Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation

Genes & Immunity volume 20, pages 520–526 (2019)Cite this article

Subjects

Abstract

Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 ηg/ml, ±SEM 7,411.1). In total 11 rare (minor allele frequency <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988;318:727–32.

    Article  CAS  Google Scholar 

  2. Obel N, Christensen K, Petersen I, Sorensen TIA, Skytthe A. Genetic and environmental influences on risk of death due to infections assessed in Danish twins, 1943–2001. Am J Epidemiol. 2010;171:1007–13.

    Article  Google Scholar 

  3. Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet. 2010;42:772–6.

    Article  CAS  Google Scholar 

  4. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med. 2015;3:53–60.

    Article  CAS  Google Scholar 

  5. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167:1655–63.

    Article  CAS  Google Scholar 

  6. Yende S, Kammerer CM, Angus DC. Genetics and proteomics: deciphering gene association studies in critical illness. Crit Care. 2006;10:227.

    Article  Google Scholar 

  7. Nelson CL, Pelak K, Podgoreanu MV, Ahn SH, Scott WK, Allen AS, et al. A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting. BMC Infect Dis. 2014;14:83.

    Article  Google Scholar 

  8. Scherag A, Schöneweck F, Kesselmeier M, Taudien S, Platzer M, Felder M, et al. Genetic factors of the disease course after sepsis: a genome-wide study for 28 day mortality. EBioMedicine. 2016;12:239–46.

    Article  Google Scholar 

  9. Grangé S, Buchonnet G, Besnier E, Artaud-Macari E, Beduneau G, Carpentier D, et al. The use of ferritin to identify critically Ill patients with secondary hemophagocytic lymphohistiocytosis. Crit Care Med. 2016;44:e1045–53.

    Article  Google Scholar 

  10. Halacli B, Unver N, Halacli SO, Canpinar H, Ersoy EO, Ocal S, et al. Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care. 2016;35:185–90.

    Article  Google Scholar 

  11. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome. Crit Care Med. 2016;44:275–81.

    Article  CAS  Google Scholar 

  12. Fisher CJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271:1836–43.

    Article  Google Scholar 

  13. Bu F, Borsa N, Gianluigi A, Smith RJH. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects. Clin Dev Immunol. 2012;2012:9.

    Article  Google Scholar 

  14. Westra D, Volokhina E, Van Der Heijden E, Vos A, Huigen M, Jansen J, et al. Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol Dial Transplant. 2010;25:2195–202.

    Article  CAS  Google Scholar 

  15. Koné-Paut I, Galeotti C. Current treatment recommendations and considerations for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol. 2015;11:1083–92.

    Article  Google Scholar 

  16. Cetica V, Sieni E, Pende D, Danesino C, De Fusco C, Locatelli F, et al. Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry. J Allergy Clin Immunol. 2016;137:188–96.

    Article  Google Scholar 

  17. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13:289–98.

    Article  CAS  Google Scholar 

  18. Yealy D, Kellum J, Huang D, Barnato A, Weissfeld L, Pike F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683–93.

    Article  CAS  Google Scholar 

  19. Knaus W, Draper E, Wagner D, Zimmerman J. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.

    Article  CAS  Google Scholar 

  20. Rudd E, Bryceson YT, Zheng C, Edner J, Wood SM, Ramme K, et al. Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. J Med Genet. 2007;45:134–41.

    Article  Google Scholar 

  21. Strippoli R, Caiello I, De Benedetti F. Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome. J Rheumatol. 2013;40:761–7.

    Article  CAS  Google Scholar 

  22. Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, et al. Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. J Infect Dis. 2016;213:1180–8.

    Article  CAS  Google Scholar 

  23. Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing HHS public access. Sci Transl Med Jan. 2011;12:65–4.

    Google Scholar 

  24. Basheer A, Padhi S, Boopathy V, Mallick S, Nair S, Varghese RGB, et al. Hemophagocytic lymphohistiocytosis: An Unusual complication of Orientia tsutsugamushi disease (scrub typhus). Mediterr J Hematol Infect Dis. 2015;7:e2015008.

    Article  Google Scholar 

  25. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118:5794–8.

    Article  CAS  Google Scholar 

  26. Zhang K, Chandrakasan S, Chapman H, Valencia CA, Husami A, Kissell D, et al. Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. Blood. 2014;124:1331–4.

    Article  CAS  Google Scholar 

  27. Aricò M, Boggio E, Cetica V, Melensi M, Orilieri E, Clemente N, et al. Variations of the UNC13D gene in patients with autoimmune lymphoproliferative syndrome. PLoS ONE. 2013;8:1–9.

    Article  Google Scholar 

  28. Kaufman KM, Linghu B, Szustakowski JD, Husami A, Yang F, Zhang K, et al. Whole exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2014;66:3486–95.

    Article  CAS  Google Scholar 

  29. Moradian MM, Sarkisian T, Ajrapetyan H, Avanesian N. Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. J Hum Genet. 2010;55:389–93.

    Article  CAS  Google Scholar 

  30. Booty M, Chae J, Masters S, Remmers E, Barham B, Le J, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009;60:1851–61.

    Article  CAS  Google Scholar 

  31. Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, et al. Clinical disease among patients heterozygous for familial mediterranean fever. Arthritis Rheum. 2009;60:1862–6.

    Article  CAS  Google Scholar 

  32. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345–57.

    Article  CAS  Google Scholar 

  33. Neocleous V, Byrou S, Toumba M, Costi C, Shammas C, Kyriakou C, et al. Evidence of digenic inheritance in autoinflammation-associated genes. J Genet. 2016;95:761–6.

    Article  CAS  Google Scholar 

  34. Naselli A, Penco F, Cantarini L, Insalaco A, Alessio M, Tommasini A, et al. Clinical characteristics of patients carrying the Q703K variant of the NLRP3 Gene: a 10-year multicentric national study. J Rheumatol. 2016;43:1093–100.

    Article  CAS  Google Scholar 

  35. Vitale A, Lucherini O, Galeazzi M, Frediani B, Cantarini L. Long-term clinical course of patients carrying the Q703K mutation in the NLRP3 gene: a case series. Clin Exp Rheumatol. 2012;30:943–6.

    PubMed  Google Scholar 

  36. Verma D, Särndahl E, Andersson H, Eriksson P, Fredrikson M, Jönsson J-I, et al. The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production. PLoS ONE. 2012;7:e34977.

    Article  CAS  Google Scholar 

  37. Tomiyama N, Higashiuesato Y, Oda T, Baba E, Harada M, Azuma M, et al. MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol. 2008;26:13–7.

    CAS  PubMed  Google Scholar 

  38. Kitade T, Horiki N, Katsurahara M, Totoki T, Harada T, Tano S, et al. Usefulness of small intestinal endoscopy in a case of adult-onset Familial Mediterranean fever associated with jejunoileitis. Intern Med. 2015;54:1343–7.

    Article  Google Scholar 

  39. Migita K, Agematsu K, Yazaki M, Nonaka F, Nakamura A, Toma T, et al. Familial Mediterranean fever: genotype-phenotype correlations in Japanese patients. Medicine. 2014;93:158–64.

    Article  CAS  Google Scholar 

  40. Singh-Grewal D, Chaitow J, Aksentijevich I, Christodoulou J. Coexistent MEFV and CIAS1 mutations manifesting as familial Mediterranean fever plus deafness. Ann Rheum Dis. 2007;66:1541

    Article  Google Scholar 

  41. Carcillo JA, Halstead ES, Hall MW, Nguyen TC, Reeder R, Aneja R, et al. Three hypothetical inflammation pathobiology phenotypes and pediatric sepsis-induced multiple organ failure outcome. Pediatr Crit Care Med. 2017;18:513–23.

    Article  Google Scholar 

  42. Nguyen TC, Cruz MA, Carcillo JA. Thrombocytopenia-associated multiple organ failure and acute kidney injury. Crit Care Clin. 2015;31:661–74.

    Article  Google Scholar 

  43. Prescott HC, Calfee CS, Taylor Thompson B, Angus DC, Liu VX. Toward smarter lumping and smarter splitting: Rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med. 2016;194:147–55.

    Article  Google Scholar 

  44. Cichocki F, Schlums H, Li H, Stache V, Holmes T, Lenvik TR, et al. Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency. J Exp Med. 2014;211:1079–91.

    Article  CAS  Google Scholar 

  45. Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15:1–10.

    Article  Google Scholar 

  46. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Article  CAS  Google Scholar 

  47. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Article  Google Scholar 

  48. Auer PL, Reiner AP, Wang G, Kang HM, Abecasis Gr, Altshuler D, et al. Guidelines for large-scale sequence-based complex trait association studies: lessons learned from the NHLBI exome sequencing project. Am J Hum Genet. 2016;99:791–801.

    Article  CAS  Google Scholar 

  49. Kryukov GV, Pennacchio LA, Sunyaev SR. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet. 2007;80:727–39.

    Article  CAS  Google Scholar 

  50. Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337:64–9.

    Article  CAS  Google Scholar 

  51. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133:1–9.

    Article  CAS  Google Scholar 

  52. Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, et al. Functional mapping of the interactions between complement C3 and regulatory proteins using atypical hemolytic uremic syndrome-associated mutations. Blood. 2015;125:2359–70.

    Article  CAS  Google Scholar 

  53. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V. French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643–57.

    Article  CAS  Google Scholar 

  54. Asif A, Nayer A, Haas CS. Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab. J Nephrol. 2016;30:347–62.

    Article  Google Scholar 

  55. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, et al. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis. 2016;68:84–93.

    Article  CAS  Google Scholar 

  56. Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:55.

    Article  CAS  Google Scholar 

  57. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267–79.

    Article  CAS  Google Scholar 

  58. Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25:55–64.

    Article  CAS  Google Scholar 

  59. Gül A. Approach to the patients with inadequate response to colchicine in familial Mediterranean fever. Best Pract Res Clin Rheumatol. 2016;30:296–303.

    Article  Google Scholar 

  60. Šedivá A, Horváth R, Maňásek V, Gregorová A, Plevová P, Horáčková M, et al. Cluster of patients with familial Mediterranean fever and heterozygous carriers of mutations in MEFV gene in the Czech Republic. Clin Genet. 2014;86:564–9.

    Article  Google Scholar 

  61. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–21.

    Article  CAS  Google Scholar 

  62. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions predicting deleterious amino acid substitutions. Genome Res. 2001;11:863–74.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Renee Andreko, Vanessa Smith and Ali Smith at the Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, Rahil Sethi, Uma Chandran of the Department of Biomedical Informatics as well as Janette Lamb and Debra Hollingshead of the Genomics Research Core and the University of Pittsburgh for their help in this project.

Funding

This work was funded by NIGMS via R01GM108168 (PHENOMS).

Author information

Authors and Affiliations

  1. Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Kate F. Kernan, John A. Kellum, Derek C. Angus & Joseph A. Carcillo

  2. Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    Kate F. Kernan, Lina Ghaloul-Gonzalez & Joseph A. Carcillo

  3. Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Lina Ghaloul-Gonzalez & Joseph A. Carcillo

  4. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Lina Ghaloul-Gonzalez

Authors
  1. Kate F. Kernan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lina Ghaloul-Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bita Shakoory
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John A. Kellum
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Derek C. Angus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph A. Carcillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kate F. Kernan.

Ethics declarations

Conflict of interest

Drs. Angus and Kellum wish to disclose a consultancy for Sobi, Inc.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kernan, K.F., Ghaloul-Gonzalez, L., Shakoory, B. et al. Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. Genes Immun 20, 520–526 (2019). https://doi.org/10.1038/s41435-018-0030-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-018-0030-3

This article is cited by

Search

Advanced search

Quick links