

Modern use of convalescent plasma

After the introduction of antibiotics, the use of convalescent serum or plasma as a therapy for infectious diseases has been restricted mainly to replacement therapy for patients with immunoglobulin deficiencies^[11] or in the context of viral epidemics or pandemics for which no widely available antiviral could be repurposed. Modern use has also included several randomized controlled trials providing conclusive evidence of efficacy. Selected viral epidemics or pandemics in which convalescent plasma has been used are reviewed below.

Argentine hemorrhagic fever

First identified in 1958, Argentine hemorrhagic fever is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina.^[22] Convalescent plasma has been used during Argentine hemorrhagic fever epidemics; a double-blind, randomized clinical trial conducted from 1974 to 1978 demonstrated that patients treated with convalescent plasma within eight days of disease onset had a 15.4% lower absolute mortality rate than patients who received control plasma without neutralizing antibodies to Argentine hemorrhagic fever virus (1.1% vs. 16.5%).^[23] Comparable results were described in subsequent outbreaks of Argentine hemorrhagic fever.^[24]

2003 SARS epidemic (SARS-CoV-1)

In 2003, a novel coronavirus SARS-CoV-1 led to an epidemic of severe acute respiratory syndrome.^[25] Convalescent plasma was used to treat SARS; the most extensive investigation of convalescent plasma during the outbreak involved 80 patients in Hong Kong.^[26] In that retrospective analysis, patients who received convalescent plasma were dichotomized into early and late transfusion groups, using 14 days between the onset of symptoms and the transfusion date as the cut point.^[26] Compared to the late transfusion group, the early group had an improved prognosis, as evidenced by a higher hospital discharge rate by day 22 (58% versus 16%). A meta-analysis including eight observational studies and 214 patients with SARS demonstrated a mortality benefit following transfusion of convalescent plasma.^[27] Further studies were not conducted because the pandemic was extinguished.

2009-2010 influenza pandemic

In 2009, a particular influenza strain A(H1N1)pdm09 that evaded seasonal flu vaccines caused an influenza pandemic, which was referred to as the swine flu pandemic. Convalescent plasma was used to treat individuals with severe H1N1 infections requiring intensive care.^[28] Despite usage very late in the disease course, patients treated with convalescent plasma had reduced respiratory viral burden, reduced serum cytokine responses, and reduced mortality.^[28]

2012-2015 MERS epidemics

Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by the Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is believed to have originated from bats.^[29] The first identified case occurred in June 2012 in Jeddah, Saudi Arabia, and most cases have occurred in the Arabian Peninsula.^[29] Convalescent plasma therapy has been used to treat MERS with mixed results; initial case reports and case series in the MERS epidemic failed to show a clinical benefit for patients transfused with convalescent plasma containing uncharacterized neutralizing antibody titers.^[30] Consistent with the principle that higher antibody content in convalescent plasma results in improved efficacy, a subsequent study demonstrated that transfusion of convalescent plasma containing a high MERS-CoV neutralizing antibody titer resulted in detectable concentrations of antibodies in the blood of the recipient (seroconversion). However, seroconversion was not achieved in patients who received convalescent plasma with a low neutralizing antibody titer.^[31] These findings highlight a challenge of convalescent plasma therapy, namely, that recovered survivors of viral diseases may not produce high-titer neutralizing antibodies, and thus not all convalescent plasma is equally potent.^[32]

2013 Ebola epidemic

Ebola virus disease was discovered in 1976 when two consecutive outbreaks of fatal hemorrhagic fever occurred in different parts of Central Africa.^[33] Convalescent plasma treatment was used during the 2013-2016 Ebola outbreak; a small nonrandomized study in Sierra Leone revealed significantly longer survival for patients treated with convalescent whole blood compared to patients receiving standard treatment.^[34] Furthermore, two patients with Ebola who were transferred to the U.S. were treated with convalescent plasma, and an experimental small interfering RNA drug, and both survived their infections.^[35]

2019 COVID-19 pandemic

In 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19) spread rapidly around the globe after first being identified in Wuhan, China.^[36] In early 2020, convalescent plasma started to be used in isolated cases and small series in China^[37] and Italy.^[38] Convalescent plasma therapy was deployed at scale in the United States through a Mayo Clinic-led Expanded Access Program^[39] and a subsequent Emergency Use Authorization issued by the United States Food & Drug Administration.^[40] Data from the Expanded Access Program demonstrated that among patients who were not mechanically ventilated, patients transfused with high-titer convalescent plasma had lower mortality than patients who received low-titer convalescent plasma (14.2% vs. 22.2%).^[5] Relatively early during the pandemic, several randomized controlled trials concluded that convalescent plasma therapy was not effective for COVID-19,^[41]^[42]^[43]^[44]^[45] but most of them focused on patients already seropositive or late in the disease course^[41]^[42]^[43]^[44]^[45] and/or used plasma units with insufficient antibody levels.^[43]^[46] Randomized controlled trials that instead focused on administering high-titer convalescent plasma early after diagnosis found that convalescent plasma treatment reduced hospital admission by ~50-80%,^[4]^[47] which is in line with results achieved with monoclonal antibodies and small chemical antivirals.^[48] An epidemiologic analysis of convalescent plasma use and mortality in the United States showed a strong inverse correlation, providing strong evidence of efficacy at a population level.^[49] From this data, it was estimated that the deployment of convalescent plasma had resulted in approximately 100,000 fewer deaths than had no plasma been used in the USA.^[49]

In the post-vaccine COVID-19 pandemic, a resurgence in the usage of convalescent plasma occurred starting in the spring of 2022, when the SARS-CoV-2 variant Omicron sublineages proved non-responsive to all anti-spike monoclonal antibody treatments authorized,^[50]^[51] and concerns emerged about contraindications and chronic exposure to small-chemical antivirals which had never been studied in immunocompromised patients at that point. Considering the urgent need to treat immunocompromised patients who were not protected after vaccination, the United States Food & Drug Administration re-authorized convalescent plasma for these patients^[52]; accordingly, convalescent plasma was recommended in guidelines issued by the Infectious Disease Society of America^[53] and the European Conference on Infections in Leukemia.^[54] In the context of the wide deployment of COVID-19 vaccines, a unique product that can be collected from convalescent vaccinees, dubbed “hybrid plasma” or “Vax-plasma” has been of interest^[55]; such double status creates heterologous immunity able to cross-react against any SARS-CoV-2 variant so far.^[56]

An online petition was launched on April 27,^[57] 2022 asking the World Health Organization to revise its guidelines issued on December 2021,^[58] which discourage convalescent plasma usage on the basis of evidence available until July 2021.^[58]

Regulatory status

In the European Directorate for the Quality of Medicines and HealthCare guidelines for blood component manufacturing, no monography exists for convalescent plasma yet as of 2022. Outside clinical trials, the only way thus far to prescribe convalescent plasma is so-called compassionate usage, a procedure which requires authorization by a local ethical committee. In the United States, the use of convalescent plasma for the treatment of COVID-19 remains under Food & Drug Administration Emergency Use Authorization.

References

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[:10-42] Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, etal, Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial, in Lancet, vol. 397, n. 10289, May 2021, pp. 2049–2059, DOI:10.1016/S0140-6736(21)00897-7.

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[51] U.S. Food and Drug Administration, FDA updates Sotrovimab emergency use authorization, in FDA, March 30, 2022.

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@@ Riga 1: / Riga 1: @@
+Il '''Plasma convalescente''' e' il plasma raccolto da un sopravvissuto ad una malattia infettiva. La raccolta e'tipicamente ottenuta attraverso la [[plasmaferesi]], ma nei Paesi a reddito medio-basso, la terapia puo' essere somministrata anche come sangue intero convalescente.  Questo plasma contiene anticorpi specifici contro un patogeno e puo' essere usato come terapia per fornire immunita' passiva quando trasfuso ad un paziente appena infettatosi con lo stesso microorganismo. Il plasma convalescente puo'essere trasfuso cosi' come e'stato raccolto o rappresentare il materiale di partenza per il [[siero iperimmune]] o per [[anticorpi monoclonali]] contr il patogeno; e'importante notare come, mentre questi ultimi consistono esclusivamente di IgG, il plasma include anche IgA ed IgM, il che ha rilevanza per la penetrazione degli anticorpi nei tessuti.
+[[File:Convalescent plasma.jpg|thumb|610x610px|'''Metodi per la raccolta, processazione e somministrazione del plasma convalescente'''. Il plasma viene raccolto tipicamente tramite aferesi produttiva. Dopo la raccolta, il plasma convalescente puo' essere aliquotato prima di essere conservato e usato per il trattamento. In alternativa, il plasma convalescente puo'essere combinato in pool di piu' donatori e processato in plasma convalescente di grado farmaceutico. Tecnologie per la riduzione dei patogeni, quali il trattamento con solvente/detergente od il trattamento con luce ed additivi, possono essere usate per inattivare eventuali patogeni contaminanti, inclusi virus, batteri, protozoi e leucociti. Il frazionamento del plasma puo'essere utilizzato per creare prodotti iperimmun concentrati. CP, convalescent plasma; HS, hyperimmune serum; PGCP, pharmaceutical-grade convalescent plasma; pharmaceutical-grade convalescent plasma; PRT, pathogen reduction technologies; S/D, solvent/detergent.]]
+== Come funziona ==
+=== Gli anticorpi ===
+Gli [[anticorpi]] specifici contro un patogeno sono ritenuti il fattore principale nel plasma che induce beneficio clinico.<ref name=":0">{{cite journal | vauthors = Focosi D, Franchini M, Pirofski LA, Burnouf T, Fairweather D, Joyner MJ, Casadevall A | title = COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors | journal = Viruses | volume = 13 | issue = 8 | date = August 2021 | page = 1594 | pmid = 34452459 | doi = 10.3390/v13081594 | pmc = 8402718 | doi-access = free }}</ref> Nel caso dei virus, la sottoclasse di anticorpi che contiene la maggior parte di questa attivita'e'quella che induce la neutralizzazione del virus, ovvero gli anticorpi neutralizzanti, che puo'essere quantificata nelle [[prove di neutralizzazione]]. Questa idea si basa su studi clinic di dose-risposta che hanno dimostrato come il beneficio clinico sia correlato direttamente al contenuto di [[anticorpo neutralizzante]],<ref>{{cite journal | vauthors = Brown JF, Dye JM, Tozay S, Jeh-Mulbah G, Wohl DA, Fischer WA, Cunningham CK, Rowe K, Zacharias P, van Hasselt J, Norwood DA, Thielman NM, Zak SE, Hoover DL | display-authors = 6 | title = Anti-Ebola Virus Antibody Levels in Convalescent Plasma and Viral Load After Plasma Infusion in Patients With Ebola Virus Disease | journal = The Journal of Infectious Diseases | volume = 218 | issue = 4 | pages = 555–562 | date = July 2018 | pmid = 29659889 | doi = 10.1093/infdis/jiy199 | pmc = 6927845 }}</ref><ref>{{cite journal | vauthors = Maor Y, Cohen D, Paran N, Israely T, Ezra V, Axelrod O, Shinar E, Izak M, Rahav G, Rahimi-Levene N, Bazofin BM, Gelman R, Dicker D, Brosh-Nissimov T, Megged O, Dahan D, Benov A, Paz A, Edward K, Moran A, Rogowski O, Sorkine P, Mayo A, Zimhony O, Chen J | display-authors = 6 | title = Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma | journal = EClinicalMedicine | volume = 26 | pages = 100525 | date = September 2020 | pmid = 32923991 | doi = 10.1016/j.eclinm.2020.100525 | pmc = 7480446 }}</ref><ref name=":7">{{cite journal | vauthors = Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernández Viña V, Álvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda Á, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, López Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sánchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, González M, Perez E, Kreplak N, Pastor Argüello S, Gibbons L, Althabe F, Bergel E, Polack FP | display-authors = 6 | title = Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults | journal = The New England Journal of Medicine | volume = 384 | issue = 7 | pages = 610–618 | date = February 2021 | pmid = 33406353 | doi = 10.1056/NEJMoa2033700 | pmc = 7793608 }}</ref><ref name=":8">{{cite journal | vauthors = Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, Theel ES, Wiggins CC, Bruno KA, Klompas AM, Lesser ER, Kunze KL, Sexton MA, Diaz Soto JC, Baker SE, Shepherd JR, van Helmond N, Verdun NC, Marks P, van Buskirk CM, Winters JL, Stubbs JR, Rea RF, Hodge DO, Herasevich V, Whelan ER, Clayburn AJ, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MN, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, Paneth NS, Fairweather D, Wright RS, Casadevall A | display-authors = 6 | title = Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19 | journal = The New England Journal of Medicine | volume = 384 | issue = 11 | pages = 1015–1027 | date = March 2021 | pmid = 33523609 | pmc = 7821984 | doi = 10.1056/NEJMoa2031893 }}</ref> and mechanistic studies that have established the antiviral activity of antibodies in convalescent plasma.<ref>{{cite journal | vauthors = Luczkowiak J, Lasala F, Mora-Rillo M, Arribas JR, Delgado R | title = Broad Neutralizing Activity Against Ebolaviruses Lacking the Mucin-Like Domain in Convalescent Plasma Specimens From Patients With Ebola Virus Disease | journal = The Journal of Infectious Diseases | volume = 218 | issue = suppl_5 | pages = S574–S581 | date = November 2018 | pmid = 29939289 | doi = 10.1093/infdis/jiy302 | pmc = 6249609 }}</ref><ref>{{cite journal | vauthors = Natarajan H, Crowley AR, Butler SE, Xu S, Weiner JA, Bloch EM, Littlefield K, Wieland-Alter W, Connor RI, Wright PF, Benner SE, Bonny TS, Laeyendecker O, Sullivan D, Shoham S, Quinn TC, Larman HB, Casadevall A, Pekosz A, Redd AD, Tobian AA, Ackerman ME | display-authors = 6 | title = Markers of Polyfunctional SARS-CoV-2 Antibodies in Convalescent Plasma | journal = mBio | volume = 12 | issue = 2 | date = April 2021 | pmid = 33879585 | doi = 10.1128/mBio.00765-21 | pmc = 8092262 }}</ref>  In aggiunta alle alte concentrazioni di anticorpi, er l'efficacia e'essenziale anche la tempestivita' di somministrazione; il plasma e'in generale piu'efficace quando somministrato come profilassi o precocemente nel corso della malattia (ovvero fino a quando persiste la replicazioene del patogeno o fino a quando si sviluppa la rispsota immunitaria endogena nel paziente)).<ref>{{cite journal | vauthors = Casadevall A, Pirofski LA, Joyner MJ | title = The Principles of Antibody Therapy for Infectious Diseases with Relevance for COVID-19 | journal = mBio | volume = 12 | issue = 2 | date = March 2021 | pmid = 33653885 | doi = 10.1128/mBio.03372-20 | pmc = 8092292 }}</ref>
+=== Altri componenti del plasma convalescente ===
+In aggiunta agli anticorpi, il plasma convalescente include una miscela di molte proteine diverse e fattori che occorrono in individui sani o che si sviluppano in parallelo durante la convalescenza.  Questi composti influenzano l'infezione, la coagulazione e l'infiammazione indipendentemente dall'effetto degli anticorpi anti-patogeno.<ref name=":0" /> Poiche'l a terapia col plasma convalescente e'in genere molto sicura,<ref>{{cite journal | vauthors = Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, Wiggins CC, Senefeld JW, Klompas AM, Hodge DO, Shepherd JR, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MN, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, van Helmond N, Butterfield BP, Sexton MA, Diaz Soto JC, Paneth NS, Verdun NC, Marks P, Casadevall A, Fairweather D, Carter RE, Wright RS | display-authors = 6 | title = Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients | journal = Mayo Clinic Proceedings | volume = 95 | issue = 9 | pages = 1888–1897 | date = September 2020 | pmid = 32861333 | pmc = 7368917 | doi = 10.1016/j.mayocp.2020.06.028 }}</ref> e gli effetti degli anticorpi neutralizzanti dominano la risposta terapeutica, la comprensioe attuale di questi potenziali effetti aggiuntivi e'limitata e costituisce un'area di ricerca tutt'ora in corso.<ref name=":0" />
+== Usi storici del plasma convalescente ==
+Nel  1890, [[Emil von Behring]] e [[Shibasaburo Kitasato]] usarono il [[siero convalescente]] ottenuto da grandi mammiferi per trattare le malattie infettive e trovarono che era particolarmente efficace nel prevenire e trattare la  [[difterite]].<ref name=":1">{{cite journal | vauthors = Kaufmann SH | title = Remembering Emil von Behring: from Tetanus Treatment to Antibody Cooperation with Phagocytes | journal = mBio | volume = 8 | issue = 1 | pages = e00117–17 | date = February 2017 | pmid = 28246359 | pmc = 5347343 | doi = 10.1128/mBio.00117-17 }}</ref> Il siero e il plasma convalescente differiscono perce' il primo include i fattori della coagulazion ma sono entrambi confrontabili per quel che riguarda il contenuto anticorpale. In generale, gli studi iniziali erano incentrati sul siero mentre quelli odierni sul plasma.  A seguito della scoperta di von Behring e Kitasato, la terapia anticorpale ottenne un supporto mondiale come trattamento contro i microorganismi.Von Behring e' stato premiato per le sue scoperte col primo Premio Nobel per la Fisiologia o Medicina nel 1901.<ref name=":1" />
+Prima dello sviluppo dgli antibiotici negli anni 30, la terapia antc
+ the development of antimicrobial treatment in the 1930s, antibody therapy in the form of serum therapy was the primary means of treating many bacterial and viral infections.<ref name=":2">{{cite journal | vauthors = Casadevall A, Scharff MD | title = Return to the past: the case for antibody-based therapies in infectious diseases | journal = Clinical Infectious Diseases | volume = 21 | issue = 1 | pages = 150–161 | date = July 1995 | pmid = 7578724 | doi = 10.1093/clinids/21.1.150 | pmc = 7197598 }}</ref> This treatment appears to have reduced the mortality of [[meningococcal meningitis]],<ref>{{cite journal | vauthors = Flexner S | title = The results of the serum treatment in thirteen hundred cases of epidemic meningitis | journal = The Journal of Experimental Medicine | volume = 17 | issue = 5 | pages = 553–576 | date = May 1913 | pmid = 19867668 | pmc = 2125091 | doi = 10.1084/jem.17.5.553 }}</ref> [[pneumonia]],<ref>{{cite journal | vauthors = Casadevall A, Scharff MD | title = Serum therapy revisited: animal models of infection and development of passive antibody therapy | journal = Antimicrobial Agents and Chemotherapy | volume = 38 | issue = 8 | pages = 1695–1702 | date = August 1994 | pmid = 7985997 | doi = 10.1128/AAC.38.8.1695 | pmc = 284624 }}</ref> and [[erysipelas]].<ref>{{Cite journal | vauthors = Symmers D, Lewis KM |date=1932-09-24 |title=The antitoxin treatment of erysipelas: further observations |journal=Journal of the American Medical Association |language=en |volume=99 |issue=13 |pages=1082 |doi=10.1001/jama.1932.02740650040010 |issn=0002-9955}}</ref>  Additionally, antibody therapy seems to have been used successfully to prevent infection after exposure to [[measles]],<ref>{{Cite journal | vauthors = Zingher A |date=1924-04-12 |title=Convalescent whole blood, plasma and serum in prophylaxis of measles |url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1924.02650410022011 |journal=JAMA: The Journal of the American Medical Association |language=en |volume=82 |issue=15 |pages=1180 |doi=10.1001/jama.1924.02650410022011 |issn=0098-7484}}</ref><ref>{{Cite journal | vauthors = Nicolle C |date=1918 |title=Pouvoir préventif du sérum d'un malade convalescent de rougeole |journal=Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris |volume=42 |issue=337}}</ref><ref>{{Cite journal | vauthors = Cenci F |date=1907 |title=Alcune esperienze di sieroimmunizzazione e sieroterapia nel morbillo |journal=Rivista di Clinica e Pediatrica |volume=5 |pages=1017–1025}}</ref> [[mumps|mumps,]]<ref>{{Cite journal | vauthors = Hess AF | title = A protective therapy for mumps. | journal = American Journal of Diseases of Children | date = August 1915 | volume = 10 | issue = 2 | pages = 99–103 |doi=10.1001/archpedi.1915.04110020024005 |issn=1072-4710| url = https://zenodo.org/record/1500365 }}</ref> and [[chickenpox]].<ref>{{Cite journal | vauthors = Weech AA |date= April 1924 |title= The prophylaxis of varicella with convalsecents' serum = |journal=JAMA: The Journal of the American Medical Association |language=en |volume=82 |issue=16 |pages=1245 |doi=10.1001/jama.1924.02650420009004 |issn=0098-7484}}</ref>
+=== 1918 Influenza pandemic ===
+The 1918 [[Spanish influenza]] pandemic was caused by an H1N1 influenza virus of avian origin, and around 500 million people, or one-third of the world’s population, became infected with this virus.<ref>{{cite journal | vauthors = Morens DM, Fauci AS | title = The 1918 influenza pandemic: insights for the 21st century | journal = The Journal of Infectious Diseases | volume = 195 | issue = 7 | pages = 1018–1028 | date = April 2007 | pmid = 17330793 | doi = 10.1086/511989 }}</ref>  The Spanish influenza pandemic was the first pandemic in which convalescent plasma was used as a therapy. A 2006 meta-analysis of eight studies from the Spanish influenza pandemic, including 1,703 patients, found that infected patients who received convalescent plasma had a 21% lower absolute mortality risk than patients not treated with convalescent plasma (16% vs. 37%).<ref name=":3">{{cite journal | vauthors = Luke TC, Kilbane EM, Jackson JL, Hoffman SL | title = Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? | journal = Annals of Internal Medicine | volume = 145 | issue = 8 | pages = 599–609 | date = October 2006 | pmid = 16940336 | doi = 10.7326/0003-4819-145-8-200610170-00139 | s2cid = 2929898 }}</ref> Consistent with the general treatment principles of antiviral therapy, the most significant clinical and mortality benefits were noted among patients receiving convalescent serum in the early stages of the disease course.<ref name=":3" />
+== Modern use of convalescent plasma ==
+After the introduction of antibiotics, the use of convalescent serum or plasma as a therapy for infectious diseases has been restricted mainly to replacement therapy for patients with immunoglobulin deficiencies<ref name=":2" /> or in the context of viral epidemics or pandemics for which no widely available antiviral could be repurposed. Modern use has also included several randomized controlled trials providing conclusive evidence of efficacy. Selected viral epidemics or pandemics in which convalescent plasma has been used are reviewed below.
+=== Argentine hemorrhagic fever ===
+First identified in 1958, [[Argentine hemorrhagic fever]] is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina.<ref>{{cite journal | vauthors = Enria DA, Briggiler AM, Sánchez Z | title = Treatment of Argentine hemorrhagic fever | journal = Antiviral Research | volume = 78 | issue = 1 | pages = 132–139 | date = April 2008 | pmid = 18054395 | pmc = 7144853 | doi = 10.1016/j.antiviral.2007.10.010 }}</ref> Convalescent plasma has been used during Argentine hemorrhagic fever epidemics; a double-blind, randomized clinical trial conducted from 1974 to 1978 demonstrated that patients treated with convalescent plasma within eight days of disease onset had a 15.4% lower absolute mortality rate than patients who received control plasma without neutralizing antibodies to Argentine hemorrhagic fever virus (1.1% vs. 16.5%).<ref>{{cite journal | vauthors = Maiztegui JI, Fernandez NJ, de Damilano AJ | title = Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome | journal = Lancet | volume = 2 | issue = 8154 | pages = 1216–1217 | date = December 1979 | pmid = 92624 | doi = 10.1016/s0140-6736(79)92335-3 | s2cid = 2882266 }}</ref> Comparable results were described in subsequent outbreaks of Argentine hemorrhagic fever.<ref>{{cite journal | vauthors = Ruggiero HA, Pérez Isquierdo F, Milani HA, Barri A, Val A, Maglio F, Astarloa L, Gonzalez Cambaceres C, Milani HL, Tallone JC | display-authors = 6 | title = [Treatment of Argentine hemorrhagic fever with convalescent's plasma. 4433 cases] | journal = Presse Medicale | volume = 15 | issue = 45 | pages = 2239–2242 | date = December 1986 | pmid = 2949253 }}</ref>
+=== 2003 SARS epidemic (SARS-CoV-1) ===
+In 2003, a novel coronavirus [[SARS-CoV-1]] led to an epidemic of [[severe acute respiratory syndrome]].<ref>{{cite journal | vauthors = Vijayanand P, Wilkins E, Woodhead M | title = Severe acute respiratory syndrome (SARS): a review | journal = Clinical Medicine | volume = 4 | issue = 2 | pages = 152–160 | date = March 2004 | pmid = 15139736 | pmc = 4954004 | doi = 10.7861/clinmedicine.4-2-152 }}</ref> Convalescent plasma was used to treat SARS; the most extensive investigation of convalescent plasma during the outbreak involved 80 patients in Hong Kong.<ref name=":4">{{cite journal | vauthors = Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng G | display-authors = 6 | title = Use of convalescent plasma therapy in SARS patients in Hong Kong | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 24 | issue = 1 | pages = 44–46 | date = January 2005 | pmid = 15616839 | pmc = 7088355 | doi = 10.1007/s10096-004-1271-9 }}</ref> In that retrospective analysis, patients who received convalescent plasma were dichotomized into early and late transfusion groups, using 14 days between the onset of symptoms and the transfusion date as the cut point.<ref name=":4" /> Compared to the late transfusion group, the early group had an improved prognosis, as evidenced by a higher hospital discharge rate by day 22 (58% versus 16%). A meta-analysis including eight observational studies and 214 patients with SARS demonstrated a mortality benefit following transfusion of convalescent plasma.<ref>{{cite journal | vauthors = Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Nguyen-Van-Tam JS, Beck CR | display-authors = 6 | title = 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 | journal = The Journal of Infectious Diseases | volume = 211 | issue = 1 | pages = 80–90 | date = January 2015 | pmid = 25030060 | pmc = 4264590 | doi = 10.1093/infdis/jiu396 }}</ref> Further studies were not conducted because the pandemic was extinguished.
+=== 2009-2010 influenza pandemic ===
+In 2009, a particular influenza strain [[A(H1N1)pdm09]] that evaded seasonal flu vaccines caused an influenza pandemic, which was referred to as the [[swine flu pandemic]]. Convalescent plasma was used to treat individuals with severe [[H1N1]] infections requiring intensive care.<ref name=":6">{{cite journal | vauthors = Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY | display-authors = 6 | title = Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection | journal = Clinical Infectious Diseases | volume = 52 | issue = 4 | pages = 447–456 | date = February 2011 | pmid = 21248066 | pmc = 7531589 | doi = 10.1093/cid/ciq106 }}</ref> Despite usage very late in the disease course, patients treated with convalescent plasma had reduced respiratory viral burden, reduced serum cytokine responses, and reduced mortality.<ref name=":6" />
+=== 2012-2015 MERS epidemics ===
+[[Middle East respiratory syndrome]] (MERS) is a viral respiratory infection caused by the Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is believed to have originated from bats.<ref name=":5">{{cite journal | vauthors = Azhar EI, Hui DS, Memish ZA, Drosten C, Zumla A | title = The Middle East Respiratory Syndrome (MERS) | journal = Infectious Disease Clinics of North America | volume = 33 | issue = 4 | pages = 891–905 | date = December 2019 | pmid = 31668197 | pmc = 7127753 | doi = 10.1016/j.idc.2019.08.001 }}</ref> The first identified case occurred in June 2012 in Jeddah, Saudi Arabia, and most cases have occurred in the Arabian Peninsula.<ref name=":5" /> Convalescent plasma therapy has been used to treat MERS with mixed results; initial case reports and case series in the MERS epidemic failed to show a clinical benefit for patients transfused with convalescent plasma containing uncharacterized neutralizing antibody titers.<ref>{{cite journal | vauthors = Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, Shin HM, Choi JY, Inn KS, Kim JH, Moon JY, Choi MS, Cho NH, Kim YS | display-authors = 6 | title = Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity | journal = Scientific Reports | volume = 6 | pages = 25359 | date = May 2016 | pmid = 27146253 | pmc = 4857172 | doi = 10.1038/srep25359 | bibcode = 2016NatSR...625359M }}</ref> Consistent with the principle that higher antibody content in convalescent plasma results in improved efficacy, a subsequent study demonstrated that transfusion of convalescent plasma containing a high MERS-CoV neutralizing antibody titer resulted in detectable concentrations of antibodies in the blood of the recipient ([[seroconversion]]). However, seroconversion was not achieved in patients who received convalescent plasma with a low neutralizing antibody titer.<ref>{{cite journal | vauthors = Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, Kim YJ, Park JK, Chung CR, Kang ES, Cho D, Müller MA, Drosten C, Kang CI, Chung DR, Song JH, Peck KR | display-authors = 6 | title = Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience | journal = Antiviral Therapy | volume = 23 | issue = 7 | pages = 617–622 | date = 2018 | pmid = 29923831 | doi = 10.3851/IMP3243 | s2cid = 49315569 }}</ref> These findings highlight a challenge of convalescent plasma therapy, namely, that recovered survivors of viral diseases may not produce high-titer neutralizing antibodies, and thus not all convalescent plasma is equally potent.<ref>{{cite journal | vauthors = Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-Omari A, Al-Hameed F, Hayden FG, Fowler R, Bouchama A, Shindo N, Al-Khairy K, Carson G, Taha Y, Sadat M, Alahmadi M | display-authors = 6 | title = Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia | journal = Emerging Infectious Diseases | volume = 22 | issue = 9 | pages = 1554–1561 | date = September 2016 | pmid = 27532807 | pmc = 4994343 | doi = 10.3201/eid2209.151164 }}</ref>
+=== 2013 Ebola epidemic ===
+[[Ebola virus disease]] was discovered in 1976 when two consecutive outbreaks of fatal hemorrhagic fever occurred in different parts of Central Africa.<ref>{{cite journal | vauthors = Jacob ST, Crozier I, Fischer WA, Hewlett A, Kraft CS, Vega MA, Soka MJ, Wahl V, Griffiths A, Bollinger L, Kuhn JH | display-authors = 6 | title = Ebola virus disease | journal = Nature Reviews. Disease Primers | volume = 6 | issue = 1 | pages = 13 | date = February 2020 | pmid = 32080199 | pmc = 7223853 | doi = 10.1038/s41572-020-0147-3 }}</ref> Convalescent plasma treatment was used during the 2013-2016 Ebola outbreak; a small nonrandomized study in Sierra Leone revealed significantly longer survival for patients treated with convalescent whole blood compared to patients receiving standard treatment.<ref>{{cite journal | vauthors = Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, Baker S, Nicol S, Conton B, Johnson W, Abiri OT, Kargbo O, Kamara P, Goba A, Russell JB, Gevao SM | display-authors = 6 | title = Evaluation of convalescent whole blood for treating Ebola Virus Disease in Freetown, Sierra Leone | journal = The Journal of Infection | volume = 74 | issue = 3 | pages = 302–309 | date = March 2017 | pmid = 27867062 | pmc = 7112610 | doi = 10.1016/j.jinf.2016.11.009 }}</ref> Furthermore, two patients with Ebola who were transferred to the U.S. were treated with convalescent plasma, and an experimental [[small interfering RNA]] drug, and both survived their infections.<ref>{{cite journal | vauthors = Kraft CS, Hewlett AL, Koepsell S, Winkler AM, Kratochvil CJ, Larson L, Varkey JB, Mehta AK, Lyon GM, Friedman-Moraco RJ, Marconi VC, Hill CE, Sullivan JN, Johnson DW, Lisco SJ, Mulligan MJ, Uyeki TM, McElroy AK, Sealy T, Campbell S, Spiropoulou C, Ströher U, Crozier I, Sacra R, Connor MJ, Sueblinvong V, Franch HA, Smith PW, Ribner BS | display-authors = 6 | title = The Use of TKM-100802 and Convalescent Plasma in 2 Patients With Ebola Virus Disease in the United States | journal = Clinical Infectious Diseases | volume = 61 | issue = 4 | pages = 496–502 | date = August 2015 | pmid = 25904375 | pmc = 4542597 | doi = 10.1093/cid/civ334 }}</ref>
+=== 2019 COVID-19 pandemic ===
+In 2019, a novel coronavirus, [[severe acute respiratory syndrome coronavirus 2]] (SARS-CoV-2), causing [[coronavirus disease 2019]] (COVID-19) spread rapidly around the globe after first being identified in Wuhan, China.<ref>{{cite journal | vauthors = Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C, Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Wang J, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wang J, Wu Y, Liu Z | display-authors = 6 | title = Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial | journal = JAMA | volume = 324 | issue = 5 | pages = 460–470 | date = August 2020 | pmid = 32492084 | pmc = 7270883 | doi = 10.1001/jama.2020.10044 }}</ref> In early 2020, convalescent plasma started to be used in isolated cases and small series in China<ref>{{cite journal | vauthors = Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L | display-authors = 6 | title = Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma | journal = JAMA | volume = 323 | issue = 16 | pages = 1582–1589 | date = April 2020 | pmid = 32219428 | pmc = 7101507 | doi = 10.1001/jama.2020.4783 }}</ref> and Italy.<ref>{{cite journal | vauthors = Perotti C, Baldanti F, Bruno R, Del Fante C, Seminari E, Casari S, Percivalle E, Glingani C, Musella V, Belliato M, Garuti M, Meloni F, Frigato M, Di Sabatino A, Klersy C, De Donno G, Franchini M | display-authors = 6 | title = Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial | journal = Haematologica | volume = 105 | issue = 12 | pages = 2834–2840 | date = December 2020 | pmid = 33256382 | pmc = 7716363 | doi = 10.3324/haematol.2020.261784 }}</ref> Convalescent plasma therapy was deployed at scale in the United States through a Mayo Clinic-led Expanded Access Program<ref>{{cite journal | vauthors = Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, Klassen SA, Klompas AM, Sexton MA, Diaz Soto JC, Grossman BJ, Tobian AA, Goel R, Wiggins CC, Bruno KA, van Buskirk CM, Stubbs JR, Winters JL, Casadevall A, Paneth NS, Shaz BH, Petersen MM, Sachais BS, Buras MR, Wieczorek MA, Russoniello B, Dumont LJ, Baker SE, Vassallo RR, Shepherd JR, Young PP, Verdun NC, Marks P, Haley NR, Rea RF, Katz L, Herasevich V, Waxman DA, Whelan ER, Bergman A, Clayburn AJ, Grabowski MK, Larson KF, Ripoll JG, Andersen KJ, Vogt MN, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, Buchholtz ZA, Pletsch MC, Wright K, Greenshields JT, Joyner MJ, Wright RS, Carter RE, Fairweather D | display-authors = 6 | title = Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study | journal = PLOS Medicine | volume = 18 | issue = 12 | pages = e1003872 | date = December 2021 | pmid = 34928960 | pmc = 8730442 | doi = 10.1371/journal.pmed.1003872 }}</ref> and a subsequent Emergency Use Authorization issued by the United States Food & Drug Administration.<ref>{{Cite web |last=US Food and Drug Administration |date=August 23, 2020 |title=FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment |website=[[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 |url-status=live}}</ref> Data from the Expanded Access Program demonstrated that among patients who were not mechanically ventilated, patients transfused with high-titer convalescent plasma had lower mortality than patients who received low-titer convalescent plasma (14.2% vs. 22.2%).<ref name=":8" /> Relatively early during the pandemic, several randomized controlled trials concluded that convalescent plasma therapy was not effective for COVID-19,<ref name=":9">{{cite journal | vauthors = Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, Savoy N, Giunta DH, Pérez LG, Sánchez MD, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH | display-authors = 6 | title = A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia | journal = The New England Journal of Medicine | volume = 384 | issue = 7 | pages = 619–629 | date = February 2021 | pmid = 33232588 | pmc = 7722692 | doi = 10.1056/NEJMoa2031304 }}</ref><ref name=":10">{{cite journal | vauthors = Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, etal | collaboration = RECOVERY Collaborative Group | title = Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial | journal = Lancet | volume = 397 | issue = 10289 | pages = 2049–2059 | date = May 2021 | pmid = 34000257 | pmc = 8121538 | doi = 10.1016/S0140-6736(21)00897-7 }}</ref><ref name=":11">{{cite journal | vauthors = 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) | journal = BMJ | volume = 371 | pages = m3939 | date = October 2020 | pmid = 33093056 | pmc = 7578662 | doi = 10.1136/bmj.m3939 }}</ref><ref name=":12">{{cite journal | vauthors = Bégin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, Fergusson DA, Cushing MM, Glesby MJ, Chassé M, Devine DV, Robitalle N, Bazin R, Shehata N, Finzi A, McGeer A, Scales DC, Schwartz L, Turgeon AF, Zarychanski R, Daneman N, Carl R, Amorim L, Gabe C, Ellis M, Sachais BS, Loftsgard KC, Jamula E, Carruthers J, Duncan J, Lucier K, Li N, Liu Y, Armali C, Kron A, Modi D, Auclair MC, Cerro S, Avram M, Arnold DM | display-authors = 6 | title = Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial | journal = Trials | volume = 22 | issue = 1 | pages = 323 | date = May 2021 | pmid = 33947446 | pmc = 8094980 | doi = 10.1186/s13063-021-05235-3 }}</ref><ref name=":13">{{cite journal | vauthors = Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJ, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DF, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, Shankar-Hari M | display-authors = 6 | title = Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial | journal = JAMA | volume = 326 | issue = 17 | pages = 1690–1702 | date = November 2021 | pmid = 34606578 | pmc = 8491132 | doi = 10.1001/jama.2021.18178 }}</ref> but most of them focused on patients already seropositive or late in the disease course<ref name=":9" /><ref name=":10" /><ref name=":11" /><ref name=":12" /><ref name=":13" /> and/or used plasma units with insufficient antibody levels.<ref name=":11" /><ref>{{cite journal | vauthors = 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 | journal = Clinical Microbiology Reviews | pages = e0020021 | date = March 2022 | pmid = 35262370 | doi = 10.1128/cmr.00200-21 | s2cid = 247318284 }}</ref> Randomized controlled trials that instead focused on administering high-titer convalescent plasma early after diagnosis found that convalescent plasma treatment reduced hospital admission by ~50-80%,<ref name=":7" /><ref>{{cite journal | vauthors = Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, Heath SL, Levine AC, Meisenberg BR, Spivak ES, Anjan S, Huaman MA, Blair JE, Currier JS, Paxton JH, Gerber JM, Petrini JR, Broderick PB, Rausch W, Cordisco ME, Hammel J, Greenblatt B, Cluzet VC, Cruser D, Oei K, Abinante M, Hammitt LL, Sutcliffe CG, Forthal DN, Zand MS, Cachay ER, Raval JS, Kassaye SG, Foster EC, Roth M, Marshall CE, Yarava A, Lane K, McBee NA, Gawad AL, Karlen N, Singh A, Ford DE, Jabs DA, Appel LJ, Shade DM, Ehrhardt S, Baksh SN, Laeyendecker O, Pekosz A, Klein SL, Casadevall A, Tobian AA, Hanley DF | display-authors = 6 | title = Early Outpatient Treatment for Covid-19 with Convalescent Plasma | journal = The New England Journal of Medicine | volume = 386 | issue = 18 | pages = 1700–1711 | date = May 2022 | pmid = 35353960 | pmc = 9006786 | doi = 10.1056/NEJMoa2119657 }}</ref> which is in line with results achieved with monoclonal antibodies and small chemical antivirals.<ref>{{cite document | vauthors = 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 | work = medRxiv | date = May 2022 | pmid = 35665014 | pmc = 9164452 | doi = 10.1101/2022.05.24.22275478 }}</ref> An epidemiologic analysis of convalescent plasma use and mortality in the United States showed a strong inverse correlation, providing strong evidence of efficacy at a population level.<ref name=":14">{{cite journal | vauthors = Casadevall A, Dragotakes Q, Johnson PW, Senefeld JW, Klassen SA, Wright RS, Joyner MJ, Paneth N, Carter RE | display-authors = 6 | title = Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality | journal = eLife | volume = 10 | pages = e69866 | date = June 2021 | pmid = 34085928 | pmc = 8205484 | doi = 10.7554/eLife.69866 }}</ref> From this data, it was estimated that the deployment of convalescent plasma had resulted in approximately 100,000 fewer deaths than had no plasma been used in the USA.<ref name=":14" />
+In the post-vaccine COVID-19 pandemic, a resurgence in the usage of convalescent plasma occurred starting in the spring of 2022, when the SARS-CoV-2 variant Omicron sublineages proved non-responsive to all anti-spike monoclonal antibody treatments authorized,<ref>{{Cite web |last=U.S. Food and Drug Administration |date=January 24, 2022 |title=Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant |website=[[Food and Drug Administration]] |url=https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron |url-status=live}}</ref><ref>{{Cite journal |last=U.S. Food and Drug Administration |date=March 30, 2022 |title=FDA updates Sotrovimab emergency use authorization |journal=FDA |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization |url-status=live}}</ref> and concerns emerged about contraindications and chronic exposure to small-chemical antivirals which had never been studied in immunocompromised patients at that point. Considering the urgent need to treat immunocompromised patients who were not protected after vaccination, the United States Food & Drug Administration re-authorized convalescent plasma for these patients<ref>{{Cite web |last=U.S. Food & Drug Administration |date=January 2022 |title=Investigational COVID-19 Convalescent Plasma |website=[[Food and Drug Administration]] |url=https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-covid-19-convalescent-plasma |url-status=live}}</ref>; accordingly, convalescent plasma was recommended in guidelines issued by the Infectious Disease Society of America<ref>{{Cite web |last=Infectious Disease Society of America |title=IDSA Guidelines on the Treatment and Management of Patients with COVID-19 |url=https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ |url-status=live}}</ref> and the European Conference on Infections in Leukemia.<ref>{{cite journal | vauthors = Cesaro S, Ljungman P, Mikulska M, Hirsch HH, von Lilienfeld-Toal M, Cordonnier C, Meylan S, Mehra V, Styczynski J, Marchesi F, Besson C, Baldanti F, Masculano RC, Beutel G, Einsele H, Azoulay E, Maertens J, de la Camara R, Pagano L | display-authors = 6 | title = Recommendations for the management of COVID-19 in patients with haematological malignancies or haematopoietic cell transplantation, from the 2021 European Conference on Infections in Leukaemia (ECIL 9) | journal = Leukemia | volume = 36 | issue = 6 | pages = 1467–1480 | date = June 2022 | pmid = 35488021 | pmc = 9053562 | doi = 10.1038/s41375-022-01578-1 }}</ref> In the context of the wide deployment of COVID-19 vaccines, a unique product that can be collected from convalescent vaccinees, dubbed “hybrid plasma” or “Vax-plasma” has been of interest<ref>{{cite journal | vauthors = Ordaya EE, Abu Saleh OM, Stubbs JR, Joyner MJ | title = Vax-Plasma in Patients With Refractory COVID-19 | journal = Mayo Clinic Proceedings | volume = 97 | issue = 1 | pages = 186–189 | date = January 2022 | pmid = 34996552 | pmc = 8585589 | doi = 10.1016/j.mayocp.2021.11.001 }}</ref>; such double status creates heterologous immunity able to cross-react against any SARS-CoV-2 variant so far.<ref>{{Cite document | vauthors = Focosi D, Franchini M, Joyner MJ, Casadevall A, Sullivan DJ |date=2021-12-25 |title=Analysis of anti-Omicron neutralizing antibody titers in plasma from pre-Omicron convalescents and vaccinees | work = medRxiv |language=en |doi=10.1101/2021.12.24.21268317|s2cid=245475195 }}</ref>
+An online petition was launched on April 27,<ref>{{Cite web |last=National COVID-19 Convalescent Plasma Project |title=Open letter to WHO for revisions to CCP recommendations |url=https://ccpp19.org/ |url-status=live}}</ref> 2022 asking the World Health Organization to revise its guidelines issued on December 2021,<ref name=":16">{{cite journal | vauthors = Agarwal A, Rochwerg B, Lamontagne F, Siemieniuk RA, Agoritsas T, Askie L, Lytvyn L, Leo YS, Macdonald H, Zeng L, Amin W, Barragan FA, Bausch FJ, Burhan E, Calfee CS, Cecconi M, Chanda D, Dat VQ, De Sutter A, Du B, Freedman S, Geduld H, Gee P, Gotte M, Harley N, Hashimi M, Hunt B, Jehan F, Kabra SK, Kanda S, Kim YJ, Kissoon N, Krishna S, Kuppalli K, Kwizera A, Lado Castro-Rial M, Lisboa T, Lodha R, Mahaka I, Manai H, Mino G, Nsutebu E, Preller J, Pshenichnaya N, Qadir N, Relan P, Sabzwari S, Sarin R, Shankar-Hari M, Sharland M, Shen Y, Ranganathan SS, Souza JP, Stegemann M, Swanstrom R, Ugarte S, Uyeki T, Venkatapuram S, Vuyiseka D, Wijewickrama A, Tran L, Zeraatkar D, Bartoszko JJ, Ge L, Brignardello-Petersen R, Owen A, Guyatt G, Diaz J, Kawano-Dourado L, Jacobs M, Vandvik PO | display-authors = 6 | title = A living WHO guideline on drugs for covid-19 | journal = BMJ | volume = 370 | pages = m3379 | date = September 2020 | pmid = 32887691 | doi = 10.1136/bmj.m3379 | s2cid = 221498813 }}</ref> which discourage convalescent plasma usage on the basis of evidence available until July 2021.<ref name=":16" />
+== Regulatory status ==
+In the European Directorate for the Quality of Medicines and HealthCare guidelines for blood component manufacturing, no monography exists for convalescent plasma yet as of 2022. Outside clinical trials, the only way thus far to prescribe convalescent plasma is so-called compassionate usage, a procedure which requires authorization by a local ethical committee. In the United States, the use of convalescent plasma for the treatment of COVID-19 remains under Food & Drug Administration Emergency Use Authorization.
+== References ==
+{{Reflist}}
 #RINVIA[[Siero convalescente]]

Plasma convalescente: differenze tra le versioni

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1918 Influenza pandemic

Modern use of convalescent plasma

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Plasma convalescente: differenze tra le versioni

Versione delle 09:40, 8 giu 2022

Come funziona

Gli anticorpi

Altri componenti del plasma convalescente

Usi storici del plasma convalescente

1918 Influenza pandemic

Modern use of convalescent plasma

Argentine hemorrhagic fever

2003 SARS epidemic (SARS-CoV-1)

2009-2010 influenza pandemic

2012-2015 MERS epidemics

2013 Ebola epidemic

2019 COVID-19 pandemic

Regulatory status

References

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