Invasive Pulmonary Aspergillosis (IPA) is the most common cause of infection-related deaths in patients with haematological cancers. Despite the availability of new antifungal drugs, the incidence of IPA is rising as a result of a wider use of broadspectrum antibiotics, novel immunomodulatory therapies and an increasing proportion of susceptible patients such as solid organ transplantation recipients or critical care patients. Dendritic Cell-Specifi c Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), Dectin-1 and Dectin-2 are transmembrane C-type lectins involved in the recognition of fungal pathogens. The recognition of Aspergillus conidia by dendritic cells or macrophages as well as the chemotactic activity mediated by CCL2/CCR2 ligand-receptor axis, are critical steps in the defence response against Aspergillus. It has been suggested that both processes might be, at least in part, genetically determined. Thus, the aim of this study was to assess whether the presence of single nucleotide polymorphisms within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes infl uence on the risk of Invasive Pulmonary Aspergillosis infection. A tag SNP approach resulted in a selection of twenty-seven tagging polymorphisms that were genotyped in 217 high-risk patients with haematological malignancies. Out of 217 haematological patients, seventy patients were diagnosed with proven or probable IPA (following the EORT/MSG criteria, 2008) and the remaining 147 patients were classifi ed as not infected. Our results revealed that patients bearing the DC-SIGN_rs4804800_G, DC-SIGN_rs11465384_T and DC-SIGN_rs7248637_A alleles had an increased risk of IPA infection (per-allele OR=2.73 95%CI 1.53-4.87; PTrend=0.0004; OR=2.73 95%CI 1.39-5.40; PTrend=0.0035 and OR=2.08 95%CI 1.16-3.72; PTrend=0.013, respectively). In addition, carriers of the DC-SIGN_rs7252229_C showed a slightly increased risk of IPA infection (per-allele OR=1.68 95%CI 0.94-3.00; PTrend=0.078). Likewise, patients harbouring the DC-SIGN_rs4804800_G or DC-SIGN_rs7252229_C alleles showed an increased frequency of galactomannan positivity that those carrying the A or G allele, respectively (p=0.06 and p=0.08). These results strong suggest that DC-SIGN polymorphisms might modulate the risk of IPA infection and might be useful as biomarkers for patient stratifi cation and to develop personalized treatment strategies. Nonetheless, these results need to be confi rmed in larger cohorts of haematological patients.
Full conference title:
Annual Meeting of the EBMT, 37th
- EBMT 37th (2011)