Host genetic variants associated with susceptibility and severity of pneumococcal pneumonia in adult patients

Springer Science and Business Media LLC - Tập 15 Số 1
Lucía Boix-Palop1,2,3, Maria Arranz4, Anna Sangil5, Beatriz Dietl1, Mariona Xercavins6, J.A. Sánchez Pérez6, Esther Calbo1,2
1Infectious Diseases Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
2Universitat Internacional de Catalunya, Barcelona, Spain
3Universitat de Barcelona, Barcelona, Spain
4Fundació Docència i Recerca Mútua Terrassa, Barcelona, Spain
5Internal Medicine Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
6Microbiology Department, CatLab, Barcelona, Spain

Tóm tắt

Abstract Background Pneumococcal community-acquired pneumonia (P-CAP) is a major cause of morbidity and hospitalization. Several host genetics factors influencing risk of pneumococcal disease have been identified, with less information about its association with P-CAP. The aim of the study was to assess the influence of single nucleotide polymorphisms (SNP) within key genes involved in the innate immune response on the susceptibility to P-CAP and to study whether these polymorphic variants were associated with the severity and outcome of the episodes in a cohort of adult Caucasian patients. Methods Seventeen SNPs from 7 genes (IL-R1, IL-4, IL-10, IL-12B, NFKBIA, NFKBIE, NFKBIZ) were analyzed. For susceptibility, a case-control study including a cohort of 57 adult with P-CAP, and 280 ethnically matched controls was performed. Genetic influence on clinical severity and outcome was evaluated in a prospective observational study including all consecutive adult P-CAP patients from November 2015 to May 2017. Results The NFKBIA polymorphism rs696 and a haplotype combination were associated with susceptibility to P-CAP (OR = 0.62, p = 0.005 and OR = 0.63, p = 0.008, respectively). The SNP IL4 rs2227284 was associated with severe P-CAP (OR = 2.17, p = 0.04). IL-R1 (rs3917267) and IL-10 (rs3024509) variants were related with respiratory failure (OR = 3.31, p = 0.001 and OR = 0.18, p = 0.003, respectively) as well as several haplotype combinations in NFKBIA, NFKBIZ, IL-R1 and IL-10 (p = 0,02, p = 0,01, p = 0,001, p = 0,03, respectively). CURB-65 values were associated with the IL-10 rs3024509 variant (beta = − 0.4, p = 0.04), and with haplotype combinations of NFKBIZ and IL-10 (p = 0.05, p = 0.04, respectively). Genetic variants in IL-10 (rs3024509) and in IL-12B (rs730691) were associated with PSI values (beta = − 0.54, p = 0.01, and beta = − 0.28, p = 0.04, respectively), as were allelic combinations in IL-R1 (p = 0.02) and IL-10 (p = 0.01). Finally, several polymorphisms in the IL-R1 gene (rs13020778, rs2160227, & rs3917267) were associated with the time elapsed until clinical stability (beta = − 0.83, p = 0.03; beta = − 1, p = 0.02 and beta = 1.07, p = 0.008, respectively). Conclusions A genetic variant in NFKBIA was associated with susceptibility to P-CAP in adult Caucasian patients and genetic variants from key cytokines of the innate immune response (Il-4, IL-10, IL-R1 and IL-12B) and NF-κB inhibitors were associated with different phenotypes of severe P-CAP. If validated, these SNPs may help to identify people at risk of P-CAP or severe P-CAP on which preventive measures could be applied.

Từ khóa


Tài liệu tham khảo

Garau J, Calbo E. Community-acquired pneumonia. Lancet. 2008;371:455–8. https://doi.org/10.1016/S0140-6736(08)60216-0.

Mandell LA. Community-acquired pneumonia: An overview. Postgrad Med. 2015;127:607–15. https://doi.org/10.1080/00325481.2015.1074030.

Musher DM, Mandell LA, Niederman MS, File TM, Dowell SF, Torres A, et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis. 2007;44:S27–72. https://doi.org/10.1086/511159.

Rozenbaum MH, Pechlivanoglou P, Van Der Werf TS, Lo-Ten-Foe JR, Postma MJ, Hak E. The role of Streptococcus pneumoniae in community-acquired pneumonia among adults in Europe: A meta-analysis. Eur J Clin Microbiol Infect Dis. 2013;32:305–16. https://doi.org/10.1007/s10096-012-1778-4.

Shoar S, Musher DM. Etiology of community-acquired pneumonia in adults: a systematic review. Pneumonia. 2020;12 https://doi.org/10.1186/s41479-020-00074-3.

Shaw D, Abad R, Amin-Chowdhury Z, Bautista A, Bennett D, Broughton K, et al. Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium. Lancet Digit Heal. 2023;5:e582–93. https://doi.org/10.1016/S2589-7500(23)00108-5.

Amin-Chowdhury Z, Alano F, Mensah A, Sheppard CL, Litt D, Fry NK, et al. Impact of the COVID-19 Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection with SARS-CoV-2: prospective national cohort study, England. Clin Infect Dis. 2021;72(5):e65–75.

Perniciaro S, Van Der Linden M, Weinberger DM. Reemergence of Invasive Pneumococcal Disease in Germany During the Spring and Summer of 2021. Clin Infect Dis. 2022;75:1149–53. https://doi.org/10.1093/cid/ciac100.

Torres A, Cilloniz C, Niederman MS, Menéndez R, Chalmers JD, Wunderink RG, et al. Pneumonia. Nat Rev Dis Prim. 2021;7 https://doi.org/10.1038/s41572-021-00259-0.

Aspa J, Rajas O, de Castro FR, Huertas MC, Borderías L, Cabello FJ, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. Eur Respir J. 2006;27:1010–9. https://doi.org/10.1183/09031936.06.00126004.

Weinberger DM, Simonsen L, Jordan R, Steiner C, Miller M, Viboud C. Impact of the 2009 influenza pandemic on pneumococcal pneumonia hospitalizations in the United States. J Infect Dis. 2012;205:458–65. https://doi.org/10.1093/infdis/jir749.

Naucler P, Darenberg J, Morfeldt E, Örtqvist Å, Normark BH. Contribution of host, bacterial factors and antibiotic treatment to mortality in adult patients with bacteraemic pneumococcal pneumonia. Thorax. 2013;68:571–9. https://doi.org/10.1136/thoraxjnl-2012-203106.

Calbo E, Garau J. Of mice and men: innate immunity in pneumococcal pneumonia. Int J Antimicrob Agents. 2010;35:107–13. https://doi.org/10.1016/j.ijantimicag.2009.10.002.

Sangil A, Xercavins M, Rodríguez-Carballeira M, Andrés M, Riera M, Espejo E, et al. Impact of vaccination on invasive pneumococcal disease in adults with focus on the immunosuppressed. J Infect. 2015;71:422–7. https://doi.org/10.1016/j.jinf.2015.07.004.

Pelton SI, Shea KM, Farkouh RA, Strutton DR, Braun S, Jacob C, et al. Rates of pneumonia among children and adults with chronic medical conditions in Germany. BMC Infect Dis. 2015;15:1–8. https://doi.org/10.1186/s12879-015-1162-y.

Dietl B, Henares D, Boix-Palop L, Muñoz-Almagro C, Garau J, Calbo E. Related Factors to Streptococcus pneumoniae Invasive Infection and Clinical Manifestations: The Potential Role of Nasopharyngeal Microbiome. Front Med. 2021;8:1–10. https://doi.org/10.3389/fmed.2021.650271.

Chapman SJ, Hill AVS. Human genetic susceptibility to infectious disease. Nat Rev Genet. 2012;13:175–88. https://doi.org/10.1038/nrg3114.

Classen DC, Evans RS, et al. The New England Journal of Medicine Downloaded from www.nejm.org at UNIVERSITY OF MICHIGAN on December 9, 2010. For personal use only. No other uses without permission. Copyright © 1992 Massachusetts Medical Society. All rights reserved. N Engl J Med. 1992;326:653–7.

Brouwer MC, de Gans J, Heckenberg SG, Zwinderman AH, van der Poll T, van de Beek D. Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:31–44. https://doi.org/10.1016/S1473-3099(08)70261-5.

Lingappa JR, Dumitrescu L, Zimmer SM, Lynfield R, McNicholl JM, Messonnier NE, et al. Identifying host genetic risk factors in the context of public health surveillance for invasive pneumococcal disease. PLoS One. 2011;6 https://doi.org/10.1371/journal.pone.0023413.

Betriu AS, Arranz MJ, Güerri-Fernández R, Pérez M, Monzón H, Payeras A, et al. Genetic susceptibility to invasive pneumococcal disease. Infect Genet Evol. 2018;59:126–31. https://doi.org/10.1016/j.meegid.2018.01.024.

Kloek AT, Brouwer MC, van de Beek D. Host genetic variability and pneumococcal disease: a systematic review and meta-analysis. BMC Med Genom. 2019;12:130. https://doi.org/10.1186/s12920-019-0572-x.

Endeman H, Herpers BL, De Jong BAW, Voorn GP, Grutters JC, Van Velzen-Blad H, et al. Mannose-binding lectin genotypes in susceptibility to community-acquired pneumonia. Chest. 2008;134:1135–40. https://doi.org/10.1378/chest.08-0642.

Garcia-Laorden MI, Sole-Violan J, de Castro FR, Aspa J, Briones ML, Garcia-Saavedra A, et al. Mannose-binding lectin and mannose-binding lectin-associated serine protease 2 in susceptibility, severity, and outcome of pneumonia in adults. J Allergy Clin Immunol. 2008:122. https://doi.org/10.1016/j.jaci.2008.05.037.

Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche JD, et al. Variants in the mannose-binding lectin gene MBL2 do not associatewith sepsis susceptibility or survival in a large european cohort. Clin Infect Dis. 2015;61:695–703. https://doi.org/10.1093/cid/civ378.

García-Laorden MI, Rodríguez de Castro F, Solé-Violán J, Rajas O, Blanquer J, Borderías L, et al. Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia : a prospective , observational , genetic study. Crit Care. 2011;15:R57. https://doi.org/10.1186/cc10030.

Endeman H, Cornips MCA, Grutters JC, Van Den Bosch JM, Ruven HJT, Van Velzen-Blad H, et al. The Fcγ receptor IIA-R/R131 genotype is associated with severe sepsis in community-acquired pneumonia. Clin Vaccine Immunol. 2009;16:1087–90. https://doi.org/10.1128/CVI.00037-09.

Solé-Violán J, García-Laorden MI, Marcos-Ramos JA, Rodríguez De Castro F, Rajas O, Borderías L, et al. The Fcγ receptor IIA-H/H131 genotype is associated with bacteremia in pneumococcal community-acquired pneumonia. Crit Care Med. 2011;39:1388–93. https://doi.org/10.1097/CCM.0b013e31820eda74.

García-Loarden MI, Rodríguez de Castro F, Solé-Violán J, Payeras A, Briones ML, Borderías L, et al. The role of mannose-binding lectin in pneumococcal infection. Eur Respir J. 2013;41:131–9. https://doi.org/10.1183/09031936.00174111.

Martín-Loeches I, Solé-Violán J, Rodríguez de Castro F, García-Loarden MI, Borderías L, Blanquer J, et al. Variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal community-acquired pneumonia. Intrensive Care Med. 2012:256–62. https://doi.org/10.1007/s00134-011-2406-y.

Garnacho-Montero J, García-Cabrera E, Jiménez-Álvarez R, Díaz-Martín A, Revuelto-Rey J, Aznar-Martín J, et al. Genetic variants of the MBL2 gene are associated with mortality in pneumococcal sepsis. Diagn Microbiol Infect Dis. 2012;73:39–44. https://doi.org/10.1016/j.diagmicrobio.2012.02.002.

Pérez-Castellano M, Peñaranda M, Payeras A, Milà J, Riera M, Vidal J, et al. Mannose-binding lectin does not act as an acute-phase reactant in adults with community-acquired pneumococcal pneumonia. Clin Exp Immunol. 2006:228–34. https://doi.org/10.1111/j.1365-2249.2006.03140.x.

Schaaf B, Rupp J, Mu M, Kruse J, Boehmke F, Maass M, et al. The interleukin-6 ÿ 174 promoter polymorphism is associated with extrapulmonary bacterial dissemination in Streptococcus pneumoniae infection. Cytokine. 2005;31:324–8. https://doi.org/10.1016/j.cyto.2005.05.008.

Schaaf BM, Boehmke F, Esnaashari H, Seitzer U, Kothe H, Maass M, et al. Pneumococcal Septic Shock Is Associated with the Interleukin-10 – 1082 Gene Promoter Polymorphism. Am J Respir Crit Care Med. 2003;168:476–80. https://doi.org/10.1164/rccm.200210-1164OC.

Postma DF, van Werkhoven CH, van Elden LJR, Thijsen SFT, Hoepelman AIM, Kluytmans JAJW, et al. Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults. N Engl J Med. 2015;372:1312–23. https://doi.org/10.1056/NEJMoa1406330.

Boix-Palop L, Obradors M, Xercavins M, Picó-Plana E, Canales L, Dietl B, et al. Improvement of pneumococcal pneumonia diagnosis using quantitative real-time PCR targeting lytA in adult patients: a prospective cohort study. Clin Microbiol Infect. 2022;28:138.e1–7. https://doi.org/10.1016/j.cmi.2021.05.049.

Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243–50.

Lim WS, Van Der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: An international derivation and validation study. Thorax. 2003;58:377–82. https://doi.org/10.1136/thorax.58.5.377.

Chapman SJ, Khor CC, Vannberg FO, Frodsham A, Walley A, Maskell NA, et al. IkappaB Genetic Polymorphisms and Invasive Pneumococcal Disease. Am J Respir Crit Care Med. 2007;176(2):18–7. https://doi.org/10.1164/rccm.200702-169OC.

Lundbo LF, Harboe ZB, Clausen LN, Hollegaard MV, Sørensen HT, Hougaard DM, et al. Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children. EBioMedicine. 2016;3:93–9. https://doi.org/10.1016/j.ebiom.2015.11.048.

Chapman SJ, Khor CC, Vannberg FO, Rautanen A, Walley A, Segal S, et al. Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease : a genetic association study. Crit Care. 2010;14:R227. https://doi.org/10.1186/cc9377.

Chapman SJ. Can your genes make you more prone to pneumococcal disease ? Expert Rev Anti Infect Ther. 2010;8:967–72.

Bozza FA, Gomes RN, Japiassú AM, Soares M, Castro-Faria-Neto HC, Bozza PT, et al. Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock. 2004;22:309–13. https://doi.org/10.1097/01.shk.0000140305.01641.c8.

Van Der Poll T, Marchant A, Keogh CV, Goldman M, Lowry SF. Interleukin-10 impairs host defense in murine pneumococcal pneumonia. J Infect Dis. 1996;174:994–1000. https://doi.org/10.1093/infdis/174.5.994.

Temple SEL, Lim E, Cheong KY, Almeida CAM, Price P, Ardlie KG, et al. Alleles carried at positions −819 and −592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics. 2003;55:629–32. https://doi.org/10.1007/s00251-003-0621-6.

Carrol ED, Payton A, Payne D, Miyajima F, Chaponda M, Mankhambo LA, et al. The IL1RN Promoter rs4251961 Correlates with IL-1 Receptor Antagonist Concentrations in Human Infection and Is Differentially Regulated by GATA-1. J Immunol. 2011;186:2329–35. https://doi.org/10.4049/jimmunol.1002402.

Zwijnenburg PJG, van der Poll T, Florquin S, Roord JJ, van Furth AM. IL-1 Receptor Type 1 Gene-Deficient Mice Demonstrate an Impaired Host Defense Against Pneumococcal Meningitis. J Immunol. 2003;170:4724–30. https://doi.org/10.4049/jimmunol.170.9.4724.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 15 Số 1

Thông tin tác giả