PTX3 Haplotype in Donors Increases Risk of Invasive Aspergillosis in Stem Cell Transplantation
In a study reported in The New England Journal of Medicine, Cunha et al found that receipt of a stem cell transplant from donors with a homozygous haplotype (h2/h2, G-A/G-A) in PTX3, the gene encoding the soluble pattern-recognition receptor pentraxin 3 (PTX3), is associated with significantly increased risk of invasive aspergillosis.
Study Details
The association of the PTX3 haplotype with increased risk for invasive aspergillosis was identified in a discovery cohort of 268 adult patients undergoing hematopoietic stem cell transplantation and their donors at the Hospital of the University of Perugia, Italy, between 2003 and 2011. Among these patients, 51 had invasive aspergillosis after transplantation.
The aspergillosis and no-aspergillosis groups were generally balanced for age, sex, sex of donor/recipient pair, underlying disease (acute leukemia in 61% and 70%, lymphoma or myeloma in 27% and 24%), disease stage, cytomegalovirus status of donor and recipient, duration of neutropenia, and frequency of grade II, III, or IV acute graft vs host disease.
All patients with aspergillosis received transplants form related donors, as did 98% of patients without aspergillosis. There was a trend for patients with aspergillosis to more frequently receive their transplant from an HLA-mismatched related donor (73% vs 56%, P = .06). Patients with aspergillosis were more likely to have received total-body irradiation (84% vs 69%, P = .04) and to have received liposomal amphotericin B as prophylaxis (96% vs 82%, P = .02; 4% and 18% received fluconazole).
Increased Risk
Risk for invasive aspergillosis was significantly higher among the 60 patients in the discovery cohort with haplotype h2/h2 donors than among the 53 with h1/h1 (A-C/A-C) donors and 137 with h1/h2 (G-A/G-A) donors (P < .001). Overall, invasive aspergillosis was observed in 37% of recipients with vs 15% of recipients without haplotype h2/h2 donors (adjusted hazard ratio [HR] = 3.08, P = .003). The increased risk associated with the haplotype was observed regardless of HLA-matching status of the donor, acute graft-vs-host disease, and type of prophylaxis.
In a multicenter confirmation study performed in 107 case patients with invasive aspergillosis and 223 matched controls without aspergillosis, risk of invasive aspergillosis was similarly increased in recipients with haplotype h2/h2 donors (adjusted HR = 2.78, P = .03).
PTX3 Deficiency and Impaired Phagocytosis
In studies of PTX3 expression in a subset of transplant recipients, higher levels of PTX were found in bronchoalveolar-lavage fluid but not in plasma in patients with vs without invasive aspergillosis. However, PTX3 levels were significantly lower in recipients with h2/h2 haplotype donors than in recipients with h1/h1 donors both in patients with (median, 2.50 vs 1.36 ng/mL, P < .001) and patients without (0.83 vs 0.47 ng/mL, P < .001) invasive aspergillosis. Similar findings of lower PTX3 expression in association with donor h2/h2 haplotype were made with immunofluorescence analysis of lung biopsy specimens from patients with invasive aspergillosis.
The h2/h2 haplotype was correlated with lower levels of PTX3 mRNA in h2/h2 neutrophil precursors vs h1/h1 precursors. Neutrophils from h2/h2 patients exhibited a significant 40% reduction in ability to phagocytose conidia of Aspergillus fumigatus compared with neutrophils from h1/h1 patients.
The investigators concluded: “Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with [hematopoietic stem cell transplantation].”
Agostinho Carvalho, PhD, of the University of Perugia, is the corresponding author for The New England Journal of Medicine article.
The study was supported by the European Society of Clinical Microbiology and Infectious Diseases and others.
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