When a French aircraft carrier set sail on 22 January, 2020 for a mission of several months, its 1,769 crewmembers were unaware of a stowaway in the form of a novel virus. The SARS-CoV-2 virus, assumed in early 2020 to be a recent arrival in Europe, was already on board. Upon the ship’s return to Toulon, the main naval base of France on the Mediterranean Sea, most of the crew were confined to their barracks and 1,688 sailors participated in health monitoring. In this issue of Haematologica, Boudin and colleagues report data from this unique epidemiological setting,1 which could have hardly been better designed, if it had been set up for the purpose of studying a SARS-CoV-2 outbreak among young professionals.
After 1 month at sea, the first case of COVID-19 was recognized. Another month went by before an epidemic broke out, which forced the ship’s early return to base within 2 weeks. Several viral strains were detected by nucleotide sequencing.1 This observation could imply the embarkation of multiple sailors who were independently infected, an unlikely scenario in Europe so early in the pandemic. Possibly, only one crewmember was the source, and the initial strain evolved within the 12 weeks’ voyage while spreading among the crew.
Due to its exponential rate of spread, the SARS-CoV-2 virus rapidly infected at least 1,279 sailors, 76% of the participants of the study, whose median age was 28 years. Only 13% were female, without difference in the infection rate between males and females.1,2 This rate seemed strikingly high among young, healthy individuals,1 although it may not differ so much from that of other SARS-CoV-2 outbreaks, but rather reflected an exceptionally thorough follow-up and documentation. Only 14% of the infected participants remained asymptomatic.1 The median age of the 19 patients requiring only oxygen therapy was 45 years; the five patients admitted to intensive care units were older than 50 years. All infected sailors recovered eventually. These relatively benign clinical courses may not be representative of COVID-19 among the general population or cruise ship passengers, with a decidedly older age profile and related comorbidities.3
A PubMed search for “ABO in COVID-19” yielded more than 50 publications including reviews and metaanalyses, 4,5 documenting this possible correlation as a topic of intense research in the past 9 months.3,6 The study by Boudin et al.1 provides data leading to an important clarification: the rate of infection among young adults is independent of ABO blood group. This study can be considered the definitive conclusion on this aspect, as the quality of the epidemiological data was optimal. Studies in smaller cohorts7-10 and less well-defined epidemiological settings7-9,11 should be considered with caution, even if there are many. They are more likely to be affected by unknown cofounders. Particular precaution should be applied when COVID-19 was associated with ABO along with other blood group systems.10 Better data on ABO blood group and SARS-CoV-2 infection may not be accrued soon, and any future study would have to measure up to the quality of the study by Boudin et al.1 Can the ABO in COVID-19 topic be considered settled?
An early study did not claim an influence of ABO on the SARS-CoV-2 infection rate.12 Rather the clinical course and disease outcome in patients, once infected, may differ depending on the ABO blood group.3,6,7,9,12,13 The lack of convincing evidence for an association between ABO and outcome in some,10,14 even many, studies cannot be construed as convincing evidence for lack of such an association. The largest and most comprehensive data set so far was from patients with respiratory failure.15
This genome-wide association study15 reported a small association signal coinciding with the chromosomal position of the ABO blood group system. Outcome was better for patients with blood group O than for those with blood group A. The study design was criticized for using blood donors as the majority of controls.14 Using flawed control cohorts is a notorious cause of erroneous conclusions,16 and blood donors are generally selected in favor of blood group O.17 However, it remains to be explored whether the odds ratio introduced by this well-founded bias of Spanish6 and Italian donor recruitment, could entirely explain the odds ratio of excess death associated with blood group A.15 Even a modest influence of ABO blood group on outcome should not be neglected, as happened once the SARS-CoV-1 epidemic abated,18 but should be investigated and resolved. Minor effects are important in precision medicine enabling comprehensive treatment of patients with COVID-19.
Less than 20% of patients with COVID-19 received blood transfusions.19-21 The details of ABO matching can easily be reported,22 as they are routinely known. When properly documented, the combined data from small prospective observational studies can amount to impressive case series.23 ABO data may offer surprising insights, as cellular blood components contain residual plasma, and often a lot. For logistical reasons, components that are not ABO-identical can be transfused in a “major ABO-compatible” way (for instance, O red cells to an A recipient), without explicitly informing the hematologists. In such cases, anti-A or anti-B from the donor will bind to cell surfaces of the recipient’s tissues and form immune complexes with A or B antigens that are soluble in the recipient’s plasma.24 This pathophysiology applies particularly to the transfusion of platelet components.18
Convalescent plasma use in randomized clinical trials,25-27 in other clinical studies,28-33 and outside of them, is monitored for safety,27,34,35 best including ABO matching. Evidence is lacking to direct our practice on ABO matching of convalescent plasma. Hence, policies reflect the understanding and application of the basic principles of ABO compatibility, which have not been corroborated for COVID-19. “Minor ABO-compatible” plasma (for instance, AB plasma to an O recipient) transfers soluble A and B antigens. When bound by the recipient’s anti-A or anti-B, immune complexes are formed.24 These are a known trigger of the innate immune system,36 which receives another boost from the complement in the transfused plasma.37 Coagulation factors differ based on the patient’s ABO blood group and are, of course, also transfused by plasma.3,38 The interaction of complement and coagulation39 is not well understood in critically ill patients with COVID-19, whose potential harm from convalescent plasma should be considered and limited.40 Convalescent plasma, containing high-titer anti-SARS-CoV-2 and neutralizing antibody,41 can be tested for isoagglutinin titers, too. Convalescent plasma with high-titer anti-A or anti-B should be transfused to ABO-identical recipients,18 and a low-titer product is best for immune globulin manufacturing. Any indication to transfuse blood components containing plasma, particularly if not ABO identical, should be carefully considered and the exposure evaluated in studies.
The ABO blood group system may have some influence on disease progression, once an individual is infected by SARS-CoV-2 and falls ill. The study by Boudin et al. in its unique epidemiological setting offered convincing evidence that becoming infected with the virus was not influenced by the ABO blood group in young professionals.1 This difference is not surprising, as the mechanisms involved likely differ between infection and disease progression.
The sailors’ experience in spring 2020 should serve as a reminder: the risk of acquiring a SARS-CoV-2 infection is exceptionally high among young adults exposed to the virus in certain circumstances and no ABO blood group type can protect an individual from becoming infected.
- Boudin L, Janvier F, Bylicki O, Dutasta F.. ABO blood groups are not associated with risk of acquiring the SARS-CoV-2 infection in young adults. Haematologica. 2020; 105(12):2841-2843. https://doi.org/10.3324/haematol.2020.265066PubMedGoogle Scholar
- Takahashi T, Ellingson MK, Wong P. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020. Google Scholar
- Yamamoto F, Yamamoto M, Muñiz-Diaz E.. Blood group ABO polymorphism inhibits SARS-CoV-2 infection and affects COVID-19 progression. Vox Sang. 2020. https://doi.org/10.1111/vox.13004PubMedPubMed CentralGoogle Scholar
- Wu BB, Gu DZ, Yu JN, Yang J, Shen WQ. Association between ABO blood groups and COVID-19 infection, severity and demise: A systematic review and meta-analysis. Infect Genet Evol. 2020; 84:104485. https://doi.org/10.1016/j.meegid.2020.104485PubMedPubMed CentralGoogle Scholar
- Pourali F, Afshari M, Alizadeh-Navaei R, Javidnia J, Moosazadeh M, Hessami A.. Relationship between blood group and risk of infection and death in COVID-19: a live meta-analysis. New Microbes New Infect. 2020; 37:100743. https://doi.org/10.1016/j.nmni.2020.100743PubMedPubMed CentralGoogle Scholar
- Muñiz-Diaz E, Llopis J, Parra R. Relationship between the ABO blood group and COVID-19 susceptibility, severity and mortality in two cohorts of patients. Blood Transfusion. 2020. Google Scholar
- Wu Y, Feng Z, Li P, Yu Q.. Relationship between ABO blood group distribution and clinical characteristics in patients with COVID-19. Clin Chim Acta. 2020; 509:220-223. https://doi.org/10.1016/j.cca.2020.06.026PubMedGoogle Scholar
- Fan Q, Zhang W, Li B, Li DJ, Zhang J, Zhao F.. Association between ABO blood group system and COVID-19 susceptibility in Wuhan. Front Cell Infect Microbiol. 2020; 10:404. https://doi.org/10.3389/fcimb.2020.00404PubMedPubMed CentralGoogle Scholar
- Zalba Marcos S, Antelo ML, Galbete A, Etayo M, Ongay E, Garcia-Erce JA. Infection and thrombosis associated with COVID-19: possible role of the ABO blood group. Med Clin (Barc). 2020; S0025-7753(20):30443-30447.2712. Google Scholar
- Latz CA, DeCarlo C, Boitano L. Blood type and outcomes in patients with COVID-19. Ann Hematol. 2020; 99:2113-2118. https://doi.org/10.1007/s00277-020-04169-1PubMedPubMed CentralGoogle Scholar
- Zhao J, Yang Y, Huang H. Relationship between the ABO blood group and the COVID-19 susceptibility. Clin Infect Dis. 2020. Google Scholar
- Leaf RK, Al-Samkari H, Brenner SK, Gupta S, Leaf DE. ABO phenotype and death in critically ill patients with COVID-19. Br J Haematol. 2020. https://doi.org/10.1111/bjh.16984PubMedPubMed CentralGoogle Scholar
- Sardu C, Marfella R, Maggi P. Implications of AB0 blood group in hypertensive patients with covid-19. BMC Cardiovasc Disord. 2020; 20:373. https://doi.org/10.1186/s12872-020-01658-zPubMedPubMed CentralGoogle Scholar
- Dzik S, Eliason K, Morris EB, Kaufman RM, North CM. COVID-19 and ABO blood groups. Transfusion. 2020. Google Scholar
- Ellinghaus D, Degenhardt F, Bujanda L. Genomewide association study of severe Covid-19 with respiratory failure. Genomewide association study of severe Covid-19 with respiratory failure. N Engl J Med. 2020. Google Scholar
- Thomson G, Bodmer WF. Population stratification as an explanation of IQ and ABO association. Nature. 1975; 254(5498):363-364. https://doi.org/10.1038/254363a0PubMedGoogle Scholar
- Hirani R, Wong J, Diaz P. A national review of the clinical use of group O D- red blood cell units. Transfusion. 2017; 57(5):1254-1261. https://doi.org/10.1111/trf.14012PubMedGoogle Scholar
- Flegel WA. CoVID-19 insights from transfusion medicine. Br J Haematol. 2020; 190(5):715-717. Google Scholar
- Cai X, Ren M, Chen F, Li L, Lei H, Wang X.. Blood transfusion during the COVID-19 outbreak. Blood Transfus. 2020; 18(2):79-82. Google Scholar
- Doyle AJ, Danaee A, Furtado CI. Blood component use in critical care in patients with COVID-19 infection: a single centre experience. Br J Haematol. 2020. https://doi.org/10.1111/bjh.17007PubMedPubMed CentralGoogle Scholar
- Barriteau CM, Bochey P, Lindhom PF, Hartman K, Sumugod R, Ramsey G. Blood transfusion utilization in hospitalized COVID-19 patients. Transfusion. 2020. https://doi.org/10.1111/trf.15947PubMedPubMed CentralGoogle Scholar
- Zaidi FZ, Zaidi ARZ, Abdullah SM, Zaidi SZA. COVID-19 and the ABO blood group connection. Transfus Apher Sci. 2020. https://doi.org/10.1016/j.transci.2020.102838PubMedGoogle Scholar
- Jiang SQ, Huang QF, Xie WM, Lv C, Quan XQ. The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol. 2020; 190(1):229-e33. https://doi.org/10.1111/bjh.16817PubMedGoogle Scholar
- Flegel WA. Pathogenesis and mechanisms of antibody-mediated hemolysis. Transfusion. 2015; 55(0):S47-S58. https://doi.org/10.1111/trf.13147PubMedPubMed CentralGoogle Scholar
- Li L, Zhang W, Hu Y. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020; 324(5):460-470. https://doi.org/10.1001/jama.2020.10044PubMedPubMed CentralGoogle Scholar
- Liu Z. Errors in trial of effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19. JAMA. 2020; 324(5):518-519. https://doi.org/10.1001/jama.2020.12607PubMedGoogle Scholar
- Casadevall A, Joyner MJ, Pirofski LA. A randomized trial of convalescent plasma for COVID-19-potentially hopeful signals. JAMA. 2020; 324(5):455-457. https://doi.org/10.1001/jama.2020.10218PubMedGoogle Scholar
- Zhang B, Liu S, Tan T. Treatment with convalescent plasma for critically Ill patients with severe acute respiratory syndrome coronavirus 2 infection. Chest. 2020; 158(1):e9-e13. https://doi.org/10.1016/j.chest.2020.03.039PubMedPubMed CentralGoogle Scholar
- Duan K, Liu B, Li C. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020; 117(17):9490-9496. https://doi.org/10.1073/pnas.2004168117PubMedPubMed CentralGoogle Scholar
- Ahn JY, Sohn Y, Lee SH. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020; 35(14):e149. https://doi.org/10.3346/jkms.2020.35.e149PubMedPubMed CentralGoogle Scholar
- Ye M, Fu D, Ren Y. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020. https://doi.org/10.1002/jmv.25882PubMedPubMed CentralGoogle Scholar
- Shen C, Wang Z, Zhao F. Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA. 2020; 323(16):1582-1589. https://doi.org/10.1001/jama.2020.4783PubMedPubMed CentralGoogle Scholar
- Zeng QL, Yu ZJ, Gou JJ. Effect of convalescent plasma therapy on viral shedding and survival in patients with coronavirus disease 2019. J Infect Dis. 2020; 222(1):38-43. https://doi.org/10.1093/infdis/jiaa228PubMedPubMed CentralGoogle Scholar
- Murphy M, Estcourt L, Grant-Casey J, Dzik S.. International survey of trials of convalescent plasma to treat COVID-19 infection. Transfus Med Rev. 2020; 34(3):151-157. https://doi.org/10.1016/j.tmrv.2020.06.003PubMedPubMed CentralGoogle Scholar
- Joyner MJ, Bruno KA, Klassen SA. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc. 2020; 95(9):1888-1897. https://doi.org/10.1016/j.mayocp.2020.06.028PubMedPubMed CentralGoogle Scholar
- Birra D, Benucci M, Landolfi L. COVID 19: a clue from innate immunity. Immunol Res. 2020; 68(3):161-168. https://doi.org/10.1007/s12026-020-09137-5PubMedPubMed CentralGoogle Scholar
- Gralinski LE, Sheahan TP, Morrison TE. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio. 2018; 9(5):e01753-18. https://doi.org/10.1128/mBio.01753-18PubMedPubMed CentralGoogle Scholar
- Al-Samkari H, Karp Leaf RS, Dzik WH. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020; 136(4):489-500. https://doi.org/10.1182/blood.2020006520PubMedPubMed CentralGoogle Scholar
- Dzik S. Complement and coagulation: cross talk through time. Transfus Med Rev. 2019; 33(4):199-206. https://doi.org/10.1016/j.tmrv.2019.08.004PubMedGoogle Scholar
- Dzik S. COVID-19 convalescent plasma: now is the time for better science. Transfus Med Rev. 2020; 34(3):141-144. https://doi.org/10.1016/j.tmrv.2020.04.002PubMedPubMed CentralGoogle Scholar
- Li L, Tong X, Chen H. Characteristics and serological patterns of COVID-19 convalescent plasma donors: optimal donors and timing of donation. Transfusion. 2020. https://doi.org/10.1111/trf.15918PubMedPubMed CentralGoogle Scholar
Figures & Tables
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.