Abstract
We sought to investigate the relationship between polymorphisms of the NOD2 gene and infectious complications following intensive induction chemotherapy in patients with acute myeloid leukaemia (AML). We hypothesised that single nucleotide polymorphisms (SNPs) of the NOD2 gene are associated with a higher rate of infections during the phase of severe neutropenia. In 131 AML patients receiving induction therapy, the presence of the three most frequent polymorphisms of NOD2 (Arg702Trp, Gly908Arg, Leu1007fsinsC) was analysed. SNP analyses by means of genomic PCR incorporating fluorescence-labelled probes with characteristic melting curves were performed using the LightCycler platform. Our data suggest a significantly lower probability of mucositis or enteritis in AML patients lacking any of the three evaluated NOD2 polymorphisms. Furthermore, bloodstream cultures of AML patients carrying either a missense or a frameshift mutation of NOD2 were significantly more frequently tested positive concerning Streptococcus spp. In contrast, the presence of NOD2 polymorphisms had no impact on such important infectious complications as systemic inflammatory response syndrome or sepsis, the rate of central venous catheter infections or the incidence of pneumonia including fungal infections. Our data represent one of the first reports investigating the impact of polymorphisms of the innate immune system on infectious complications in patients with neutropenia following chemotherapy. A correlation between NOD2 polymorphisms and infectious events in AML patients is demonstrated.
Similar content being viewed by others
References
Damon LE et al (1994) Post-remission cytopenias following intense induction chemotherapy for acute myeloid leukemia. Leukemia 8(4):535–41
Gupta A et al (2010) Infections in acute myeloid leukemia: an analysis of 382 febrile episodes. Med Oncol 27(4):1037–45
Syrjala H et al (2010) Blood stream infections during chemotherapy-induced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters. Eur J Clin Microbiol Infect Dis 29(10):1211–8
Specchia G et al (2003) Pneumonia in acute leukemia patients during induction therapy: experience in a single institution. Leuk Lymphoma 44(1):97–101
Brown KL et al (2007) Complexities of targeting innate immunity to treat infection. Trends Immunol 28(6):260–6
Ito T et al (2012) Notch system in the linkage of innate and adaptive immunity. J Leukoc Biol 92(1):59–65
Elphick DA, Mahida YR (2005) Paneth cells: their role in innate immunity and inflammatory disease. Gut 54(12):1802–9
Selsted ME, Ouellette AJ (2005) Mammalian defensins in the antimicrobial immune response. Nat Immunol 6(6):551–7
Gutierrez O et al (2002) Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277(44):41701–5
Lala S et al (2003) Crohn's disease and the NOD2 gene: a role for Paneth cells. Gastroenterology 125(1):47–57
Girardin SE et al (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278(11):8869–72
Ogura Y et al (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276(7):4812–8
Hugot JP et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411(6837):599–603
Ogura Y et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411(6837):603–6
Li J et al (2004) Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 13(16):1715–25
Netea MG et al (2005) NOD2 3020insC mutation and the pathogenesis of Crohn's disease: impaired IL-1beta production points to a loss-of-function phenotype. Neth J Med 63(8):305–8
Kobayashi KS et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731–4
Uehara A et al (2007) Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 44(12):3100–11
Wehkamp J et al (2004) NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 53(11):1658–64
Bevins CL, Stange EF, Wehkamp J (2009) Decreased Paneth cell defensin expression in ileal Crohn's disease is independent of inflammation, but linked to the NOD2 1007fs genotype. Gut 58(6):882–3, discussion 883–4
Van der Graaf CA et al (2006) Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 17(1):29–34
Wurfel MM et al (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178(7):710–20
Brenmoehl J et al (2007) Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med 33(9):1541–8
Klostergaard A et al (2010) Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms. Eur J Haematol 85(1):58–64
Choi EH et al (2005) Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients. Med Mycol 43(4):349–53
Holler E et al (2004) Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104(3):889–94
Elmaagacli AH et al (2006) Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation 81(2):247–54
Estey E, Dohner H (2006) Acute myeloid leukaemia. Lancet 368(9550):1894–907
Becker C et al (2004) High complete remission rate in patients with acute myeloid leukemia (AML) above the age of 60 years: A report of the AML97#38 Study of the East German Hematology and Oncology Study Group. ASH Annual Meeting Abstracts 104(11):880
Basara N et al (2009) Early related or unrelated haematopoietic cell transplantation results in higher overall survival and leukaemia-free survival compared with conventional chemotherapy in high-risk acute myeloid leukaemia patients in first complete remission. Leukemia 23(4):635–40
Ruegg C et al (2004) Detection of the Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms of the NOD2/CARD15 gene by real-time PCR with melting curve analysis. Clin Chem Lab Med 42(5):494–8
Reinhart K et al. (2010) Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin (DIVI)). Ger Med Sci 8: p Doc14
De Pauw B et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–21
Lecat A, Piette J, Legrand-Poels S (2010) The protein Nod2: an innate receptor more complex than previously assumed. Biochem Pharmacol 80(12):2021–31
Kaser A, Niederreiter L, Blumberg RS (2011) Genetically determined epithelial dysfunction and its consequences for microflora-host interactions. Cell Mol Life Sci 68(22):3643–9
Cuthbert AP et al (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122(4):867–74
Camera A et al (2003) Intestinal toxicity during induction chemotherapy with cytarabine-based regimens in adult acute myeloid leukemia. Hematol J 4(5):346–50
Hogan WJ et al (2002) Neutropenic colitis after treatment of acute myelogenous leukemia with idarubicin and cytosine arabinoside. Mayo Clin Proc 77(8):760–2
Opitz B et al (2004) Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. J Biol Chem 279(35):36426–32
Koppe U, Suttorp N, Opitz B (2012) Recognition of Streptococcus pneumoniae by the innate immune system. Cell Microbiol 14(4):460–6
Henckaerts L et al (2009) Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 37(1):192–201, e1-3
Wong M et al (2012) Mannose-binding lectin 2 polymorphisms do not influence frequency or type of infection in adults with chemotherapy induced neutropaenia. PLoS One 7(2):e30819
Acknowledgments
This work was supported by a grant from the Deutsche José Carreras Leukämie-Stiftung (Project 11/03).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yomade, O., Spies-Weisshart, B., Glaser, A. et al. Impact of NOD2 polymorphisms on infectious complications following chemotherapy in patients with acute myeloid leukaemia. Ann Hematol 92, 1071–1077 (2013). https://doi.org/10.1007/s00277-013-1734-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-013-1734-0