Convalescent plasma

Source: Wikipedia, the free encyclopedia.

Convalescent plasma is the blood plasma collected from a survivor of an infectious disease. Collection is typically achieved by apheresis, but in low-to-middle income countries, the treatment can be administered as convalescent whole blood. This plasma contains antibodies specific to a pathogen and can be used therapeutically by providing passive immunity when transfusing it to a newly infected patient with the same condition. Convalescent plasma can be transfused as it has been collected or become the source material for hyperimmune serum or anti-pathogen monoclonal antibodies; of relevance, while the latter consists exclusively of IgG, convalescent plasma also includes IgA and IgM, which has relevance for antibody penetration into tissues.

How it works

Antibodies

Specific antibodies to a pathogen are thought to be the primary driver of clinical benefit from convalescent plasma.[1] In the case of viral pathogens, the subset of antibodies that retain most of the activity is the one that drives viral neutralization, i.e. neutralizing antibodies, which can be quantified in a viral neutralization assay. This belief is based on dose-response clinical studies demonstrating that clinical benefit is directly related to the content of neutralizing antibodies,[2][3][4][5] and mechanistic studies that have established the antiviral activity of antibodies in convalescent plasma.[6][7] In addition to higher antibody concentrations being more effective, convalescent plasma therapy timing is essential; preparations are typically most effective when given prophylactically or early in the disease course (i.e. until pathogen replication persists or until the infected host's endogenous immune response develops).[8]

Other components of convalescent plasma

In addition to antibodies, convalescent plasma includes a mix of many different proteins and nonprotein factors that can occur in healthy individuals as well as develop in parallel with convalescence. These compounds may affect infection, coagulation, and inflammation independently of the effect of anti-pathogen antibodies.[1] Because convalescent plasma therapy is generally safe,[9] and the effects of neutralizing antibodies dominate the therapeutic response, the current understanding of these potential additional effects is limited and constitutes an area of ongoing research.[1]

Historical use of convalescent plasma

In 1890, Emil von Behring and Shibasaburo Kitasato used convalescent serum obtained from large mammals to treat infectious diseases and found that it was particularly effective at preventing and treating diphtheria.[10] Convalescent serum and plasma differ in that the former has all the coagulation components intact, but both are comparable in regards of their antibody content. Hence, the older literature is focused on serum while today most preparations use plasma. Following discovery by von Behring and Kitasato, antibody therapy garnered support worldwide as a treatment for infections. Von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901 for his discoveries.[10]

Before 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;[26] in a retrospective analysis from Hong Kong that included 80 patients, early convalescent plasma treatment (14 days between the onset of symptoms and the transfusion date) was associated with an improved prognosis vs late transfusion (after 14 days since symptom onset) in terms of a higher hospital discharge rate by day 22 (58% vs 16%).[27] A review and meta-analysis that included eight observational studies (214 total patients) with SARS found a mortality benefit associated with convalescent plasma treatment.[28] 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.[29] 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.[29]

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.[30] The first identified case occurred in June 2012 in Jeddah, Saudi Arabia, and most cases have occurred in the Arabian Peninsula.[30] 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.[31] 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.[32] 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.[33]

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.[34] 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.[35] 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.[36]

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.[37] In early 2020, convalescent plasma started to be used in isolated cases and small series in China[38] and Italy.[39] Convalescent plasma therapy was deployed at scale in the United States through a Mayo Clinic-led Expanded Access Program for convalescent plasma[40] and a subsequent Emergency Use Authorization issued by the United States Food & Drug Administration.[41] 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,[42][43][44][45][46] but most of them focused on patients already seropositive or late in the disease course[42][43][44][45][46] and/or used plasma units with insufficient antibody levels.[44][47] 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][48] which is in line with results achieved with monoclonal antibodies and small chemical antivirals.[49] 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.[50] 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.[50]

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,[51][52] 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;[53] accordingly, convalescent plasma was recommended in guidelines issued by the Infectious Disease Society of America[54] and the European Conference on Infections in Leukemia.[55] 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;[56] such double status creates heterologous immunity able to cross-react against any SARS-CoV-2 variant so far.[57]

An online petition was launched on April 27, 2022,[58] asking the World Health Organization to revise its guidelines issued in December 2021,[59] which discouraged convalescent plasma usage on the basis of evidence available until July 2021.[59]

As of June 2022 research had found no good evidence that convalescent plasma was of benefit in treating COVID-19.[60]

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

  1. ^ a b c Focosi D, Franchini M, Pirofski LA, Burnouf T, Fairweather D, Joyner MJ, Casadevall A (August 2021). "COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors". Viruses. 13 (8): 1594. doi:10.3390/v13081594. PMC 8402718. PMID 34452459.
  2. ^ Brown JF, Dye JM, Tozay S, Jeh-Mulbah G, Wohl DA, Fischer WA, et al. (July 2018). "Anti-Ebola Virus Antibody Levels in Convalescent Plasma and Viral Load After Plasma Infusion in Patients With Ebola Virus Disease". The Journal of Infectious Diseases. 218 (4): 555–562. doi:10.1093/infdis/jiy199. PMC 6927845. PMID 29659889.
  3. ^ Maor Y, Cohen D, Paran N, Israely T, Ezra V, Axelrod O, et al. (September 2020). "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". EClinicalMedicine. 26: 100525. doi:10.1016/j.eclinm.2020.100525. PMC 7480446. PMID 32923991.
  4. ^ a b Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. (February 2021). "Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults". The New England Journal of Medicine. 384 (7): 610–618. doi:10.1056/NEJMoa2033700. PMC 7793608. PMID 33406353.
  5. ^ a b Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al. (March 2021). "Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19". The New England Journal of Medicine. 384 (11): 1015–1027. doi:10.1056/NEJMoa2031893. PMC 7821984. PMID 33523609.
  6. ^ Luczkowiak J, Lasala F, Mora-Rillo M, Arribas JR, Delgado R (November 2018). "Broad Neutralizing Activity Against Ebolaviruses Lacking the Mucin-Like Domain in Convalescent Plasma Specimens From Patients With Ebola Virus Disease". The Journal of Infectious Diseases. 218 (suppl_5): S574–S581. doi:10.1093/infdis/jiy302. PMC 6249609. PMID 29939289.
  7. ^ Natarajan H, Crowley AR, Butler SE, Xu S, Weiner JA, Bloch EM, et al. (April 2021). "Markers of Polyfunctional SARS-CoV-2 Antibodies in Convalescent Plasma". mBio. 12 (2). doi:10.1128/mBio.00765-21. PMC 8092262. PMID 33879585.
  8. ^ Casadevall A, Pirofski LA, Joyner MJ (March 2021). "The Principles of Antibody Therapy for Infectious Diseases with Relevance for COVID-19". mBio. 12 (2). doi:10.1128/mBio.03372-20. PMC 8092292. PMID 33653885.
  9. ^ Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, et al. (September 2020). "Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients". Mayo Clinic Proceedings. 95 (9): 1888–1897. doi:10.1016/j.mayocp.2020.06.028. PMC 7368917. PMID 32861333.
  10. ^ a b Kaufmann SH (February 2017). "Remembering Emil von Behring: from Tetanus Treatment to Antibody Cooperation with Phagocytes". mBio. 8 (1): e00117–17. doi:10.1128/mBio.00117-17. PMC 5347343. PMID 28246359.
  11. ^ a b Casadevall A, Scharff MD (July 1995). "Return to the past: the case for antibody-based therapies in infectious diseases". Clinical Infectious Diseases. 21 (1): 150–161. doi:10.1093/clinids/21.1.150. PMC 7197598. PMID 7578724.
  12. ^ Flexner S (May 1913). "The results of the serum treatment in thirteen hundred cases of epidemic meningitis". The Journal of Experimental Medicine. 17 (5): 553–576. doi:10.1084/jem.17.5.553. PMC 2125091. PMID 19867668.
  13. ^ Casadevall A, Scharff MD (August 1994). "Serum therapy revisited: animal models of infection and development of passive antibody therapy". Antimicrobial Agents and Chemotherapy. 38 (8): 1695–1702. doi:10.1128/AAC.38.8.1695. PMC 284624. PMID 7985997.
  14. ^ Symmers D, Lewis KM (1932-09-24). "The antitoxin treatment of erysipelas: further observations". Journal of the American Medical Association. 99 (13): 1082. doi:10.1001/jama.1932.02740650040010. ISSN 0002-9955.
  15. ^ Zingher A (1924-04-12). "Convalescent whole blood, plasma and serum in prophylaxis of measles". JAMA: The Journal of the American Medical Association. 82 (15): 1180. doi:10.1001/jama.1924.02650410022011. ISSN 0098-7484.
  16. ^ Nicolle C (1918). "Pouvoir préventif du sérum d'un malade convalescent de rougeole". Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris. 42 (337).
  17. ^ Cenci F (1907). "Alcune esperienze di sieroimmunizzazione e sieroterapia nel morbillo". Rivista di Clinica e Pediatrica. 5: 1017–1025.
  18. ^ Hess AF (August 1915). "A protective therapy for mumps". American Journal of Diseases of Children. 10 (2): 99–103. doi:10.1001/archpedi.1915.04110020024005. ISSN 1072-4710.
  19. ^ Weech AA (April 1924). "The prophylaxis of varicella with convalsecents' serum =". JAMA: The Journal of the American Medical Association. 82 (16): 1245. doi:10.1001/jama.1924.02650420009004. ISSN 0098-7484.
  20. ^ Morens DM, Fauci AS (April 2007). "The 1918 influenza pandemic: insights for the 21st century". The Journal of Infectious Diseases. 195 (7): 1018–1028. doi:10.1086/511989. PMID 17330793.
  21. ^ a b Luke TC, Kilbane EM, Jackson JL, Hoffman SL (October 2006). "Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?". Annals of Internal Medicine. 145 (8): 599–609. doi:10.7326/0003-4819-145-8-200610170-00139. PMID 16940336. S2CID 2929898.
  22. ^ Enria DA, Briggiler AM, Sánchez Z (April 2008). "Treatment of Argentine hemorrhagic fever". Antiviral Research. 78 (1): 132–139. doi:10.1016/j.antiviral.2007.10.010. PMC 7144853. PMID 18054395.
  23. ^ Maiztegui JI, Fernandez NJ, de Damilano AJ (December 1979). "Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome". Lancet. 2 (8154): 1216–1217. doi:10.1016/s0140-6736(79)92335-3. PMID 92624. S2CID 2882266.
  24. ^ Ruggiero HA, Pérez Isquierdo F, Milani HA, Barri A, Val A, Maglio F, et al. (December 1986). "[Treatment of Argentine hemorrhagic fever with convalescent's plasma. 4433 cases]". Presse Médicale. 15 (45): 2239–2242. PMID 2949253.
  25. ^ Vijayanand P, Wilkins E, Woodhead M (March 2004). "Severe acute respiratory syndrome (SARS): a review". Clinical Medicine. 4 (2): 152–160. doi:10.7861/clinmedicine.4-2-152. PMC 4954004. PMID 15139736.
  26. ^ Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. (January 2005). "Use of convalescent plasma therapy in SARS patients in Hong Kong". European Journal of Clinical Microbiology & Infectious Diseases. 24 (1): 44–46. doi:10.1007/s10096-004-1271-9. PMC 7088355. PMID 15616839.
  27. ^ Cheng, Y.; Wong, R.; Soo, Y. O. Y.; Wong, W. S.; Lee, C. K.; Ng, M. H. L.; Chan, P.; Wong, K. C.; Leung, C. B.; Cheng, G. (January 2005). "Use of convalescent plasma therapy in SARS patients in Hong Kong". European Journal of Clinical Microbiology & Infectious Diseases. 24 (1): 44–46. doi:10.1007/s10096-004-1271-9. ISSN 0934-9723. PMC 7088355. PMID 15616839.
  28. ^ Mair-Jenkins, John; Saavedra-Campos, Maria; Baillie, J. Kenneth; Cleary, Paul; Khaw, Fu-Meng; Lim, Wei Shen; Makki, Sophia; Rooney, Kevin D.; Nguyen-Van-Tam, Jonathan S.; Beck, Charles R.; Convalescent Plasma Study Group (2015-01-01). "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". The Journal of Infectious Diseases. 211 (1): 80–90. doi:10.1093/infdis/jiu396. ISSN 1537-6613. PMC 4264590. PMID 25030060.
  29. ^ a b Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, et al. (February 2011). "Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection". Clinical Infectious Diseases. 52 (4): 447–456. doi:10.1093/cid/ciq106. PMC 7531589. PMID 21248066.
  30. ^ a b Azhar EI, Hui DS, Memish ZA, Drosten C, Zumla A (December 2019). "The Middle East Respiratory Syndrome (MERS)". Infectious Disease Clinics of North America. 33 (4): 891–905. doi:10.1016/j.idc.2019.08.001. PMC 7127753. PMID 31668197.
  31. ^ Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, et al. (May 2016). "Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity". Scientific Reports. 6: 25359. Bibcode:2016NatSR...625359M. doi:10.1038/srep25359. PMC 4857172. PMID 27146253.
  32. ^ Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, et al. (2018). "Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience". Antiviral Therapy. 23 (7): 617–622. doi:10.3851/IMP3243. PMID 29923831. S2CID 49315569.
  33. ^ Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, et al. (September 2016). "Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia". Emerging Infectious Diseases. 22 (9): 1554–1561. doi:10.3201/eid2209.151164. PMC 4994343. PMID 27532807.
  34. ^ Jacob ST, Crozier I, Fischer WA, Hewlett A, Kraft CS, Vega MA, et al. (February 2020). "Ebola virus disease". Nature Reviews. Disease Primers. 6 (1): 13. doi:10.1038/s41572-020-0147-3. PMC 7223853. PMID 32080199.
  35. ^ Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, et al. (March 2017). "Evaluation of convalescent whole blood for treating Ebola Virus Disease in Freetown, Sierra Leone". The Journal of Infection. 74 (3): 302–309. doi:10.1016/j.jinf.2016.11.009. PMC 7112610. PMID 27867062.
  36. ^ Kraft CS, Hewlett AL, Koepsell S, Winkler AM, Kratochvil CJ, Larson L, et al. (August 2015). "The Use of TKM-100802 and Convalescent Plasma in 2 Patients With Ebola Virus Disease in the United States". Clinical Infectious Diseases. 61 (4): 496–502. doi:10.1093/cid/civ334. PMC 4542597. PMID 25904375.
  37. ^ Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. (August 2020). "Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial". JAMA. 324 (5): 460–470. doi:10.1001/jama.2020.10044. PMC 7270883. PMID 32492084.
  38. ^ Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. (April 2020). "Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma". JAMA. 323 (16): 1582–1589. doi:10.1001/jama.2020.4783. PMC 7101507. PMID 32219428.
  39. ^ Perotti C, Baldanti F, Bruno R, Del Fante C, Seminari E, Casari S, et al. (December 2020). "Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial". Haematologica. 105 (12): 2834–2840. doi:10.3324/haematol.2020.261784. PMC 7716363. PMID 33256382.
  40. ^ Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, et al. (December 2021). "Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study". PLOS Medicine. 18 (12): e1003872. doi:10.1371/journal.pmed.1003872. PMC 8730442. PMID 34928960.
  41. ^ US Food and Drug Administration (August 23, 2020). "FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment". Food and Drug Administration.{{cite web}}: CS1 maint: url-status (link)
  42. ^ a b Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al. (February 2021). "A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia". The New England Journal of Medicine. 384 (7): 619–629. doi:10.1056/NEJMoa2031304. PMC 7722692. PMID 33232588.
  43. ^ a b Abani O, Abbas A, Abbas F, Abbas M, Abbasi S, Abbass H, et al. (RECOVERY Collaborative Group) (May 2021). "Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial". Lancet. 397 (10289): 2049–2059. doi:10.1016/S0140-6736(21)00897-7. PMC 8121538. PMID 34000257.
  44. ^ a b c Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P (October 2020). "Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)". BMJ. 371: m3939. doi:10.1136/bmj.m3939. PMC 7578662. PMID 33093056.
  45. ^ a b Bégin P, Callum J, Heddle NM, Cook R, Zeller MP, Tinmouth A, et al. (May 2021). "Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial". Trials. 22 (1): 323. doi:10.1186/s13063-021-05235-3. PMC 8094980. PMID 33947446.
  46. ^ a b Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, et al. (November 2021). "Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial". JAMA. 326 (17): 1690–1702. doi:10.1001/jama.2021.18178. PMC 8491132. PMID 34606578.
  47. ^ Focosi D, Franchini M, Pirofski LA, Burnouf T, Paneth N, Joyner MJ, Casadevall A (March 2022). "COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes". Clinical Microbiology Reviews: e0020021. doi:10.1128/cmr.00200-21. PMID 35262370. S2CID 247318284.
  48. ^ Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, et al. (May 2022). "Early Outpatient Treatment for Covid-19 with Convalescent Plasma". The New England Journal of Medicine. 386 (18): 1700–1711. doi:10.1056/NEJMoa2119657. PMC 9006786. PMID 35353960.
  49. ^ Sullivan DJ, Focosi D, Hanley D, Franchini M, Ou J, Casadevall A, Paneth N (May 2022). "Effective antiviral regimens to reduce COVID-19 hospitalizations: a systematic comparison of randomized controlled trials". medRxiv. doi:10.1101/2022.05.24.22275478. PMC 9164452. PMID 35665014.
  50. ^ a b Casadevall A, Dragotakes Q, Johnson PW, Senefeld JW, Klassen SA, Wright RS, et al. (June 2021). "Convalescent plasma use in the USA was inversely correlated with COVID-19 mortality". eLife. 10: e69866. doi:10.7554/eLife.69866. PMC 8205484. PMID 34085928.
  51. ^ U.S. Food and Drug Administration (January 24, 2022). "Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant". Food and Drug Administration.{{cite web}}: CS1 maint: url-status (link)
  52. ^ U.S. Food and Drug Administration (March 30, 2022). "FDA updates Sotrovimab emergency use authorization". FDA.{{cite journal}}: CS1 maint: url-status (link)
  53. ^ U.S. Food & Drug Administration (January 2022). "Investigational COVID-19 Convalescent Plasma". Food and Drug Administration.{{cite web}}: CS1 maint: url-status (link)
  54. ^ Infectious Disease Society of America. "IDSA Guidelines on the Treatment and Management of Patients with COVID-19".{{cite web}}: CS1 maint: url-status (link)
  55. ^ Cesaro S, Ljungman P, Mikulska M, Hirsch HH, von Lilienfeld-Toal M, Cordonnier C, et al. (June 2022). "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)". Leukemia. 36 (6): 1467–1480. doi:10.1038/s41375-022-01578-1. PMC 9053562. PMID 35488021.
  56. ^ Ordaya EE, Abu Saleh OM, Stubbs JR, Joyner MJ (January 2022). "Vax-Plasma in Patients With Refractory COVID-19". Mayo Clinic Proceedings. 97 (1): 186–189. doi:10.1016/j.mayocp.2021.11.001. PMC 8585589. PMID 34996552.
  57. ^ Focosi D, Franchini M, Joyner MJ, Casadevall A, Sullivan DJ (2021-12-25). "Analysis of anti-Omicron neutralizing antibody titers in plasma from pre-Omicron convalescents and vaccinees". medRxiv. doi:10.1101/2021.12.24.21268317. S2CID 245475195.
  58. ^ National COVID-19 Convalescent Plasma Project. "Open letter to WHO for revisions to CCP recommendations".{{cite web}}: CS1 maint: url-status (link)
  59. ^ a b Agarwal A, Rochwerg B, Lamontagne F, Siemieniuk RA, Agoritsas T, Askie L, et al. (September 2020). "A living WHO guideline on drugs for covid-19". BMJ. 370: m3379. doi:10.1136/bmj.m3379. PMID 32887691. S2CID 221498813.
  60. ^ Long B, Chavez S, Carius BM, Brady WJ, Liang SY, Koyfman A, Gottlieb M (June 2022). "Clinical update on COVID-19 for the emergency and critical care clinician: Medical management". Am J Emerg Med (Review). 56: 158–170. doi:10.1016/j.ajem.2022.03.036. PMC 8956349. PMID 35397357.