ABSTRACT
Pulmonary blastomycosis is a respiratory disease that is caused by the fungus Blastomyces spp, which is acquired through inhalation of the fungal spores. Blastomycosis is relatively uncommon, with yearly incidence rate of 1-2 cases per 100 000 people. Blastomycosis is a disease that is endemic to the midwest and southern regions of the USA, most commonly affecting immunocompromised patients. About 50% of patients are asymptomatic, but for those who progress to acute respiratory distress syndrome (ARDS) mortality can be as high as 80%. Patients with severe blastomycosis are initially treated with intravenous amphotericin B, followed by long-term itraconazole maintenance therapy. In this Grand Round, we present the case of an immunocompetent 35-year-old man diagnosed with chronic pulmonary blastomycosis who had a poor response to 10 days of intravenous liposomal amphotericin B (L-AmB). He was endotracheally intubated and eventually cannulated for extracorporeal membrane oxygenation (ECMO), due to worsening respiratory function. L-AmB was replaced with a continuous infusion of intravenous amphotericin B deoxycholate (AmB-d). He improved significantly and was decannulated from ECMO on day 9 of AmBd continuous infusion and extubated on day 12 Although L-AmB is considered first-line treatment for blastomycosis, mortality remains high for patients with ARDS associated with blastomycosis. This case highlights the importance of considering AmB-d continuous infusions for patients with severe blastomycosis who might have poor clinical responses to L-AmB.
Subject(s)
Blastomycosis , Respiratory Distress Syndrome , Male , Humans , Adult , Amphotericin B/therapeutic use , Blastomycosis/drug therapy , Blastomycosis/diagnosis , Antifungal Agents/therapeutic use , Respiratory Distress Syndrome/drug therapyABSTRACT
OBJECTIVES: Recent data suggest functional interactions between NOD2 and other receptors of the innate immune system modulating inflammatory responses. Here we analyzed the role of Toll-like receptor 9 (TLR-9) gene variants with respect to susceptibility to inflammatory bowel disease (IBD) and tested for genetic interactions with NOD2 and other susceptibility genes for Crohn's disease (CD). METHODS: The single-nucleotide polymorphisms (SNPs) -1237T/C (rs5743836) and 2848A/G (rs352140=p.Pro545Pro) in TLR9, the main CD-associated variants within the genes for NOD2, IL23R, ATG16L1, and variants in the IBD5 locus and in the DLG5 gene were assessed in 956 patients with IBD (606 CD and 350 ulcerative colitis) and in 792 healthy controls. The associations with disease susceptibility and phenotype, and epistatic gene-gene interactions, were analyzed. RESULTS: The TLR9 -1237T/C polymorphism showed significant interactions with NOD2 mutations. The frequency of -1237C was significantly higher in CD patients with at least one NOD2 mutation (P=0.004 vs. controls, odds ratio (OR) 1.60, 95% confidence interval (CI) (1.15-2.21)) and further increased in CD patients with two mutated NOD2 alleles (P=0.002 vs. controls, OR 2.37, 95% CI (1.35-4.15)). Significant gene-gene interactions were also observed for the TLR9 polymorphism -1237T/C with IL23R variants (most significantly with rs1004819, P=0.0007), with a particular high frequency of -1237C in CD patients carrying CD-protective IL23R variants. Epistatic interactions of the TLR9 -1237T/C SNP were also noted with the DLG5 113G/A variant (P=0.0007). CONCLUSIONS: Our results provide evidence for genetic interactions between polymorphisms in TLR9 and CD-associated variants in NOD2, IL23R, and DLG5, differentially modulating CD susceptibility.
Subject(s)
Crohn Disease/genetics , Epistasis, Genetic , Genetic Predisposition to Disease/epidemiology , Nod2 Signaling Adaptor Protein/genetics , Receptors, Interleukin/genetics , Toll-Like Receptor 9/genetics , Adolescent , Adult , Aged , Analysis of Variance , Case-Control Studies , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/physiopathology , Crohn Disease/epidemiology , Crohn Disease/physiopathology , Female , Genetic Variation , Genome-Wide Association Study , Germany , Humans , Incidence , Logistic Models , Male , Middle Aged , Polymorphism, Single Nucleotide , Probability , Prognosis , Reference Values , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index , Young AdultABSTRACT
HLA-G is a non-classical MHC class Ib molecule predominantly expressed in cytotrophoblasts and under pathological conditions also in chronically inflamed and in malignant tissues. Recently an increased expression of HLA-G was found in ulcerative colitis (UC), but not in Crohn's disease (CD). The HLA-G gene is located in IBD3, a linkage region for inflammatory bowel disease (IBD). A 14-bp deletion polymorphism (Del+/Del-) within exon 8 of the HLA-G gene might influence transcription activity and is therefore of potential functional relevance. To investigate whether the 14-bp deletion polymorphism is associated with IBD, 371 patients with CD, 257 patients with UC and 739 controls were genotyped. The heterozygous genotype (P = 0.031) and the Del+ phenotype (P = 0.038) were significantly increased, whereas the homozygous Del- phenotype (P = 0.038) was significantly decreased in UC when compared with CD. Thus, the 14-bp deletion polymorphism within the HLA-G gene displayed significant differences between UC and CD. Moreover, a significant increase of the Del+ allele (P = 0.002) and the Del+/Del+ genotype (P = 0.013) and a consecutive decrease of the Del-/- genotype (P = 0.024) were observed in those CD cases positive for ileocecal resection. Thus, a potential effect of the HLA-G gene in IBD may affect both UC and CD. Other polymorphisms linked to the 14-bp deletion polymorphism might also contribute to immunopathogenesis. As there are several partly functional polymorphisms within the promoter region potentially influencing HLA-G expression, further studies in IBD are necessary in the context of differential expression of HLA-G between UC and CD.
