Magnetic Resonance Imaging Detects Chronic Rhinosinusitis in Infants and Preschool Children with Cystic Fibrosis.

Rationale: Chronic rhinosinusitis (CRS) contributes to disease burden of patients with cystic fibrosis (CF). However, its onset and progression in infants and preschool children with CF remain poorly understood.Objectives: To determine the prevalence and extent of CRS in young children with CF using magnetic resonance imaging (MRI).Methods: MRI was performed in sedation in 67 infants and preschool children with CF (mean age 2.3 ± 2.1 yr; range 0-6 yr) and 30 non-CF control subjects (3.5 ± 2.0 yr; range 0-6 yr). Paranasal sinus dimensions and structural abnormalities, including mucosal swelling; mucopyoceles; and nasal polyps of the maxillary, frontal, sphenoid, and ethmoid sinuses; and, in addition, medial maxillary sinus wall deformation, were assessed using a dedicated CRS MRI scoring system.Results: Pneumatization and dimensions of paranasal sinuses did not differ between the two groups. MRI detected an increased prevalence of mucosal swelling (83% vs. 17%; P < 0.001), mucopyoceles (75% vs. 2%; P < 0.001), polyps (26% vs. 7%; P < 0.001), and maxillary sinus wall deformation (68% vs. 2%; P < 0.001) in infants and preschool children with CF compared with age-matched control subjects. Furthermore, the extent of these abnormalities was also increased with a MRI sum score of 22.9 ± 10.9 in CF compared with 4.5 ± 7.6 in non-CF control subjects (P < 0.001).Conclusions: MRI detected normal dimensions of paranasal sinuses, and a high prevalence and severity of paranasal sinus abnormalities due to CRS in infants and preschool children with CF without radiation exposure. Our results support the development of MRI for sensitive noninvasive diagnosis and monitoring of CRS in young children with CF, and as outcome measures for clinical trials.Clinical trial registered with www.clinicaltrials.gov (NCT00760071).

Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease.

RATIONALE: Studies demonstrating early structural lung damage in infants and preschool children with cystic fibrosis (CF) suggest that noninvasive monitoring will be important to identify patients who may benefit from early therapeutic intervention. Previous studies demonstrated that magnetic resonance imaging (MRI) detects structural and functional abnormalities in lungs from older patients with CF without radiation exposure. OBJECTIVES: To evaluate the potential of MRI to detect abnormal lung structure and perfusion in infants and preschool children with CF, and to monitor the response to therapy for pulmonary exacerbation. METHODS: MRI studies were performed in 50 children with CF (age, 3.1 ± 2.1 yr; range, 0-6 yr) in stable clinical condition (n = 40) or pulmonary exacerbation before and after antibiotic treatment (n = 10), and in 26 non-CF control subjects (age, 2.9 ± 1.9 yr). T1- and T2-weighted sequences before and after intravenous contrast and first-pass perfusion imaging were acquired, and assessed on the basis of a dedicated morphofunctional score. MEASUREMENTS AND MAIN RESULTS: MRI demonstrated bronchial wall thickening/bronchiectasis, mucus plugging, and perfusion deficits from the first year of life in most stable patients with CF (global score, 10.0 ± 4.0), but not in non-CF control subjects (score, 0.0 ± 0.0; P < 0.001). In patients with exacerbations, the global MRI score was increased to 18.0 ± 2.0 (P < 0.001), and was significantly reduced to 12.0 ± 3.0 (P < 0.05) after antibiotic therapy. CONCLUSIONS: MRI detected abnormalities in lung structure and perfusion, and response to therapy for exacerbations in infants and preschool children with CF. These results support the development of MRI for noninvasive monitoring and as an end point in interventional trials for early CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT00760071).

Validation of Fourier decomposition MRI with dynamic contrast-enhanced MRI using visual and automated scoring of pulmonary perfusion in young cystic fibrosis patients.

PURPOSE: To validate Fourier decomposition (FD) magnetic resonance (MR) imaging in cystic fibrosis (CF) patients with dynamic contrast-enhanced (DCE) MR imaging. MATERIALS AND METHODS: Thirty-four CF patients (median age 4.08 years; range 0.16-30) were examined on a 1.5-T MR imager. For FD MR imaging, sets of lung images were acquired using an untriggered two-dimensional balanced steady-state free precession sequence. Perfusion-weighted images were obtained after correction of the breathing displacement and Fourier analysis of the cardiac frequency from the time-resolved data sets. DCE data sets were acquired with a three-dimensional gradient echo sequence. The FD and DCE images were visually assessed for perfusion defects by two readers independently (R1, R2) using a field based scoring system (0-12). Software was used for perfusion impairment evaluation (R3) of segmented lung images using an automated threshold. Both imaging and evaluation methods were compared for agreement and tested for concordance between FD and DCE imaging. RESULTS: Good or acceptable intra-reader agreement was found between FD and DCE for visual and automated scoring: R1 upper and lower limits of agreement (ULA, LLA): 2.72, -2.5; R2: ULA, LLA: ± 2.5; R3: ULA: 1.5, LLA: -2. A high concordance was found between visual and automated scoring (FD: 70-80%, DCE: 73-84%). CONCLUSIONS: FD MR imaging provides equivalent diagnostic information to DCE MR imaging in CF patients. Automated assessment of regional perfusion defects using FD and DCE MR imaging is comparable to visual scoring but allows for percentage-based analysis.

Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?

UNLABELLED: We report on a 6-month-old premature boy from consanguineous parents. He presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia shortly after birth. Persisting respiratory symptoms and failure to thrive prompted cystic fibrosis diagnostics, which showed the lack of wild-type signal for the mutation R347P suggesting a homozygous deletion or an alteration different from the known mutation at this position. Sequencing of this region revealed the homozygous substitution 1175 T > A (HGVS: c.1043 T > A) in exon 7 resulting in the homozygous amino acid change M348K. This mutation has never been reported in homozygosity before. Computational analysis tools classified M348K as 'presumably disease causing.' In our patient, sweat testing and electrophysiological assessment of CFTR function in native rectal epithelium demonstrated normal Cl(-) secretion. CONCLUSION: We assume that the homozygous alteration M348K is a harmless variant rather than a CF-causing mutation.

Intracerebral human regulatory T cells: analysis of CD4+ CD25+ FOXP3+ T cells in brain lesions and cerebrospinal fluid of multiple sclerosis patients.

Impaired suppressive capacity of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) from peripheral blood of patients with multiple sclerosis (MS) has been reported by multiple laboratories. It is, however, currently unresolved whether Treg dysfunction in MS patients is limited to reduced control of peripheral T cell activation since most studies analyzed peripheral blood samples only. Here, we assessed early active MS lesions in brain biopsies obtained from 16 patients with MS by FOXP3 immunohistochemistry. In addition, we used six-color flow cytometry to determine numbers of Treg by analysis of FOXP3/CD127 expression in peripheral blood and cerebrospinal fluid (CSF) of 17 treatment-naïve MS patients as well as quantities of apoptosis sensitive CD45RO(hi)CD95(hi) cells in circulating and CSF Treg subsets. Absolute numbers of FOXP3(+) and CD4(+) cells were rather low in MS brain lesions and Treg were not detectable in 30% of MS biopsies despite the presence of CD4(+) cell infiltrates. In contrast, Treg were detectable in all CSF samples and Treg with a CD45RO(hi)CD95(hi) phenotype previously shown to be highly apoptosis sensitive were found to be enriched in the CSF compared to peripheral blood of MS patients. We suggest a hypothetical model of intracerebral elimination of Treg by CD95L-mediated apoptosis within the MS lesion.

Regulatory T cells and tolerance induction.

Transplantation tolerance is the ultimate goal of organ transplantation. Natural regulatory T cells (Treg) have been expected to reach clinical applications for tolerance induction because their initial description. More than ten yr later, Treg have started moving from experimental animal models into clinical applications. Although the molecular mechanism of contact-dependent inhibition remains to be unraveled, alterations of Treg numbers have been shown in several human diseases: Whereas several autoimmune diseases have been reported to be associated with decreased Treg numbers, Treg are frequently accumulated in solid tumors and hematologic malignancies. Monitoring of Treg numbers could be instrumental in identifying patients with risk of graft failure and might help minimizing immunosuppressive therapy in transplant recipients. Molecular mechanisms of Treg proliferation and Treg elimination such as CD95 ligand (CD95L)-mediated apoptosis are currently explored for their clinical usability as therapeutical targets. Immunosuppressive drugs might modulate the number of Tregs. Expansion of the Treg numbers in vivo or in vitro resembles a novel therapeutical strategy to reach partial or even operational tolerance after organ transplantation.