https://orcid.org/0000-0001-9740-2994
Figures
Abstract
Methods
Following STROBE guidance for observational research, we explored the distribution of ABO blood group in patients hospitalized for acute COVID-19 and in those with Long COVID. Contingency tables were made and risk factors were explored using crude and adjusted Mantle-Haentzel odds ratios (OR and 95% CI).
Results
Up to September 2022, there were a total of 5,832 acute COVID-19 hospitalizations in our hospital, corresponding to 5,503 individual patients, of whom blood group determination was available for 1,513 (27.5%). Their distribution by ABO was: 653 (43.2%) group 0, 690 (45.6%) A, 113 (7.5%) B, and 57 (3.8%) AB, which corresponds to the expected frequencies in the general population. In parallel, of 676 patients with Long COVID, blood group determination was available for 135 (20.0%). Their distribution was: 60 (44.4%) from group 0, 61 (45.2%) A, 9 (6.7%) B, and 5 (3.7%) AB. The distribution of the ABO system of Long COVID patients did not show significant differences with respect to that of the total group (p ≥ 0.843). In a multivariate analysis adjusting for age, sex, ethnicity, and severity of acute COVID-19 infection, subgroups A, AB, and B were not significantly associated with developing Long COVID with an OR of 1.015 [0.669–1.541], 1.327 [0.490–3.594] and 0.965 [0.453–2.058], respectively. The effect of the Rh+ factor was also not significant 1,423 [0.772–2,622] regarding Long COVID.
Citation: Soriano JB, Peláez A, Busquets X, Rodrigo-García M, Pérez-Urría EÁ, Alonso T, et al. (2023) ABO blood group as a determinant of COVID-19 and Long COVID: An observational, longitudinal, large study. PLoS ONE 18(6): e0286769. https://doi.org/10.1371/journal.pone.0286769
Editor: Antonio Jesus Barrenechea-Pulache, Universidad Cientifica del Sur, PERU
Received: March 4, 2023; Accepted: May 23, 2023; Published: June 2, 2023
Copyright: © 2023 Soriano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Upon request and formal ethics approval, unidentified data and materials could be available, as there are legal or ethical restrictions on sharing data publicly from our Ethics Committee, that is CEIm La Princesa University Hospital. Contact details are: Dra. Mª del Mar Ortega Gómez, Secretary of CEIm, CEIm La Princesa University Hospital. C/ Diego de León, 62. 28006. Madrid, Email: ceim.hlpr@salud.madrid.org, Tel: +34 91 520 24 76, Fax: +34 91 520 25 60.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
The COVID-19 pandemic is far from over [1–3]. Now we know that many COVID-19 patients do not fully recover, and suffer for months (or years) a condition called Long COVID [4, 5]. This new yet ill-defined condition [6], encompasses a series of symptoms and ailments that has received many names [7]. It has been recently estimated that about one in seven individuals do not fully recover after the acute infection with SARS-CoV-2 at twelve months [8].
The available information about risk and protective factors of incident COVID-19 and Long COVID is rich and still growing [9]. In 2020, it was hypothesized that the ABO blood group could be related to the predisposition to and severity of COVID-19 [10]. Contrary to other determinants, this relationship of ABO blood group with COVID-19 has been highly controversial. A number of systematic reviews and meta-analyses are already available, signaling to a modest association, initially with type A and later with AB [11–14]. Notably, others have meta-analysed the same evidence, yet with inconclusive findings [15].
It is established that differences in ABO blood group antigen expression can increase or decrease host susceptibility to a number of infectious agents [16], including viruses [17–20]. It is also well established that SARS-CoV-2 binds to human cells through the angiotensin-converting enzyme II (ACE-2) receptor. Red blood cells precursors express ACE-2 receptor and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection [21].
However, any association of ABO blood types with COVID-19 remains questionable. Finally, to date a possible association of the ABO group with the development of Long COVID has not been explored, except from a small study from Najaf, Iraq [22].
Our objective is to determine the association of ABO group types (if any) in hospitalized patients admitted acutely for COVID-19, and to explore it also in patients with Long COVID.
Methods
This is an observational, longitudinal study in a prospective cohort of hospitalized patients with COVID-19 admitted at the Hospital de La Princesa, Madrid, Spain from February 2020 to September 2022. We obtained information from clinical records of all adult patients (age ≥ 18 years) with a positive COVID-19 clinical diagnosis upon hospital admission, confirmed either by positive antigen or polymerase chain reaction (PCR) tests. Further details about this cohort are available elsewhere [23, 24]. The research protocol was approved (CEIm 10/21 with N° 4.468). No individual consent form was required, as we only use and report unidentified administrative data.
Briefly, we were initially interested on determinants and clinical outcomes from any COVID-19-related admission up to 30 days post discharge, which was obtained from the electronic medical records of our hospital system. The biometric, laboratory (blood and urine), and comorbidity variables were obtained and analyzed following STROBE guidelines for observational research [25]. ABO blood group was determined in the cohort of patients hospitalized for acute COVID-19 and in those patients with Long COVID seen in the post-COVID consultation. For reference population, we used published statistics [26, 27].
Statistical methods
A first descriptive analysis of the patients’ characteristics was performed by calculating central tendency and dispersion measures of quantitative variables. For qualitative variables, comparison of proportions was tested by using the χ2 test or the Fisher exact test, whenever necessary. Contingency tables were made and risk factors were explored using crude and adjusted Mantle-Haentzel odds ratios (OR and 95% CI). In addition to descriptive statistics, a Kaplan-Meier analysis of in-hospital mortality up to 30 days post-discharge was performed. To obtain the hazards ratios, a Cox proportional regression was fitted over the statistically significant variables obtained from the bivariate analysis. A p-value below 0.05 was considered to indicate statistical significance in all analyses. Data management, statistical calculations, and graphical plots were conducted using the R statistical software.
Results
From February 2020 to September 2022, there were a total of 5,832 acute COVID-19 hospitalizations in our hospital, corresponding to 5,503 individual patients, of whom blood group determination was available for 1,513 (27.5%) (Fig 1). Of interest, those who had blood group assessed, were not significantly different from those not tested in their gender and smoking status distribution (S1 Table). However, they were on average, older, required a longer hospitalization and had worse clinical outcomes in all assessments (all p <0.05), likely related with the medical decision to type their blood group. Further, there were more persons of Latin-American origin (p<0.05), confirming our earlier publication (Table 1) [24].
In parallel, out of 676 patients with Long COVID seen in our post-COVID external consultation, blood group determination was available for 135 (20.0%) (Fig 1). In this subsample with Long COVID, those who had blood group assessed, were not significantly different from those not tested in their gender and smoking status distribution again (S2 Table), and in this case on Latino origin too; however, they were on average, older, required a longer hospitalization and had many (but not all) poorer adverse clinical outcomes (p <0.05).
Among admitted patients with COVID-19, their distribution by ABO was: 653 (43.2%) group 0, 690 (45.6%) A, 113 (7.5%) B, and 57 (3.8%) AB (Table 1), which corresponds to the expected frequencies in the general Spanish population (See Methods as 45% belong to group 0, 42% to A, 10% to B, and 3% to AB) (p >0.05). Applying customary survival statistics in here, the Kaplan-Meier survival curves of patients admitted for COVID-19 up to 60-days post discharge were not statistically significant by all four ABO blood group types (Fig 2).
When exploring those with Long COVID, their ABO type distribution was: 60 (44.4%) from group 0, 61 (45.2%) A, 9 (6.7%) B, and 5 (3.7%) AB. And, the distribution of the ABO system of Long COVID patients did not show significant differences with respect to that of the total group of COVID-19 patients (p ≥ 0.843) (Table 1).
Finally, in a multivariate analysis adjusting for age, sex, ethnicity, and severity of acute COVID-19 infection, subgroups A, AB, and B were not significantly associated with developing Long COVID with an OR of 1.015 [0.669–1.541], 1.327 [0.490–3.594] and 0.965 [0.453–2.058], respectively. The effect of the Rh+ factor was also not significant 1,423 [0.772–2,622] regarding Long COVID (Table 2).
Discussion
Beyond established risk factors of COVID-19 and of Long COVID, the search for novel determinants of both remains an unmet need [2, 28]. Our study confirms established risk factors for susceptibility to both conditions, such as middle age, Latin-American origin and former smoking status. However, we were unable to identify within our study population any relationship of ABO blood group types neither with acute COVID-19 nor with Long COVID.
Our research has some strengths, including: a large size; research spanning seven different pandemic waves lasting two full years; blinding on the primary aim of this research; and the multivariate statistics applied. However, a number of limitations must be highlighted. ABO blood group was only determined according to patient’s medical needs. As in S1 Table, those patients admitted with COVID-19 whose ABO blood group was determined were significantly older and had more severe disease overall. However, a potential type II error favors our negative conclusion. Other limitations include: inability to test patients who died quickly due to critical illness; single ethnic group, although those of LatinAmerican origin were further explored. Situation is likely very complex, influenced by successive vaccinations and boosters, different mechanism of Long COVID, and other factors [29].
Plausibility and mechanisms
The mechanism of action underlying the association of blood type and viral infections is still ill known [30, 31]. Hypotheses are based on the fact that blood group antigens can function as protein receptors for viruses and as a consequence activate the endophagic cellular mechanisms that facilitate the intracellular uptake of the viruses [16]. The receptor-binding domain (RBD) of S protein of SARS-CoV-2 [32], located in the N-terminal part of the protein mediates ACE-2 binding [33], and this RBD is highly sensitive to neutralizing antibodies [34].
Guillon P, et al. [35], demonstrated in a cell culture-based binding assay mimicking the interaction between the S protein and ACE-2 [36], that natural antibodies of the ABO system block the S protein ACE-2 binding in SARS-CoV [37]. Natural anti-A or -B antibodies from group 0, B, and A individuals could bind to the S protein and impair its binding with ACE-2, preventing infection [11–14].
Implications for the future
To date most studies have been small (low double-digit) [38], from a handful of countries [11–14], and not following STROBE guidance in full [25]. Therefore Type I error cannot yet be ruled out, so more evidence meta-analyzed from patients in all COVID-19 severities including those pauci-asymptomatic [39], and other geographical locations, is needed [40].
Within this research, comorbidities were not identified as independent drivers in our null association with ABO blood group. However, in our previous research comorbidities were found to be major drivers of health outcomes in COVID-9 and Long COVID, and we identified that both number of and specific comorbidities, such as obesity, previous chronic respiratory disease or cardiovascular disease [23, 24].
The situation might be different, and more complex, in Long COVID. Given there are different pathophyisiological mechanisms identified, it must be ruled out whether some/any mechanisms be associated with susceptibility/protection to develop it [41, 42]. We have to concur with Kim Y, et al. there does not appear to be any relationship between blood type and COVID-19–related severity of illness or mortality [15].
We conclude that in our study population there was no association identified of any ABO blood type with either suffering acute hospitalization for COVID-19 or later developing Long COVID.
Supporting information
S1 Table. STROBE non-response table comparing demographic and clinical characteristics of patients admitted for COVID-19 with/without ABO blood group determined.
https://doi.org/10.1371/journal.pone.0286769.s001
(DOCX)
S2 Table. STROBE non-response table comparing demographic and clinical characteristics of patients with Long COVID with/without ABO blood group determined.
https://doi.org/10.1371/journal.pone.0286769.s002
(DOCX)
S1 Checklist. STROBE statement—Checklist of items that should be included in reports of observational studies.
https://doi.org/10.1371/journal.pone.0286769.s004
(DOC)
References
- 1. Cohen J, Normile D. New SARS-like virus in China triggers alarm. Science. 2020 Jan 17;367(6475):234–235. pmid:31949058.
- 2. Soriano JB, Infante A. Aiming for the end of the COVID-19 pandemic: the what, how, who, where, and when. Chin Med J 2023 (in press). pmid:36752803
- 3.
WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int [accessed on 20 December 2022].
- 4. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature. 2021 Jun;594(7862):259–264. Epub 2021 Apr 22. pmid:33887749.
- 5. Wise J. Long covid: One in seven children may still have symptoms 15 weeks after infection, data show. BMJ. 2021 Sep 1;374:n2157. pmid:34470745
- 6. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22(4):e102–e107. Epub 2021 Dec 21. pmid:34951953.
- 7. Hayes LD, Ingram J, Sculthorpe NF. More Than 100 Persistent Symptoms of SARS-CoV-2 (Long COVID): A Scoping Review. Front Med (Lausanne). 2021 Nov 1;8:750378. eCollection 2021. pmid:34790680.
- 8. Wulf Hanson S, Abbafati C, Aerts JG, Al-Aly Z, Ashbaugh C, Ballouz T, et al. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022 Oct 25;328(16):1604–1615. pmid:36215063.
- 9.
Clinical management of COVID-19: living guideline, 15 September 2022. Geneva: World Health Organization; 2022 (WHO/2019-nCoV/Clinical/2022.2). Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/WHO-2019-nCoV-Clinical-2022.2 [accessed on 14 December 2022].
- 10. Severe Covid-19 GWAS Group, Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020 Oct 15;383(16):1522–1534. Epub 2020 Jun 17. pmid:32558485.
- 11. Zhao J, Yang Y, Huang H, Li D, Gu D, Lu X, et al. Relationship Between the ABO Blood Group and the Coronavirus Disease 2019 (COVID-19) Susceptibility. Clin Infect Dis. 2021 Jul 15;73(2):328–331. pmid:32750119.
- 12. Bhattacharjee S, Banerjee M, Pal R. ABO blood groups and severe outcomes in COVID-19: A meta-analysis. Postgrad Med J. 2022 Mar;98(e2):e136–e137. pmid:35232874.
- 13. Balaouras G, Eusebi P, Kostoulas P. Systematic review and meta-analysis of the effect of ABO blood group on the risk of SARS-CoV-2 infection. PLoS One. 2022 Jul 28;17(7):e0271451. eCollection 2022. pmid:35901063.
- 14. Abuawwad MT, Taha MJJ, Abu-Ismail L, Alrubasy WA, Sameer SK, Abuawwad IT, et al. Effects of ABO blood groups and RH-factor on COVID-19 transmission, course and outcome: A review. Front Med (Lausanne). 2023 Jan 12;9:1045060. eCollection 2022. pmid:36714134.
- 15. Kim Y, Latz CA, DeCarlo CS, Lee S, Png CYM, Kibrik P, et al. Relationship between blood type and outcomes following COVID-19 infection. Semin Vasc Surg. 2021 Sep;34(3):125–131. Epub 2021 Jul 18. pmid:34642032.
- 16. Cooling L. Blood Groups in Infection and Host Susceptibility. Clin Microbiol Rev. 2015 Jul;28(3):801–70. pmid:26085552.
- 17. Anstee DJ. The relationship between blood groups and disease. Blood. 2010 Jun 10;115(23):4635–43. Epub 2010 Mar 22. pmid:20308598.
- 18. Cheng Y, Cheng G, Chui CH. ABO blood group and susceptibility to severe acute respiratory syndrome. JAMA. 2005 Mar 23;293(12):1450–1. pmid:15784866
- 19. Lindesmith L, Moe C, Marionneau S. Human susceptibility and resistance to Norwalk virus infection. Nat Med. 2003 May;9(5):548–53. Epub 2003 Apr 14. pmid:12692541
- 20. Wang DS, Chen DL, Ren C. ABO blood group, hepatitis B viral infection and risk of pancreatic cancer. Int J Cancer. 2012 Jul 15;131(2):461–8. Epub 2011 Nov 30. pmid:21858814
- 21. Kronstein-Wiedemann R, Stadtmüller M, Traikov S, Georgi M, Teichert M, Yosef H, et al. SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism. Stem Cell Rev Rep. 2022 Jun;18(5):1809–1821. Epub 2022 Feb 18. pmid:35181867.
- 22. Nafakhi A, Rabeea IS, Al-Darraji R, Nafakhi H, Mechi A, Al-Khalidi A, et al. Association of ABO blood group with in-hospital adverse outcome and long term persistent symptoms of COVID-19 infection: A single-center longitudinal observational study. Health Sci Rep. 2022 May 23;5(3):e656. eCollection 2022 May. pmid:35620543.
- 23. Bengelloun AK, Ortega GJ, Ancochea J, Sanz-Garcia A, Rodríguez-Serrano DA, Fernández-Jiménez G, et al. Usefulness of the CONUT index upon hospital admission as a potential prognostic indicator of COVID-19 health outcomes. Chin Med J (Engl). 2021 Oct 26;135(2):187–193. pmid:34711718.
- 24. Bengelloun AK, Ortega GJ, Soriano JB; en nombre del Grupo de Investigación Coronita Princesa. Impact of COVID-19 on the Latin American population in Spain during the first and second waves. Med Clin (Barc). 2021 Nov 26;157(10):496–497. Epub 2021 May 27. pmid:34120757.
- 25. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008 Apr;61(4):344–9. pmid:18313558.
- 26.
Distribución de los grupos sanguíneos en España. Consejo Superior de Investigaciones Científicas. Instituto Juan Sebastián Elcano, Madrid. 1947.
- 27.
Google grupos sanguíneo en España. https://www.google.com/search?q=grupos+sangu%C3%ADneo+espa%C3%B1a&biw=1462&bih=660&ei=RcmGY-OiOKHAkdUPmNiF-AE&ved=0ahUKEwij2bzl9tT7AhUhYKQEHRhsAR8Q4dUDCA8&uact=5&oq=grupos+sangu%C3%ADneo+espa%C3%B1a&gs_lcp=Cgxnd3Mtd2l6LXNlcnAQAzIHCAAQgAQQDTIICAAQBxAeEAoyCAgAEAUQBxAeOgoIABBHENYEELADOgUIABCABDoGCAAQBRAeSgQIQRgASgQIRhgAUIgFWOMGYOASaAJwAHgAgAFdiAGtAZIBATKYAQCgAQHIAQjAAQE&sclient=gws-wiz-serp [accessed on 14 December 2022].
- 28. Burke MJ, Del Rio C. Long COVID has exposed medicine’s blind-spot. Lancet Infect Dis. 2021 Aug;21(8):1062–1064. Epub 2021 Jun 18. pmid:34153235.
- 29. Nunhofer V, Weidner L, Hoeggerl AD, Zimmermann G, Badstuber N, Grabmer C, et al. Persistence of Naturally Acquired and Functional SARS-CoV-2 Antibodies in Blood Donors One Year after Infection. Viruses. 2022 Mar 18;14(3):637. pmid:35337044.
- 30. Ward SE, O’Sullivan JM, O’Donnell JS. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood. 2020 Dec 17;136(25):2864–2874. pmid:32785650.
- 31. Ortel TL, Berliner N. Introduction to a review series on COVID-19 and the hematologist. Blood. 2022 Jul 21;140(3):163–164. pmid:35661194.
- 32. Candido KL, Eich CR, de Fariña LO, Kadowaki MK, da Conceição Silva JL, et al. Spike protein of SARS-CoV-2 variants: a brief review and practical implications. Braz J Microbiol. 2022 Sep;53(3):1133–1157. Epub 2022 Apr 9. pmid:35397075
- 33. Consortium AA Structural and functional comparison of SARS-CoV-2-spike receptor binding domain produced in Pichia pastoris and mammalian cells. Sci Rep. 2020;10:21779. pmid:33311634
- 34. Thomson EC, Rosen LE, Shepherd JG, Spreafico R, da Silva Filipe A, Wojcechowskyj JA, et al. Circulating SARS-CoV-2 spike N439K variants maintain fitness while evading antibody-mediated immunity. Cell. 2021;184:1171–1187.e20. pmid:33621484
- 35. Guillon P, Clément M, Sébille V, Rivain J-G, Chou C-F, Ruvoën-Clouet N, et al. Inhibition of the interaction between the SARS-CoV Spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology. 2008 Dec;18(12):1085–93. Epub 2008 Sep 25. pmid:18818423
- 36. Chou C-F, Shen S, Tan Y-J, Fielding BC, Tan THP, Fu J, et al. A novel cell-based binding assay system reconstituting interaction between SARS-CoV S protein and its cellular receptor. J Virol Methods. 2005 Jan;123(1):41–8. pmid:15582697
- 37. Marionneau S, Cailleau-Thomas A, Rocher J, Le Moullac-Vaidye B, Ruvoën-clouet N, Clément M, et al. ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world. Biochimie. 2001 Jul;83(7):565–73. pmid:11522384
- 38. Miotto M, Di Rienzo L, Gosti G, Milanetti E, Ruocco G. Does blood type affect the COVID-19 infection pattern? PLoS One. 2021 May 13;16(5):e0251535. eCollection 2021. pmid:33984040.
- 39. Lund LC, Hallas J, Nielsen H, Koch A, Mogensen SH, Brun NC, et al. Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study. Lancet Infect Dis. 2021 Oct;21(10):1373–1382. Epub 2021 May 10. pmid:33984263.
- 40. Peñalvo JL, Mertens E, Ademović E, Akgun S, Baltazar AL, Buonfrate D, et al. Unravelling data for rapid evidence-based response to COVID-19: a summary of the unCoVer protocol. BMJ Open. 2021 Nov 18;11(11):e055630. pmid:34794999.
- 41. Gavriilaki E, Kokoris S. COVID-19 sequelae: can long-term effects be predicted? Lancet Infect Dis. 2022 Dec;22(12):1651–1652. Epub 2022 Aug 26. pmid:36030797.
- 42. Houchen-Wolloff L, Poinasamy K, Holmes K, Tarpey M, Hastie C, Raihani K, et al. Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19. Thorax. 2022 Jul;77(7):717–720. Epub 2022 Mar 30. pmid:35354642.