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.

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.

Standardizing submaximal exercise intensities for use of supine push-pull exercise during cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging during supine exercise at (sub)maximal oxygen consumption (VO2 ) offers unique diagnostic insights. However, maximal VO2 is not achievable in the supine position and standardizing submaximal exercise intensities remains challenging. Using heart rate or workload could be a viable option to translate VO2 -based submaximal exercise intensities. AIM: To translate submaximal exercise intensities upright cycling exercise (UCE) to supine push-pull exercise (SPPE), by comparing heart rate or workload determined during UCE, with heart rate and workload during SPPE at similar exercise intensities. METHODS AND RESULTS: Sixteen healthy young adults (20.4 ± 2.2 years; 8 female) underwent cardiopulmonary UCE and SPPE testing [mean ± standard deviation maximal VO2 : 3.2 ± 0.6 vs. 5 ± 0.3 L min-1 , p < 0.001 and median (interquartile range) of the maximum workload: 310 (244, 361) vs. 98 (98, 100), p < 0.001, respectively]. Heart rate at 40% and 60% of maximal VO2 , as determined by UCE, showed low bias (-3 and 0 bpm, respectively) and wide limits of agreement (±26 and ±28 bpm, respectively), in Bland-Altman analysis. VO2 /Workload relation was exponential and less efficient during SPPE compared to UCE. Generalized estimated equation analysis predicted model-based mean workload during SPPE, with acceptable 95% confidence interval. CONCLUSION: Heart rate during UCE at submaximal exercise intensities can reasonably well be used to for SPPE in healthy subjects. Using workload, an ergometer specific, model-based mean can be used to determine exercise intensities during SPPE. Individual variations in response to posture and movement change are high. During clinical interpretation of exercise CMR, individual exercise intensity has to be considered.

Patient-driven healthcare recommendations for adults with esophageal atresia and their families.

BACKGROUND: Adults with esophageal atresia (EA) require a multidisciplinary follow-up approach, taking into account gastroesophageal problems, respiratory problems and psychosocial wellbeing. Too little is known about the full scope of these individuals' healthcare needs. We aimed to map all medical and psychosocial needs of adults with EA and their family members, and to formulate healthcare recommendations for daily practice. METHODS: A qualitative study was performed, using data from recorded semi-structured interviews with two focus groups, one consisting of adult patients with EA (n = 15) and one of their family members (n = 13). After verbatim transcription and computerized thematic analysis, results were organized according to the International Classification of Functioning, Disability and Health. Ethical approval had been obtained. RESULTS: Healthcare needs were described through 74 codes, classified into 20 themes. Most important findings for patients included the impact of gastrointestinal and pulmonary problems on daily life, long-term emotional distress of patients and parents and the need of a standardized multidisciplinary follow-up program during both child- and adulthood. CONCLUSION: The focus groups revealed numerous physical and mental health problems, as well as social difficulties, that require attention from different healthcare providers. We have formulated several healthcare recommendations that physicians may use in long-term follow-up.

What Works When Treating Granulomatous Disease in Genetically Undefined CVID? A Systematic Review.

Background: Granulomatous disease is reported in at least 8-20% of patients with common variable immunodeficiency (CVID). Granulomatous disease mainly affects the lungs, and is associated with significantly higher morbidity and mortality. In half of patients with granulomatous disease, extrapulmonary manifestations are found, affecting e.g. skin, liver, and lymph nodes. In literature various therapies have been reported, with varying effects on remission of granulomas and related clinical symptoms. However, consensus recommendations for optimal management of extrapulmonary granulomatous disease are lacking. Objective: To present a literature overview of the efficacy of currently described therapies for extrapulmonary granulomatous disease in CVID (CVID+EGD), compared to known treatment regimens for pulmonary granulomatous disease in CVID (CVID+PGD). Methods: The following databases were searched: Embase, Medline (Ovid), Web-of-Science Core Collection, Cochrane Central, and Google Scholar. Inclusion criteria were 1) CVID patients with granulomatous disease, 2) treatment for granulomatous disease reported, and 3) outcome of treatment reported. Patient characteristics, localization of granuloma, treatment, and association with remission of granulomatous disease were extracted from articles. Results: We identified 64 articles presenting 95 CVID patients with granulomatous disease, wherein 117 different treatment courses were described. Steroid monotherapy was most frequently described in CVID+EGD (21 out of 53 treatment courses) and resulted in remission in 85.7% of cases. In CVID+PGD steroid monotherapy was described in 15 out of 64 treatment courses, and was associated with remission in 66.7% of cases. Infliximab was reported in CVID+EGD in six out of 53 treatment courses and was mostly used in granulomatous disease affecting the skin (four out of six cases). All patients (n = 9) treated with anti-TNF-α therapies (infliximab and etanercept) showed remission of extrapulmonary granulomatous disease. Rituximab with or without azathioprine was rarely used for CVID+EGD, but frequently used in CVID+PGD where it was associated with remission of granulomatous disease in 94.4% (17 of 18 treatment courses). Conclusion: Although the number of CVID+EGD patients was limited, data indicate that steroid monotherapy often results in remission, and that anti-TNF-α treatment is effective for granulomatous disease affecting the skin. Also, rituximab with or without azathioprine was mainly described in CVID+PGD, and only in few cases of CVID+EGD.

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

BACKGROUND: B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease. OBJECTIVE: 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. METHODS: 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. RESULTS: Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low 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. CONCLUSIONS: 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.

Somatostatin receptor scintigraphy patterns in patients with sarcoidosis.

PURPOSE: Sarcoidosis is a multisystem granulomatous disorder, most frequently involving the lungs, skin, or eyes. Somatostatin receptor scintigraphy (SRS) can visualize sarcoid granulomas through binding of a radionuclide-coupled somatostatin analog to somatostatin receptors that are expressed in sarcoidosis. Uptake and patterns on SRS were studied and correlated to clinical and conventional findings. PATIENTS AND METHODS: Data of 218 SRSs undertaken for the analysis of potential sarcoidosis were studied. These scintigraphies were retrospectively studied on intensity uptake degrees and localization of sarcoidosis-associated lesions, and compared with conventional radiological techniques (chest x-ray and CT). RESULTS: In all but 1 of the 175 evaluable patients, SRS demonstrated uptake. In patients with thoracic sarcoidosis-associated lesions, SRS improved the yield of visualization of chest x-ray in 20 (36%) and CT in 7 (32%) of histologically unproven patients, and in 31 (30%) and 8 (14%) of the histologically proven patients, respectively. Mediastinal lesions together with either eye, salivary glands, clavicular, or hilar localizations were most frequent demonstrated on SRS and constituted characteristic patterns. Exclusive extrapulmonary disease was found in 6% of the patients. CONCLUSIONS: Somatostatin receptor scintigraphy enhances the yield of investigations in sarcoidosis patients and therefore provides a useful and sensitive imaging technique to monitor organ involvement and therapeutic efficacy in patients with sarcoidosis.

Calcium and vitamin D in sarcoidosis: is supplementation safe?

Granulomas in sarcoidosis express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1α-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.

Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis?

RATIONALE: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis. OBJECTIVES: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease. METHODS: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses. MEASUREMENTS AND MAIN RESULTS: Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses. CONCLUSIONS: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.

[Sarcoidosis: changing insights in therapy]. / Sarcoïdose: verandering in therapeutische inzichten.

Sarcoidosis is a granulomatous disease of unknown etiology. Standard treatment with immune suppressants such as glucocorticoids is started when vital organ function is threatened. Biotechnology has resulted in new treatments ('biologicals'), in particular monoclonal antibodies, that may be effective in the treatment of sarcoidosis. In patients with sarcoidosis, only the use of monoclonal antibodies that block tumour necrosis factor (TNF) has been studied scientifically, other biologicals hardly at all. TNF-blockers are used at present in patients with therapy refractory sarcoidosis.