Abstract
Infection is a leading cause of morbidity following allogeneic hematopoietic stem cell transplantation (allo-HCT). In a previous retrospective study of related, HLA-matched myeloablative transplants, we identified associations between common inherited polymorphisms in the MBL2 gene encoding the mediator of innate immunity, mannose-binding lectin (MBL), and risk of major infection. Missense mutations resulting in low circulating MBL levels were associated with increased infection, and high-producing promoter haplotypes were protective. However, subsequent studies have been conflicting, there are no data examining non-myeloablative transplants, and the relationship between MBL2 genotype and serum MBL levels peri-transplant has not been studied. This is important as MBL is an acute phase reactant primarily synthesized by the liver, and many conditioning regimens are hepatotoxic. Here we report a prospective study examining MBL2 genotype, MBL levels and risk of major infection following HLA-matched sibling myeloablative and non-myeloablative allo-HCT. Data is available for 138 transplants, 81 myeloablative and 57 non-myeloablative. 49 of the myeloablative transplants utilized total body irradiation (TBI) based conditioning regimens. Five promoter and missense MBL2 polymorphisms were genotyped, and plasma MBL mannan-binding and C4-deposition levels were measured pretransplant for donor and recipient, and at days 0, 14 and 28 post-transplant. Major infection was defined as invasive or systemic episodes of microbiologically confirmed sepsis. MBL levels were higher in recipients than donors at baseline (t test P<0.0001), reflecting an acute phase response induced by disease and prior treatment. Recipient MBL levels increased during the peritransplant period (ANOVA P=0.0002), most strikingly in individuals without MBL2 coding mutations undergoing TBI. 59 of 138 (42.8%) recipients experienced at least one episode of major infection (myeloablative 38/81, 46.9%, non-myeloablative 21/57 (36.8%), P=NS). The most significant clinical risk factor for infection was the use of myeloablative TBI (HR 2.8, CI 1.39–5.8, p=0.004). Analyzing all transplants, MBL2 genotype (recipient P=0.07, donor p=0.08), and recipient mannan-binding MBL levels (P=0.10) were weak risk factors for infection, however the association was highly dependent upon the type and intensity of conditioning. No association was observed in non-myeloablative transplants, but a significant interaction was observed between recipient MBL2 coding mutations and the use of TBI in myeloablative transplants (Cox P=0.002). For example, 70.6% of recipients with a coding MBL2 mutation receiving TBI developed major sepsis, compared with 20% of those without mutations not receiving TBI. Our results confirm the association of MBL status with risk of infection risk post allo-HCT. Importantly, the association is restricted to myeloablative, TBI-conditioned transplants. Further studies examining the role of MBL replacement in this setting are warranted.
Association of Mannose Binding Lectin (MBL) Levels and Invasive Fungal Disease (IFD) in Hematologic Malignancy Patients Undergoing Hematopoietic Stem Cell Transplantation (HSCT) or Receiving Chemotherapy
