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Association of ABO blood group with respiratory disease hospitalization and severe outcomes: a retrospective cohort study in blood donors

  • Author Footnotes
    # Co-first authors with equal contribution.
    Shu Su
    Footnotes
    # Co-first authors with equal contribution.
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China

    Clinical Research Management Office, The Second Affiliated Hospital of ChongQing Medical University

    China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
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  • Author Footnotes
    # Co-first authors with equal contribution.
    Lingxia Guo
    Footnotes
    # Co-first authors with equal contribution.
    Affiliations
    Planning Development and Information Office, Health Commission of Shaanxi Province
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  • Ting Ma
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
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  • Yang Sun
    Affiliations
    Data Center, Shaanxi Provincial People's Hospital. Xi'an, China
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  • Aowei Song
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
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  • Wenhua Wang
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
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  • Xiaoyun Gu
    Affiliations
    Department of Information Technological, Shaanxi Health Information Center, Xi'an, Shaanxi, China
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  • Wenjie Wu
    Affiliations
    Department of Information Technological, Shaanxi Health Information Center, Xi'an, Shaanxi, China
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  • Xinxin Xie
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
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  • Leilei Zhang
    Affiliations
    China-Australia Joint Research Center for Infectious Diseases, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
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  • Author Footnotes
    ╪ Authors contributed to supervision equally.
    ,
    Author Footnotes
    ╪ Authors contributed to supervision equally.
    Lei Zhang
    Correspondence
    Lei Zhang, China-Australia Joint Research Center for Infectious Diseases School of Public Health, Xi’an Jiaotong University Health Science Center, 28 Xian Ning West Road, Xi’an, Shaanxi, 710061, China. Phone: +8629 82655135.
    Footnotes
    ╪ Authors contributed to supervision equally.
    ╪ Authors contributed to supervision equally.
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China

    Clinical Research Management Office, The Second Affiliated Hospital of ChongQing Medical University

    Artificial Intelligence and Modelling in Epidemiology Program, Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia

    Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia

    Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan, China
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  • Author Footnotes
    ╪ Authors contributed to supervision equally.
    ,
    Author Footnotes
    ╪ Authors contributed to supervision equally.
    Jiangcun Yang
    Correspondence
    Correspondence to: Jiangcun Yang, Department of Transfusion Medicine, Shaanxi Provincial People’s Hospital, 256 Youyi West Road, Xi’an, 710068, China. Phone:+8629 85253261-3073.
    Footnotes
    ╪ Authors contributed to supervision equally.
    ╪ Authors contributed to supervision equally.
    Affiliations
    Department of Transfusion Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
    Search for articles by this author
  • Author Footnotes
    # Co-first authors with equal contribution.
    ╪ Authors contributed to supervision equally.
Open AccessPublished:May 10, 2022DOI:https://doi.org/10.1016/j.ijid.2022.05.019

      Abstract

      Objectives

      Environmental, socioeconomic, and genetic factors all are associated with respiratory diseases. We aimed to investigate the association between the ABO blood group and the susceptibility to respiratory diseases.

      Methods

      We constructed a retrospective cohort study of blood donors in Shaanxi, China between January 1, 2012, and December 31, 2018, to investigate the impacts of the ABO blood group on the risk of hospitalization due to respiratory diseases.

      Results

      Of 1,686,263 enrolled participants (680,788 females), 26,597 were admitted to the hospital for respiratory diseases. Compared with blood group O, blood groups A, B, and AB all demonstrated a higher risk for diseases of the upper respiratory tract (International Classification of Diseases, Tenth Revision: J30–J39) (ARR (Adjusted relative risk) 1.139, 95% confidence interval [1.106–1.225]; 1.095 [1.019–1.177]; 1.178 [1.067–1.30], respectively). Conversely, blood group A was found to have a lower risk (0.86 [0.747–0.991]) for influenza (J09–J11) and blood group B had a lower risk for pneumonia (J12–J18) (0.911 [0.851–0.976]) than blood group O. The duration of hospitalization was significantly different across the blood groups in J09–J11 and J30–J39 (P <0.05).

      Conclusion

      The blood group appears to be a prognostic factor in differentiating the occurrence of specific respiratory diseases and duration.

      Keywords

      Introduction

      The association between ABO blood groups and risk of disease have been studied almost one century ago (
      • Groot HE
      • Sierra LEV
      • Said MA
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      • Karper JC
      • van der Harst P.
      Genetically determined ABO blood group and its associations with health and disease.
      ) since it was discovered in 1901 (
      • Dean L.
      National Center for Biotechnology Information (US).
      ). ABO blood groups have been shown to be associated with health and diseases such as diabetes, cancers, and cardiovascular diseases (
      • Kasner M
      • Konkle B
      • Cary M
      • Kimmel S.
      ABO blood type and the risk of cardovascular events: an analysis of Framingham data and meta-analysis.
      ;
      • Vasan SK
      • Rostgaard K
      • Majeed A
      • Ullum H
      • Titlestad KE
      • Pedersen OB
      • et al.
      ABO blood group and risk of thromboembolic and arterial disease: a study of 1.5 million blood donors.
      ;
      • Zhang BL
      • He N
      • Huang YB
      • Song FJ
      • Chen KX.
      ABO blood groups and risk of cancer: a systematic review and meta-analysis.
      ). It was found that the blood group distribution in the occurrence of these diseases differs significantly, which may be due to the ABO antigen, which is present in blood group A, B, or AB but not in group O (
      • Lindqvist PG
      • Dahlbäck B.
      Carriership of factor V Leiden and evolutionary selection advantage.
      ;
      • Trégouët DA
      • Heath S
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      • Schved JF
      • Pernod G
      • et al.
      Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach.
      ) or genetic variation in the ABO locus (
      • Paré G
      • Chasman DI
      • Kellogg M
      • Zee RY
      • Rifai N
      • Badola S
      • et al.
      Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women.
      ). Recently, because COVID-19 has rapidly evolved into a global pandemic, a number of studies have tried to explore the association between blood groups and this infection, but the results are inconsistent (
      • Barnkob MB
      • Pottegård A
      • Støvring H
      • Haunstrup TM
      • Homburg K
      • Larsen R
      • et al.
      Reduced prevalence of SARS-CoV-2 infection in ABO blood group O. Blood.
      ;
      • Hoiland RL
      • Fergusson NA
      • Mitra AR
      • Griesdale DEG
      • Devine DV
      • Stukas S
      • et al.
      The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19.
      ;
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      • Boitano L
      • Png CYM
      • Patell R
      • Conrad MF
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      Blood type and outcomes in patients with COVID-19.
      ;
      • 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.
      ;
      • Zhang L
      • Huang B
      • Xia H
      • Fan H
      • Zhu M
      • Zhu L
      • et al.
      Retrospective analysis of clinical features in 134 coronavirus disease 2019 cases.
      ;
      • 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.
      ;
      • Zietz M
      • Zucker J
      • Tatonetti NP.
      Associations between blood type and COVID-19 infection, intubation, and death.
      ). Two meta-analyses have concluded that individuals with blood group A have a significantly higher risk of being infected with SARS-CoV-2, which causes COVID-19; in comparison, blood group O has a lower risk of being infected (
      • 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.
      ;
      • 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.
      ). Although it has attracted more attention on the possible mechanisms underlying ABO blood group in respiratory diseases, the potential association is not entirely identified.
      Respiratory diseases are the third leading cause of death worldwide. It primarily makes up five of the 30 most common causes of death: chronic obstructive pulmonary disease (COPD) is the third; lower respiratory tract infection is the fourth; tracheal, bronchial, and lung cancers are the sixth; tuberculosis is the 12th; and asthma is the 28th (
      • Wang H
      • Naghavi M
      • Allen C
      • Barber RM
      • Bhutta ZA
      • Carter A
      • et al.
      Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ) cause of the global mortality. Respiratory diseases are mainly determined by environmental and socioeconomic variables, including smoking, air pollution, and so on, and genetic predisposition. Previous studies have worked on exploring the association of the occurrence of COPD and asthma with the ABO system, but the result was not significant. Except this, there is only one study exploring the association between blood group and acute respiratory distress syndrome (ARDS); it found that blood group A is associated with an increased risk for ARDS in White patients with major trauma and severe sepsis (
      • Reilly JP
      • Meyer NJ
      • Shashaty MGS
      • Feng R
      • Lanken PN
      • Gallop R
      • et al.
      ABO blood type A is associated with increased risk of ARDS in whites following both major trauma and severe sepsis.
      ). Except for COVID-19, for another communicable respiratory disease, one study conducted in 1961 demonstrated that individuals with blood group A have a higher risk of being infected with tuberculosis (
      • Lewis JG
      • Woods AC.
      The ABO and rhesus blood groups in patients with respiratory disease.
      ). Although some specific respiratory disease has been found to be significantly associated with ABO blood group, to our knowledge, no study has classified the disease (International Classification of Diseases, Tenth Revision [ICD-10] J00–J99) from the anatomical sites because the respiratory disease in the different positions has different pathogenesis. Evidence of a connection between blood groups and susceptibility to each subtype of respiratory disease is required to draw explicit conclusions.
      It is also an assumption that the blood group may have effects in the progression of respiratory diseases. There is a study working on ABO blood group, indicating no correlation with increased mortality in adult patients with acute hypoxemic respiratory failure who were mechanically ventilated (
      • Rezoagli E
      • Gatti S
      • Villa S
      • Villa G
      • Muttini S
      • Rossi F
      • et al.
      ABO blood types and major outcomes in patients with acute hypoxaemic respiratory failure: a multicenter retrospective cohort study.
      ). In this study, we compared the discharge status and the duration of hospitalization among different blood groups to check whether there is a significant difference.
      In this study, we derived the Shaanxi resident's electronic health records (EHR) of the blood donor cohort over the period from January 2012 to December 2018 to investigate the association between ABO blood group and site-specific respiratory diseases, classified by the different anatomical sites and chronic and acute and communicable and noncommunicable respiratory diseases according to the ICD-10 codes.

      Method

      Data source

      We included 1.7 million blood donors in this cohort and built comprehensive data linkages of Shaanxi residents’ EHR (
      • Zhang L
      • Li H
      • Su S
      • Wood Erica
      • Ma T
      • Sun Y
      • et al.
      CohortProfile: The Shaanxi Blood DonorCohort in China.
      ). Shaanxi province is located in northwest China, with a permanent resident population of approximate 39 million in 2019. The donors’ information were collected from the Shaanxi Blood Donor's Database, which was established in 1998 and recorded blood groups of approximately all voluntary blood donors in the province by December 2018. The database covered all ten prefectures (Xi'an, Xianyang, Tongchuan, Baoji, Weinan, Yan'an, Hanzhong, Yulin, Ankang, and Shangluo) in Shaanxi. A unique personal identification number was assigned to all residents in the database. The creation of the blood donation database was approved by the regional ethics committees in Xi'an, Shaanxi, and the ethical approval for the study was obtained from the institutional review board of People's Hospital of Shaanxi Province (No: 2020-R002). The study was preregistered at China National Medical Research Register and Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx), the registration numbers are MR-61-21-011750 and ChiCTR2200055983, respectively. Reporting follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
      The blood donation database was subsequently integrated with Shaanxi resident's EHR, administered by Shaanxi Provincial Health Planning Policy Evaluation and Information Center. EHR was a key digital health initiative implemented nationwide by the Chinese government in 2009 and widely recorded in Shaanxi since 2012 (
      • Gao X
      • Xu J
      • Sorwar G
      • Croll P.
      Implementation of e-health record systems and E-medical record systems in China.
      ). The database maintained continuous and trackable medical records for its residents and provide health stakeholders with evidence for disease trends and distribution. It collected basic health information from locally registered residents and residents from other Chinese provinces who have lived in Shaanxi for more than six months. The records include basic demographic information, health examinations, and key population health management records. EHR data were collected through household surveys, disease screening, health checkups, and records from community health service centers. We matched the Shaanxi Blood Donor Database with EHR on the basis of unique resident identification numbers, allowing for long-term follow-up. We have withdrawn the basic characteristics and hospitalization record from the database between January 2012 to December 2018. The clinical diagnosis was recorded in the ICD codes, which is a secure way to demonstrate the actual diagnosis. The linkage resulted in 1,704,691 EHR records, which were matched to the blood donor dataset. After excluding duplications and entries that miss essential information, 1,686,263 blood donors were found in EHRs and were included in this study (Figure 1).

      Study design

      The primary study outcome was the prevalence of hospitalization for respiratory disease, which was defined as the first diagnosis during the study period from 2012 to 2018. We further classified the hospitalization records linked with donors into 11 specific diseases of the respiratory system according to the international ICD-10 code as follows. Acute upper respiratory infections (J00–J06), influenza (J09–J11), pneumonia (J12–J18), other acute lower respiratory infections (J20–J22), other diseases of the upper respiratory tract (J30–J39), chronic lower respiratory diseases (J40–J47), lung diseases due to external agents (J60–J70), other respiratory diseases principally affecting the interstitium (J80–J84), suppurative and necrotic conditions of the lower respiratory tract (J85–J86), other diseases of the pleura (J90–J94), intraoperative and postprocedural complications and disorders of the respiratory system, not elsewhere classified (J95–J95.89), and other diseases of the respiratory system (J96–J99) (). Because age is a vital factor in respiratory disease, we considered this factor in the model and classified the participants into three age groups, 18–35, 36–55, and >55 years, according to the WHO age-graded standard and the legal age for donation was 18–55 years in China (
      Chinese Ministry of Health
      Whole blood and component donor selection requirements.
      ). Additional variables collected included gender, education, ethics, blood groups, and occupation. These were used to adjust the risk factors associated with respiratory diseases.
      The second study outcome was the severity of the respiratory disease. We compared the discharged status and the duration of the first hospitalization among different blood groups. The discharged status was classified by death, recovery, and transfer. We assumed the patients with longer inpatient days have more severe symptoms. The duration was defined as the period between the date of the hospitalization admission and the date of the discharge. We compared the discharge status of the overall disease and all the duration among the respiratory diseases classified by 11 categorized diseases as above.
      We categorized the participants into blood groups A, B, AB, and O. Donors who are eligible to donate, the donated blood should be tested for ABO blood group twice. The blood group was first tested by a rapid test before donating blood. Then, after each donation, the confirmatory test was performed by agglutination test to make sure that the blood matches the blood recipients’ blood group. All the test was completed by the professional staff in the blood station. All blood stations on the prefecture-level city adopted a standardized blood group detection and information management system.

      Statistical analysis

      Differences in baseline characteristics between subjects with blood groups A, B, and AB and those with blood group O were assessed with t tests for continuous variables and with χ2 tests for categorical variables. In the analyses of first occurrences (i.e., incident cases) we followed up donors from the date of first electronically recorded blood donation during the study period until the date of first respiratory disease event or the end of follow-up (December 31, 2018), whichever came first. Poisson regression models were used to estimate prevalence rate ratios as measures of relative risk. The relative risk of respiratory diseases in individuals with blood groups A, AB, and B compared with individuals with blood group O was expressed as prevalence rate ratios, estimated with log-linear Poisson regression models. We had adjusted for attained age, gender, residence, education, occupation, and ethics. Interactions between blood group and gender, residence, follow-up period, age, and the respective comorbidities were individually tested. We also tested for differences in the blood groups of the same disease in the duration of hospitalization by ANOVA test. All data were entered and analyzed using the statistical software SAS 9.2 (Statistical Analysis System). A P-value of less than 0.05 was considered significant in the final model.

      Results

      Baseline Characteristics

      A total of 1,686,263 blood donors were recruited in the study and their hospitalization record was followed up from January 2012 to December 2018. The A, B, AB, and O blood groups were found in 28.7%, 30.5%, 10.0%, and 30.8% of the participants, respectively. At baseline, the study participants had an average age of 29.7 ± 9.4 years. Among the participants, Han ethnicity represented a significantly higher proportion than non-Han ethnicity, but the distribution among four blood groups was not statistically significant for both Han and non-Han ethnicity (P = 0.31). Participants had no significant difference in the distribution of education (P = 0.17) and occupation (P = 0.09) (Table 1).
      Table 1Characteristics of the Study Participants.
      OABABP-value
      Subjects, n (% of total)519249 (30.79)484389 (28.73)513829 (30.47)168796 (10.01)
      Gender0.37
       Female210635 (40.57)194245 (40.10)207706 (40.42)68202 (40.41)
       Male308614 (59.43)290144 (59.90)306123 (59.58)100594 (59.60)
      Age at study entry0.42
       18–35182323 (35.11)168865 (34.86)180892 (35.20)59397 (35.19)
       36–55276459 (53.24)259060 (53.48)272799 (53.09)89689 (53.13)
       >5560467 (11.65)56464 (11.66)60138 (11.70)19710 (11.68)
       Mean age ± SD29.70 ± 9.7329.74 ± 9.7129.71 ± 9.7629.72 ± 9.74
      Ethnicity0.31
       Han511692 (98.54)477253 (98.53)506251 (98.53)166259 (98.50)
       Non-Han7557 (1.46)7136 (1.47)7578 (14.75)2537 (1.50)
      Comorbidity during the follow-up
       Cancer (C00–C97)1222 (0.24)1187 (0.25)1216 (0.24)403 (0.24)0.43
       Diabetes (E11)2348 (0.45)2348 (0.48)2510 (0.49)798 (0.47)0.03
       Hypertension (I10)3113 (0.60)2906 (0.60)3016 (0.59)1040 (0.62)0.53
       Cardiovascular disease (I20–I25)2775 (0.53)2778 (0.57)2859 (0.56)952 (0.56)0.08
       Cerebrovascular disease (I60–I69)3119 (0.60)2935 (0.61)3062 (0.60)989 (0.59)0.47

      Hospitalization rates

      During the observation period, we found 26,597 inpatients with at least one record of hospitalization for respiratory diseases (ICD-10 J00–J99) (Figure 1). The highest prevalence was observed in participants with blood group AB (1.62%), whereas the lowest was in blood group B (1.55%), but there was no significant difference in the distribution of respiratory disease by blood groups in all age categories. Among all the respiratory diseases, pneumonia (J12–J18) was the most prevalent respiratory disease in blood groups O (21.4%), B (20.4%), and AB (20.3%). Other diseases of the upper respiratory tract (J30–J39) had constituted the highest proportion among participants with blood group A (20.7%). From the Poisson regression, compared with blood group O, blood groups A, B, and AB were all associated with a higher risk for upper respiratory tract disease (J30–J39) (ARR: 1.139, 95% confidence interval [1.106–1.225]; 1.095 [1.019–1.177]; 1.178 [1.067–1.30], respectively). The highest ratio was observed for participants with blood group A older than 55 years (1.456 [1.038–2.042]). Participants with blood group A had a lower risk for influenza (0.86 [0.747–0.99]), whereas participants with blood group B showed a lower risk for pneumonia (0.911 [0.851–0.976]). It was consistently found in blood group B aged 36–55 and >55, respectively. We have further stratified J30–J39 and demonstrated the difference between blood groups (Table S1). All the results were adjusted by age, gender, education, occupation, and ethnicity (Table 2).
      Table 2Risk of respiratory disease among inpatients in relation to blood group, overall and stratified by age.
      All respiratory diseasesO (%)ARRA (%)ARRB (%)ARRAB (%)ARR
      All ages combined8249/519249 (1.59)Ref7644/484389 (1.58)0.994 (0.962–1.028)7974/513829 (1.55)0.972 (0.941–1.004)2730/168796 (1.62)1.03 (0.984–1.078)
      18–352110/182323 (1.16)Ref2012/168865 (1.19)1.033 (0.969–1.102)2201/180892 (1.22)1.045 (0.982–1.113)695/59397 (1.17)1.022 (0.935–1.117)
      36–554337/276459 (1.57)Ref3994/259060 (1.54)0.986(0.943–1.032)4125/272799 (1.51)0.962 (0.920–1.006)1435/89689 (1.60)1.037 (0.974–1.104)
      >551802/60467 (2.98)Ref1638/56464 (2.90)0.970(0.904–1.041)1648/60138(2.74)0.949 (0.843–1.068)600/19710 (3.04)1.023 (0.928–1.128)
      Acute upper respiratory infections (J00–J06)
      All ages combined1411 (0.27)Ref1352 (0.28)1.041 (0.963–1.126)1351 (0.26)0.975 (0.901–1.054)459 (0.27)1.022 (0.916–1.14)
      18–35475 (0.26)Ref453 (0.27)1.051 (0.920–1.202)472 (0.26)1.013 (0.887–1.157)154 (0.26)0.967 (0.798–1.171)
      36–55737 (0.27)Ref707 (0.27)1.035 (0.929–1.153)693 (0.25)0.955 (0.856–1.066)237 (0.26)1.045 (0.898–1.215)
      >55199 (0.33)Ref192 (0.34)1.042 (0.848–1.281)186 (0.31)0.950 (0.772–1.170)68 (0.35)1.064 (0.800–1.414)
      Influenza (J09–J11)
      All ages combined470 (0.09)Ref369 (0.08)0.86 (0.747–0.99)481 (0.09)0.988 (0.866–1.128)158 (0.09)1.032 (0.858–1.242)
      18–35198 (0.11)Ref165 (0.1)0.863 (0.698–1.067)203 (0.11)0.948 (0.775–1.159)62 (0.1)0.883 (0.657–1.186)
      36–55223 (0.08)Ref167 (0.06)0.841 (0.683–1.036)225 (0.08)1.007 (0.83–1.221)69 (0.08)1.009 (0.767–1.328)
      >5551 (0.08)Ref43 (0.08)0.941 (0.681–1.594)56 (0.09)0.935 (0.754–1.698)30 (0.15)0.987 (0.940–3.184)
      Pneumonia (J12–J18)
      All ages combined1850 (0.36)Ref1635 (0.34)0.947 (0.883–1.014)1700 (0.33)0.911 (0.851–0.976)577 (0.34)0.961 (0.873–1.059)
      18–35886 (0.49)Ref778 (0.46)0.947 (0.856–1.047)847 (0.47)0.955 (0.866–1.054)265 (0.45)0.948 (0.823–1.092)
      36–55792 (0.29)Ref710 (0.27)0.93 (0.837–1.033)696 (0.26)0.868 (0.785–0.971)260 (0.29)0.972 (0.84–1.125)
      >55154 (0.25)Ref147 (0.26)1.038 (0.824–1.308)144 (0.24)0.897 (0.71–1.134)52 (0.26)0.989 (0.715–1.368)
      Other acute lower respiratory infections (J20–J22)
      All ages combined1498 (0.29)Ref1367 (0.28)0.978 (0.906–1.055)1436 (0.28)0.966 (0.896–1.042)497 (0.29)1.033 (0.93–1.048)
      18–35642 (0.35)Ref592 (0.35)0.989 (0.881–1.111)621 (0.34)0.967 (0.862–1.084)228 (0.38)1.097 (0.938–1.283)
      36–55733 (0.27)Ref665 (0.26)0.968 (0.867–1.080)678 (0.25)0.941 (0.844–1.050)236 (0.26)1.014 (0.871–1.181)
      >55123 (0.20)Ref110 (0.19)0.974 (0.746–1.273)137 (0.23)1.100 (0.854–1.417)33 (0.17)0.815 (0.547–1.213)
      Other diseases of upper respiratory tract (J30–J39)
      All ages combined1571 (0.30)Ref1657 (0.34)1.139 (1.06–1.225)1677 (0.33)1.095 (1.019–1.177)574 (0.34)1.178 (1.067–1.30)
      18–35812 (0.45)Ref898 (0.53)1.215 (1.099–1.342)926 (0.51)1.186 (1.074–1.310)316 (0.53)1.271 (1.111–1.454)
      36–55695 (0.25)Ref676 (0.26)1.027 (0.919–1.147)679 (0.25)0.987 (0.884–1.103)237 (0.26)1.077 (0.924–1.255)
      >5564 (0.11)Ref83 (0.15)1.456 (1.038–2.042)72 (0.12)1.131 (0.797–1.607)21 (0.11)1.09 (0.661–1.795)
      Chronic lower respiratory diseases (J40–J47)
      All ages combined1050 (0.20)Ref917 (0.19)0.931 (0.849–1.022)960 (0.19)0.926 (0.845–1.015)329 (0.19)0.936 (0.82–1.067)
      18–35473 (0.26)Ref229 (0.14)0.903 (0.751–1.084)248 (0.14)0.911 (0.761–1.090)174 (0.29)0.782 (0.594–1.029)
      36–55535 (0.19)Ref590 (0.23)0.917 (0.853–1.014)410 (0.15)0.951 (0.845–1.077)141 (0.16)0.871 (0.632–1.135)
      >5542 (0.07)Ref38 (0.07)0.905 (0.836–1.047)31 (0.05)0.944 (0.855–1.052)15 (0.08)0.815 (0.547–1.213)
      Lungx diseases due to external agents (J60–J70)
      All ages combined15 (0.01)Ref28 (0.01)1.909 (0.916–3.59)17 (0.01)1.132 (0.559–2.294)6 (0.01)1.292 (0.501–3.331)
      18–354 (0.01)Ref16 (0.01)1.611 (0.940–3.184)9 (0.01)1.244 (0.781–2.339)3 (0.01)1.151 (0.920–1.202)
      36–559 (0.01)Ref9 (0.01)1.232 (0.925–2.876)5 (0.01)1.198 (0.844–2.546)2 (0.01)1.135 (0.929–1.153)
      >552 (0.01)Ref3 (0.01)1.309 (0.897–2.376)3 (0.01)1.209 (0.857–2.366)1 (0.01)1.056 (0.848–1.281)
      Other respiratory diseases principally affecting the interstitium (J80–J84)
      All ages combined76 (0.01)Ref64 (0.01)0.925 (0.658–1.299)79 (0.02)0.918 (0.658–1.282)20 (0.01)0.839 (0.511–1.378)
      18–3547 (0.01)Ref44 (0.01)0.959 (0.866–1.128)55 (0.01)1.013 (0.887–1.157)14 (0.01)0.814 (0.636–1.145)
      36–5523 (0.01)Ref11 (0.01)0.961 (0.775–1.159)13 (0.01)1.102 (0.797–1.239)3 (0.01)0.855 (0.718–1.266)
      >556(0.01)Ref9 (0.01)0.964 (0.77–1.158)11 (0.01)1.071 (0.813–1.175)3 (0.01)0.847(0.611–1.328)
      Suppurative and necrotic conditions of the lower respiratory tract (J85–J86)
      All ages combined20 (0.01)Ref14 (0.01)0.742 (0.314–1.313)23 (0.01)0.958 (0.509–1.802)6 (0.01)0.888 (0.355–2.222)
      18–3514 (0.01)Ref9 (0.01)0.870 (0.773–1.192)16 (0.01)0.941 (0.863–1.126)4 (0.01)0.834 (0.624–1.329)
      36–554 (0.01)Ref3 (0.01)0.851 (0.745–1.277)4 (0.01)0.933 (0.890–1.311)2 (0.01)0.863 (0.645–1.235)
      >552 (0.01)Ref2 (0.01)0.839 (0.805–1.152)3 (0.01)0.945 (0.829–1.153)0 (0)-
      Other diseases of the pleura (J90–J94)
      All ages combined207 (0.04)Ref165 (0.03)0.851 (0.688–1.052)190 (0.04)0.944 (0.77–1.158)69 (0.04)1.027 (0.774–1.363)
      18–35152 (0.08)Ref103 (0.06)0.975 (0.901–1.054)125 (0.07)0.961 (0.873–1.059)47 (0.08)1.057 (0.867–1.180)
      36–5531 (0.01)Ref40 (0.02)1.013 (0.887–1.157)37 (0.01)0.948 (0.823–1.092)15 (0.02)0.969(0.846–1.091)
      >5524 (0.04)Ref22 (0.04)0.955 (0.856–1.066)28 (0.05)0.972 (0.84–1.125)7 (0.04)0.974 (0.746–1.273)
      Intraoperative and postprocedural complications and disorders of respiratory system, not elsewhere classified (J95–J95.89)
      All ages combined0 (0)Ref0 (0)-0 (0)-1 (0.001)-
      18–350 (0)Ref0 (0)-0 (0)-0 (0)-
      36–550 (0)Ref0 (0)-0 (0)-1 (0.001)-
      >550 (0)Ref0 (0)-0 (0)-0 (0)-
      Other diseases of the respiratory system (J96–J99)
      All ages combined482 (0.09)Ref427 (0.09)0.918 (0.801–1.052)437 (0.09)0.879 (0.767–1.008)152(0.09)0.955 (0.789–1.156)
      18–35377 (0.21)Ref337 (0.20)0.917 (0.856–1.047)309 (0.17)0.959 (0.862–1.084)111 (0.19)0.966 (0.798–1.171)
      36–5581 (0.03)Ref70 (0.03)0.933 (0.837–1.033)76 (0.03)0.971 (0.844–1.050)29 (0.03)0.959 (0.898–1.215)
      >5524 (0.04)Ref20 (0.04)0.898 (0.824–1.311)52 (0.09)1.105 (0.854–1.417)12 (0.06)0.931 (0.800–1.414)

      Severity of hospitalization

      Regarding the severity of diseases, we compared the discharge status of the diseases. A total of 24 death cases (A:6 B:9 AB:2 O:7) and 79 transferred cases (A:21 B:24 AB:10 O:24) were observed over the study period, and the majority of outcomes of discharged respiratory disease were recovery; the distribution was not significant among blood groups. In addition, we compared the duration of hospitalization for each disease in relation to blood groups. We found that the average length of stay in hospital for blood group O was 7.8 ± 3.9, blood group A was 7.7 ± 3.8, blood group B was 7.9 ± 3.9, and blood group AB was 7.7 ± 3.8; no statistical difference was observed between these blood groups. It was shown that patients with blood group O had a shorter inpatient stay due to J30–J39 than those with any of the other three blood groups (P = 0.033) and the same outcome was also observed among the patients older than 55 years old with J30–J39 (P = 0.024). Patients with blood group O aged 36–55 and >55 both had a longer length of stay due to influenza (J09–J11) than those with any of the other three blood groups (P = 0.01). In contrast, patients with blood group O had a fewer inpatient days for other diseases of the upper respiratory tract (J30–J39) than the other blood groups (P = 0.033) and this was also observed in the people aged >55 (P = 0.024) (Table 3).
      Table 3Inpatient days of respiratory diseases in relation to blood group, overall and stratified by age.
      All respiratory diseasesO (days)A (days)B (days)AB (days)P-value
      All ages combined7.8 ± 3.97.7 ± 3.87.9 ± 3.97.7 ± 3.80.615
      18–357.3 ± 3.87.3 ± 3.67.4 ± 3.77.3 ± 3.80.519
      36–558.4 ± 4.08.4 ± 3.98.5 ± 4.18.2 ± 3.90.371
      >559.4 ± 4.48.9 ± 3.69.1 ± 4.08.9 ± 3.90.427
      Acute upper respiratory infections (J00–J06)P-value
      All ages combined6.3 ± 3.26.4 ± 3.26.7 ± 3.46.4 ± 3.10.248
      18–356.0 ± 3.36.2 ± 3.26.3 ± 3.26.0 ± 2.90.269
      36–557.0 ± 3.06.9 ± 3.07.6 ± 3.87.0 ± 3.20.131
      >559.0 ± 3.88.6 ± 3.27.2 ± 3.16.0 ± 3.00.091
      Influenza (J09–J11)P-value
      All ages combined6.8 ± 4.45.6 ± 3.96.0 ± 4.16.1 ± 4.20.277
      18–355.2 ± 3.54.9 ± 3.35.4 ± 3.95.7 ± 3.90.158
      36–558.7 ± 4.57.2 ± 4.27.5 ± 4.97.9 ± 4.30.035
      >559.2 ± 5.57.4 ± 3.78.3 ± 2.58.1 ± 5.40.01
      Pneumonia (J12–J18)P-value
      All ages combined8.6 ± 3.98.5 ± 4.08.4 ± 4.08.5 ± 4.30.284
      18–358.2 ± 3.98.0 ± 3.57.8 ± 3.78.2 ± 4.40.411
      36–559.0 ± 4.09.1 ± 4.48.6 ± 4.29.0 ± 4.20.356
      >559.9 ± 4.99.2 ± 3.49.0 ± 4.39.3 ± 4.60.482
      Other acute lower respiratory infections (J20–J22)P-value
      All ages combined7.5 ± 3.37.4±3.47.4±3.37.1±3.10.183
      18–357.0 ± 3.17.1±3.16.9±3.66.6±3.50.215
      36–557.8 ± 2.78.1±3.58.2±3.37.7±3.10.269
      >558.2 ± 4.68.0±4.38.5±3.78.4±4.90.312
      Other diseases of upper respiratory tract (J30–J39)P-value
      All ages combined7.0 ± 3.47.8 ± 3.28.1 ± 3.38.5 ± 3.30.035
      18–356.5 ± 3.57.2 ± 3.77.4 ± 2.87.5 ± 3.10.246
      36–557.6 ± 4.38.2 ± 3.48.2 ± 2.98.4 ± 3.50.195
      >558.0 ± 3.99.0 ± 4.08.1 ± 3.18.8 ± 2.60.075
      Chronic lower respiratory diseases (J40–J47)P-value
      All ages combined8.2 ± 3.88.3 ± 3.78.5 ± 4.08.3 ± 3.90.19
      18–357.5 ± 4.17.5 ± 3.87.9 ± 4.27.7 ± 4.10.393
      36–558.3 ± 3.98.4 ± 4.19.1 ± 3.89.3 ± 4.40.405
      >558.5 ± 3.18.9 ± 3.79.4 ± 4.210.0 ± 3.70.255
      Lung diseases due to external agents (J60–J70)P-value
      All ages combined9.1 ± 3.511.2 ± 6.713.1 ± 6.410.0 ± 4.50.538
      18–358.8 ± 3.110.2 ± 7.212.2 ± 7.49.5 ± 5.50.438
      36–559.9 ± 3.110.8 ± 7.212.5 ± 7.410.8 ± 5.50.277
      >559.4 ± 5.210.5 ± 3.97.711.3 ± 4.90.682
      Other respiratory diseases principally affecting the interstitium (J80–J84)P-value
      All ages combined9.6 ± 5.99.7 ± 4.89.9 ± 5.89.0 ± 5.20.278
      18–358.6 ± 4.98.5 ± 3.98.7 ± 4.38.5 ± 4.60.423
      36–559.8 ± 5.59.9 ± 5.19.6 ± 6.29.5 ± 5.60.395
      >557.6 ± 3.18.6 ± 5.211.1 ± 5.78.0 ± 5.50.244
      Suppurative and necrotic conditions of the lower respiratory tract (J85–J86)P-value
      All ages combined14.2 ± 8.012.9 ± 5.813.9 ± 8.210.2 ± 7.00.103
      18–3513.4 ± 6.412.2 ± 4.913.1 ± 7.79.8 ± 6.30.351
      36–5514.5 ± 5.913.4 ± 6.113.1 ± 7.79.8 ± 6.30.236
      >557.5 ± 2.1615-0.714
      Other diseases of the pleura (J90–J94)P-value
      All ages combined9.9 ± 5.78.9 ± 5.08.8 ± 4.59.3 ± 6.20.114
      18–359.2 ± 5.58.5 ± 4.68.1 ± 4.39.0 ± 6.70.153
      36–5511.4 ± 5.710.0 ± 5.79.2 ± 5.111.1 ± 5.70.216
      >5514.8 ± 8.311.3 ± 6.810.5 ± 1.912.6 ± 7.20.079
      Intraoperative and postprocedural complications and disorders of respiratory system, not elsewhere classified (J95–J95.89)P-value
      All ages combined---16-
      18–35-----
      36–55---16-
      >55-----
      Other diseases of the respiratory system (J96–J99)P-value
      All ages combined9.2 ± 5.09.3 ± 4.69.2 ± 4.89.0 ± 4.20.897
      18–358.5 ± 4.38.8 ± 5.08.7 ± 4.78.7 ± 4.20.207
      36–559.7 ± 5.19.5 ± 4.29.7 ± 5.09.6 ± 4.10.969
      >5513.2 ± 7.410.0 ± 5.410.4 ± 4.98.0 ± 3.00.164

      Discussion

      We found that the risk of upper respiratory tract infections, influenza, and pneumonia were significantly different by blood groups. Specifically, compared with participants with blood group O, participants with blood groups A, B, and AB all had a higher risk for other diseases of the upper respiratory tract, whereas participants with blood group A had shown a lower risk for hospitalization due to influenza and blood group B had shown a lower risk for the hospitalization due to pneumonia. Regarding the duration of hospitalization, participants with blood group O older than 36 years seemed to have the longest inpatient stay for influenza, and those who were older than 55 had shown the shortest stay for upper respiratory tract infections except for acute ones.
      Using a large database comprising almost all Shaanxi blood donors in the past two decades, we were able to show that individuals with blood groups A, B, and AB were at no increased risk for the overall hospitalization due to respiratory diseases (J00–J99) compared with individuals with blood group O. Although only blood donors were participants in the study, their blood group distribution was like that of the general population.
      When it came to individual diseases, however, participants with blood group A had a lower risk of influenza, although the risk reduction was comparatively modest compared with participants with blood group O. Consistently, it was also found that patients with blood group A had a shorter inpatient stay for influenza than those with other blood groups. Although influenza is also a communicable respiratory disease, the result is not consistent with the conclusion in COVID-19 that blood group A had a higher risk for being infected, which may indicate that the mechanisms of the two infections were different. A previous study has found an impact of ABO antigens on the binding of human salivary mucoglycoprotein to the influenza virus (
      • Cohen M
      • Hurtado-Ziola N
      • Varki A.
      ABO blood group glycans modulate sialic acid recognition on erythrocytes.
      ). Another study has demonstrated that the inhibitor of influenza B virus hemagglutination in human saliva is inactivated by neuraminidase and is associated with the mucous glycoprotein fraction (ABO blood group substance) of this secretion (
      • Boat TF
      • Davis J
      • Stern RC
      • Cheng PW.
      Effect of blood group determinants on binding of human salivary mucous glycoproteins to influenza virus.
      ). However, these studies were published a long time ago and no epidemiological evidence has been added in this field.
      In this study, participants with blood group B showed a lower risk for pneumonia than those with blood group O. The result is contradicting the findings regarding COVID-19 that group O has a lower risk. It may imply that there is more complexity and susceptibility of the COVID-19 disease compared with previous pneumonia (
      • Kong X
      • Qi Y
      • Huang J
      • Zhao Y
      • Zhan Y
      • Qin X
      • et al.
      Epidemiological and clinical characteristics of cancer patients with COVID-19: A systematic review and meta-analysis of global data.
      ,
      • Wang W
      • Chai Z
      • Cooper Mark
      • Zimmet Paul
      • Guo H
      • Ding J
      • et al.
      High Fasting Blood Glucose Level With Unknown Prior History of Diabetes Is Associated With High Risk of Severe Adverse COVID-19 Outcome.
      ). Only one study has proposed the possible mechanisms underlying the association. It found the specificity of FcsSBP for the blood group A and B antigens: the carbohydrate transport machinery of S. pneumoniae is capable of recognizing distinctive carbohydrate antigens, namely the A and B antigens (
      • Higgins MA
      • Abbott DW
      • Boulanger MJ
      • Boraston AB.
      Blood group antigen recognition by a solute-binding protein from a serotype 3 strain of Streptococcus pneumoniae.
      ).
      Our study demonstrated no significant association between blood groups and lower tract respiratory diseases except for pneumonia. A Danish study also reported that no single blood group was a risk indicator for lower respiratory infection (
      • Vestbo J
      • Hein HO
      • Suadicani P
      • Sørensen H
      • Gyntelberg F.
      Genetic markers for chronic bronchitis and peak expiratory flow in the Copenhagen Male Study.
      ). Another study suggested that ABO nonsecretor status is not a significant risk factor for the development of COPD (J44), one of the chronic lower respiratory diseases (
      • Walter R
      • Gottlieb DJ
      • O'Connor GT
      Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease.
      ). In contrast, a statistically significant association of salivary nonsecretor with low lung function was reported in the Johns Hopkins genetic epidemiological study conducted in 1980 (
      • Cohen BH
      • Bias WB
      • Chase GA
      • Diamond EL
      • Graves CG
      • Levy DA
      • et al.
      Is ABH nonsecretor status a risk factor for obstructive lung disease?.
      ). A study concluded that non-O blood groups, such as A, B, and AB, predominate in asthma (J45) (
      • Mroczek B
      • Sitko Z
      • Sujewicz A
      • Wolińska W
      • Karpeta-Pawlak I
      • Kurpas D.
      Blood group and incidence of asthma and chronic obstructive pulmonary disease.
      ). This may be due to a possible small protective effect of the secretion of ABO antigens on smoking-induced damage to the airways (
      • Taylor-Cousar JL
      • Zariwala MA
      • Burch LH
      • Pace RG
      • Drumm ML
      • Calloway H
      • et al.
      Histo-blood group gene polymorphisms as potential genetic modifiers of infection and cystic fibrosis lung disease severity.
      ). The inconsistent results may need further investigation from both epidemiological and laboratory studies.
      This study was subject to several limitations. First, as a retrospective study, the records were exported from EHR, and the number of people who have left the province was not recorded, so it may have affected the hospitalization rate. However, the current data show that immigrants of Shaanxi account for approximately 10%, a proportion that will not affect the outcomes significantly. Second, the study did not consider the participants’ environment and family disease history, both of which may have an impact on respiratory diseases. Third, the duration of hospitalization may be affected by the economic situation and the quality of healthcare of admitted hospitals and cannot be considered in the comparison. Fourth, our data cannot explain the etiology of the respiratory viruses binding with blood group antigens from the epidemiological field, further laboratory/genetic support is necessary to verify a definitive etiological association of ABO blood groups. Despite these limitations, to our knowledge, our study is the first largest population-based study to provide comprehensive evidence of the association between blood groups and respiratory diseases.

      Conclusion

      We conclude that non-O blood groups, such as A, B, and AB, predominate in upper respiratory tract diseases, and participants with blood group A have less risk of being infected with influenza and blood group B patients with blood group are less likely to be infected with pneumonia compared with patients with blood group O. The result for influenza is consistent with the comparison of the length of hospitalization stay for each blood group. Blood group appears to be a prognostic differentiator between the occurrence of diseases among inpatients and the length of their inpatient stay. However, further investigation is required to understand the predisposing role of the ABO antigens in respiratory diseases. The possible relationship between the blood group and the pathogenesis of respiratory diseases may, following further such research, enhance the predictive power for the development of such diseases.

      Author contributions

      Shu Su, Lei Zhang, and Jiangcun Yang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Lei Zhang and Jiangcun Yang. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Shu Su, Lingxia Guo, and Ting Ma. Critical revision of the manuscript for important intellectual content: Yang Sun, Aowei Song, Wenhua Wang, and Xiaoyun Gu. Statistical analysis: Shu Su and Leilei Zhang. Supervision: Jiangcun Yang and Lei Zhang.

      Funding/Support

      Lei Zhang is supported by the National Natural Science Foundation of China (Grant number: 81950410639); Outstanding Young Scholars Support Program (Grant number: 3111500001); Xi'an Jiaotong University Basic Research and Profession Grant (Grant number: xtr022019003, xzy032020032); Epidemiology modeling and risk assessment (Grant number: 20200344); and Xi'an Jiaotong University Young Scholar Support Grant (Grant number: YX6J004). Jiangcun Yang is supported by the 2021 Science and Technology Talent Support Program of Shaanxi Provincial People's Hospital (Grant Number: 2021LJ-14). Shu Su is supported by the 2022 Science and Technology Talent Support Program of The Second Affiliated Hospital of ChongQing Medical University (Grant Number: 2022ssky).

      Acknowledgments

      We thank the following individuals at Shaanxi Provincial Blood Center: Hengxin Li, Xiaoli Cao, and Zhendong Sun. We also acknowledge the data interpretation assistance of Ke Ding at Hanzhong blood center, Bing Shi at Yanan blood center, Erqin Bai at Yulin blood center, Shengli Yan at Weinan blood center, Guoqiang Zhang at Tongchuan blood center, Hailin Zhang at Baoji blood center, Zhangxue Hu at Ankang blood center, Guancheng Yuan at Shangluo blood center, Xin liang at Xianyang blood center, and Keqian Cheng at Shaanxi Health Information Center.

      Appendix. Supplementary materials

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