Cardiopulmonary Morbidity in Adults Born With Congenital Diaphragmatic Hernia

OBJECTIVES: Studies concerning cardiopulmonary outcomes of adults born with congenital diaphragmatic hernia (CDH) are sparse. Moreover, they don't include participants who have been treated with extracorporeal membrane oxygenation (ECMO) during the neonatal period. This study evaluated the cardiopulmonary morbidities in young adults born with CDH.METHODS: We assessed 68 participants between the ages of 18 and 30 years. The assessment included auxology assessment, lung function tests, pulmonary imaging, cardiopulmonary exercise testing, and echocardiography.RESULTS: Lung function parameters in the overall group were significantly worse than normal values. Mean (SD) scores postbronchodilator forced expiratory volume in 1 second were -2.91 (1.38) in the ECMO-treated and -1.20 (1.53) in the non-ECMO-treated participants. Chest computed tomography scans showed mild to moderate abnormal lung structure in all ECMO-treated participants, and to a lesser extent in non-ECMO treated participants. A recurrent diaphragmatic defect was observed in 77% of the ECMO-treated group and in 43% of the non-ECMO-treated group. Except for 2 cases with acute symptoms, no clinical problems were noted in cases of recurrence. Cardiopulmonary exercise testing revealed mean (SD) percentage predicted peak oxygen consumption per kilogram of 73 (14)% and 88 (16)% in ECMO-treated and non-ECMO-treated participants, respectively. The mean (SD) workload was normal in the non-ECMO-treated group (111 [25]% predicted); in the ECMO-treated group, it was 89 (23)%. Cardiac evaluation at rest revealed no signs of pulmonary hypertension.CONCLUSIONS: In young adults who survived treatment of CDH, significant pulmonary morbidity, reduced exercise capacity, and frequent hernia recurrence should be anticipated. Lifelong follow-up care, with the emphasis on prevention of further decline, is to be recommended.</p

Development and validation of a condition-specific quality of life instrument for adults with esophageal atresia: the SQEA questionnaire

The importance of multidisciplinary long-term follow-up for adults born with esophageal atresia (EA) is increasingly recognized. Hence, a valid, condition-specific instrument to measure health-related quality of life (HRQoL) becomes imperative. This study aimed to develop and validate such an instrument for adults with EA. The Specific Quality of life in Esophageal atresia Adults (SQEA) questionnaire was developed through focus group-based item generation, pilot testing, item reduction and a multicenter, nationwide field test to evaluate the feasibility, reliability (internal and retest) and validity (structural, construct, criterion and convergent), in compliance with the consensus-based standards for the selection of health measurement instruments guidelines. After pilot testing (n = 42), items were reduced from 144 to 36 questions. After field testing (n = 447), three items were discarded based on item-response theory results. The final SQEA questionnaire (33 items) forms a unidimensional scale generating an unweighted total score. Feasibility, internal reliability (Cronbach's alpha 0.94) and test-retest agreement (intra-class coefficient 0.92) were good. Construct validity was discriminative for esophageal replacement (P < 0.001), dysphagia (P < 0.001) and airway obstruction (P = 0.029). Criterion validity showed a good correlation with dysphagia (area under the receiver operating characteristic 0.736). SQEA scores correlated well with other validated disease-specific HRQoL scales such as the GIQLI and SGRQ, but poorly with the more generic RAND-36. Overall, this first condition-specific instrument for EA adults showed satisfactory feasibility, reliability and validity. Additionally, it shows discriminative ability to detect disease burden. Therefore, the SQEA questionnaire is both a valid instrument to assess the HRQoL in EA adults and an interesting signaling tool, enabling clinicians to recognize more severely affected patients

B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy

<div><p>Background</p><p>B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn’s disease.</p><p>Objective</p><p>To elucidate the involvement of B cells in Crohn’s disease, we here performed an ‘in depth’ analysis of intestinal and blood B-cells in this chronic inflammatory disease.</p><p>Methods</p><p>Patients with Crohn’s disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.</p><p>Results</p><p>Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21^low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.</p><p>Conclusions</p><p>B cells in patients with Crohn’s disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn’s disease, which could be targeted with new therapeutics that specifically regulate B-cell function.</p></div

IgA and IgG subclass analysis.

<p><b>A,</b> Schematic representation of the constant region of the human IGH locus. <b>B,</b> Distribution of IgA and IgG subclass use in switched transcripts of healthy controls and patients with Crohn’s disease. Total numbers of analyzed sequences are indicated in the middle of the plots. χ² Test was performed to analyze differences in distributions. <b>C,</b> Combined <i>IGHV</i> mutation frequencies in IgA and IgG transcripts in patients and controls (total numbers of sequences indicated between brackets). Grey dots represent unique sequences; red lines represent median values. Statistical analysis was performed with the Mann-Whitney test; *, P<0.05; **, P<0.01; ***, P<0.001.</p

Replication history and SHM levels in <i>IGHV</i> genes of natural effector B cells.

<p><b>A,</b> Replication history of naïve and natural effector B cells as assessed using the KREC assay [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160103#pone.0160103.ref025" target="_blank">25</a>]. <b>B,</b> <i>IGHV</i> mutation frequencies in rearranged <i>IGH</i> genes of natural effector B cells in patients and controls (total numbers of sequences indicated between brackets). Grey dots represent unique sequences; red lines represent median values. <b>C</b>, Selection for replacement mutation in IGHV-CDR (red line) and IGHV-FR regions (blue lines) as determined with the BASELINe program [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160103#pone.0160103.ref028" target="_blank">28</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160103#pone.0160103.ref029" target="_blank">29</a>]. Solid lines represent patients; dashed lines represent healthy controls. Selection Strengths >0 indicate positive selection. <b>D,</b> IGH-CDR3 size distributions. All individual sizes are indicated as grey dots, red lines representing median values. The dashed line represents median values for centroblasts and centrocytes. Sorted cells were analyzed from patients 15, 16, 18 and 19. Controls were published previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160103#pone.0160103.ref030" target="_blank">30</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160103#pone.0160103.ref031" target="_blank">31</a>]. Statistical analysis was performed with the Mann-Whitney test; *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001.</p

Clinical and basic immunological characteristics of patients with Crohn’s disease.

<p>Clinical and basic immunological characteristics of patients with Crohn’s disease.</p

Composition of the blood B-cell compartment in patients with Crohn’s disease.

<p><b>A.</b> Schematic overview of peripheral B-cell subsets. <b>B.</b> Average numbers of blood B cell subsets of 21 patients affected with Crohn’s disease (black bars) and 28 healthy controls (light grey bars). <b>C.</b> Distribution of IgM, IgA and IgG within CD21^low in patients and controls <b>D.</b> Total CD21^low B cells in relation to disease duration. Statistical analyses were performed with the Mann-Whitney test or Spearman correlation; *, P<0.05; **, P<0.01.</p