Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

Exhaled breath analyses for bronchial thermoplasty in severe asthma patients.

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Although multiple trials have demonstrated clinical improvement after BT, optimal patient selection remains a challenge and the mechanism of action is incompletely understood. The aim of this study was to examine whether exhaled breath analysis can contribute to discriminate between BT-responders and non-responders at baseline and to explore pathophysiological insights of BT. METHODS: Exhaled breath was collected from patients at baseline and six months post-BT. Patients were defined as responders or non-responders based on a half point increase in asthma quality of life questionnaire scores. Gas chromatography-mass spectrometry was used for volatile organic compounds (VOCs) detection and analyses. Analytical workflow consisted of: 1) detection of VOCs that differentiate between responders and non-responders and those that differ between baseline and six months post-BT, 2) identification of VOCs of interest and 3) explore correlations between clinical biomarkers and VOCs. RESULTS: Data was available from 14 patients. Nonanal, 2-ethylhexanol and 3-thujol showed a significant difference in intensity between responders and non-responders at baseline (p = 0.04, p = 0.01 and p = 0.03, respectively). After BT, no difference was found in the compound intensity of these VOCs. A negative correlation was observed between nonanal and IgE and BALF eosinophils (r = -0.68, p < 0.01 and r = -0.61, p = 0.02 respectively) and 3-thujol with BALF neutrophils (r = -0.54, p = 0.04). CONCLUSIONS: This explorative study identified discriminative VOCs in exhaled breath between BT responders and non-responders at baseline. Additionally, correlations were found between VOC's and inflammatory BALF cells. Once validated, these findings encourage research in breath analysis as a non-invasive easy to apply technique for identifying airway inflammatory profiles and eligibility for BT or immunotherapies in severe asthma.

Airway smooth muscle and long-term clinical efficacy following bronchial thermoplasty in severe asthma.

The mechanism of action of bronchial thermoplasty (BT) treatment for patients with severe asthma is incompletely understood. This study investigated the 2.5-year impact of BT on airway smooth muscle (ASM) mass and clinical parameters by paired data analysis in 22 patients. Our findings demonstrate the persistence of ASM mass reduction of >50% after 2.5 years. Furthermore, sustained improvement in asthma control, quality of life and exacerbation rates was found, which is in line with previous reports. An association was found between the remaining ASM and both the exacerbation rate (r=0.61, p=0.04 for desmin, r=0.85, p<0.01 for alpha smooth muscle actin (SMA)) and post-bronchodilator forced expiratory volume in 1 s predicted percentage (r=-0.69, p=0.03 for desmin, r=-0.58, p=0.08 for alpha SMA). This study provides new insight into the long-term impact of BT.

Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma.

BACKGROUND: Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling. OBJECTIVE: We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes. METHODS: This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored. RESULTS: Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 µm to 5.74 µm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV1 reversibility. CONCLUSIONS: Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV1 reversibility.

Airway Inflammation Before and After Bronchial Thermoplasty in Severe Asthma.

Background: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma, of which the working mechanism and responder profile are partly unknown. The aim of this study is to analyse whether BT alters airway inflammation by epithelial gene expression, inflammatory cell counts and cytokines, and whether this relates to treatment response. Methods: In this clinical trial, 28 severe asthma patients underwent bronchoscopy before and after treatment to obtain bronchial brushes and bronchoalveolar lavage fluid (BALF) from treated and untreated airways. RNA was extracted from bronchial brushes for transcriptome analysis, and BALF cells and cytokines were analysed. Asthma quality of life questionnaires were used to distinguish responders from non-responders. We compared results before and after treatment, between treated and untreated airways, and between responders and non-responders. Results: Gene expression of airway epithelium related to airway inflammation gene set was significantly downregulated in treated airways compared to untreated airways, although this did not differ for patients before and after treatment. No differences were observed in cell counts and cytokines, neither from the untreated compared to treated airways, nor before and after treatment. At baseline, compared to non-responders, the expression of genes related to glycolysis in bronchial epithelium was downregulated and both BALF and blood eosinophil counts were higher in responders. Conclusion: Local differences in gene sets pertaining to epithelial inflammatory status were identified between treated and untreated airways after treatment, not resulting in changes in differential cell counts and cytokine analyses in BALF. Secondly, baseline epithelial glycolysis genes and eosinophil counts in BALF and blood were different between responders and non-responders. The observations from this study demonstrate the potential impact of BT on epithelial gene expression related to airway inflammation while also identifying a possible responder profile.

Metabolic differences between bronchial epithelium from healthy individuals and patients with asthma and the effect of bronchial thermoplasty.

BACKGROUND: Asthma is a heterogeneous disease with differences in onset, severity, and inflammation. Bronchial epithelial cells (BECs) contribute to asthma pathophysiology. OBJECTIVE: We determined whether transcriptomes of BECs reflect heterogeneity in inflammation and severity in asthma, and whether this was affected in BECs from patients with severe asthma after their regeneration by bronchial thermoplasty. METHODS: RNA sequencing was performed on BECs obtained by bronchoscopy from healthy controls (n = 16), patients with mild asthma (n = 17), patients with moderate asthma (n = 5), and patients with severe asthma (n = 17), as well as on BECs from treated and untreated airways of the latter (also 6 months after bronchial thermoplasty) (n = 23). Lipidome and metabolome analyses were performed on cultured BECs from healthy controls (n = 7); patients with severe asthma (n = 9); and, for comparison, patients with chronic obstructive pulmonary disease (n = 7). RESULTS: Transcriptome analysis of BECs from patients showed a reduced expression of oxidative phosphorylation (OXPHOS) genes, most profoundly in patients with severe asthma but less profoundly and more heterogeneously in patients with mild asthma. Genes related to fatty acid metabolism were significantly upregulated in asthma. Lipidomics revealed enhanced levels of lipid species (phosphatidylcholines, lysophosphatidylcholines. and bis(monoacylglycerol)phosphate), whereas levels of OXPHOS metabolites were reduced in BECs from patients with severe asthma. BECs from patients with mild asthma characterized by hyperresponsive production of mediators implicated in neutrophilic inflammation had decreased expression of OXPHOS genes compared with that in BECs from patients with mild asthma with normoresponsive production. BECs obtained after thermoplasty had significantly increased expression of OXPHOS genes and decreased expression of fatty acid metabolism genes compared with BECs obtained from untreated airways. CONCLUSION: BECs in patients with asthma are metabolically different from those in healthy individuals. These differences are linked with inflammation and asthma severity, and they can be reversed by bronchial thermoplasty.

Bronchial Thermoplasty Induced Airway Smooth Muscle Reduction and Clinical Response in Severe Asthma. The TASMA Randomized Trial.

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT, but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important.Objectives: First, to assess the effect of BT on ASM mass, and second, to identify patient characteristics that correlate with BT response.Methods: Patients with severe asthma (n = 40) were randomized to immediate (n = 20) or delayed (n = 20) BT treatment. Before randomization, clinical, functional, blood, and airway biopsy data were collected. In the delayed control group, reassessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analysis software. Associations between baseline characteristics and Asthma Control Questionnaire and Asthma Quality of Life Questionnaire (AQLQ) improvement were explored.Measurements and Main Results: Median ASM mass decreased by >50% in the immediate BT group (n = 17) versus no change in the delayed control group (n = 19) (P = 0.0004). In the immediate group, Asthma Control Questionnaire scores improved with -0.79 (interquartile range [IQR], -1.61 to 0.02) compared with 0.09 (IQR, -0.25 to 1.17) in the delayed group (P = 0.006). AQLQ scores improved with 0.83 (IQR, -0.15 to 1.69) versus -0.02 (IQR, -0.77 to 0.75) (P = 0.04). Treatment response in the total group (n = 35) was positively associated with serum IgE and eosinophils but not with baseline ASM mass.Conclusions: ASM mass significantly decreases after BT when compared with a randomized non-BT-treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass.

Resistance of the respiratory system measured with forced oscillation technique (FOT) correlates with bronchial thermoplasty response.

BACKGROUND: Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways. AIM: To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response. METHODS: Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response. RESULTS: Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (±0.96) to 4.90 (±1.14) and ACQ 2.64 (±0.60) to 2.11 (±1.04), p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV1 correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement (r = - 0.52 and r = - 0.53 respectively, p = 0.01 (both)). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz). CONCLUSION: Pulmonary function remained stable after BT. Improvement in FEV1 correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02225392; Registered 26 August 2014.

In vivo multifunctional optical coherence tomography at the periphery of the lungs.

Remodeling of tissue, such as airway smooth muscle (ASM) and extracellular matrix, is considered a key feature of airways disease. No clinically accepted diagnostic method is currently available to assess airway remodeling or the effect of treatment modalities such as bronchial thermoplasty in asthma, other than invasive airway biopsies. Optical coherence tomography (OCT) generates cross-sectional, near-histological images of airway segments and enables identification and quantification of airway wall layers based on light scattering properties only. In this study, we used a custom motorized OCT probe that combines standard and polarization sensitive OCT (PS-OCT) to visualize birefringent tissue in vivo in the airway wall of a patient with severe asthma in a minimally invasive manner. We used optic axis uniformity (OAxU) to highlight the presence of uniformly arranged fiber-like tissue, helping visualizing the abundance of ASM and connective tissue structures. Attenuation coefficient images of the airways are presented for the first time, showing superior architectural contrast compared to standard OCT images. A novel segmentation algorithm was developed to detect the surface of the endoscope sheath and the surface of the tissue. PS-OCT is an innovative imaging technique that holds promise to assess airway remodeling including ASM and connective tissue in a minimally invasive, real-time manner.

Bronchial Thermoplasty-Induced Acute Airway Effects Assessed with Optical Coherence Tomography in Severe Asthma.

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic treatment for severe asthma targeting airway smooth muscle (ASM) with radiofrequent energy. Although implemented worldwide, the effect of BT treatment on the airways is unclear. Optical coherence tomography (OCT) is a novel imaging technique, based on near-infrared light, that generates high-resolution cross-sectional airway wall images. OBJECTIVE: To assess the safety and feasibility of OCT in severe asthma patients and determine acute airway effects of BT by OCT and compare these to the untreated right middle lobe (RML). METHODS: Severe asthma patients were treated with BT (TASMA trial). During the third BT procedure, OCT imaging was performed immediately following BT in the airways of the upper lobes, the right lower lobe treated 6 weeks prior, and the untreated RML. RESULTS: 57 airways were imaged in 15 patients. No adverse events occurred. Three distinct OCT patterns were discriminated: low-intensity scattering pattern of (1) bronchial and (2) peribronchial edema and (3) high-intensity scattering pattern of epithelial sloughing. (Peri)bronchial edema was seen in all BT-treated airways, and less pronounced in only 1/3 of the RML airways. These effects extended beyond the ASM layer and more distal than the directly BT-treated areas and were reduced, but not resolved, after 6 weeks. Epithelial sloughing occurred in 11/14 of the BT-treated airways and was absent in untreated RML airways. CONCLUSIONS: Acute BT effects can be safely assessed with OCT and 3 distinct patterns were identified. The acute effects extended beyond the targeted ASM layer and distal of directly BT-treated airway areas, suggesting that BT might also target smaller distal airways.

[Catamenial pneumothorax: an intriguing cause of recurrent pneumothorax in women]. / Catameniale pneumothorax.

BACKGROUND: Thoracic endometriosis (TE) is one of the causes of secondary pneumothorax in women. According to the literature, 1 in 3 premenopausal women with pneumothorax can be diagnosed with 'catamenial pneumothorax'. The diagnosis is often not or only belatedly made in practice, even though treatment is significantly different than that of primary pneumothorax. CASE DESCRIPTION: A 40-year-old woman came to the emergency department because of dyspnoea and right-sided chest pain. The patient had recurrent pneumothorax and chest pain related to the menstrual cycle. Thoracoscopy revealed thoracic endometriosis. The endometriosis lesions were removed and the patient subsequently received hormonal menstrual suppression treatment. CONCLUSION: In premenopausal women with pneumothorax or a recurrence of pneumothorax, it is important to consider catamenial pneumothorax. Infertility, earlier proven abdominal endometriosis and chest pain linked to menstruation are indications of thoracic endometriosis or catamenial pneumothorax.

Optical coherence tomography for identification and quantification of human airway wall layers.

BACKGROUND: High-resolution computed tomography has limitations in the assessment of airway wall layers and related remodeling in obstructive lung diseases. Near infrared-based optical coherence tomography (OCT) is a novel imaging technique that combined with bronchoscopy generates highly detailed images of the airway wall. The aim of this study is to identify and quantify human airway wall layers both ex-vivo and in-vivo by OCT and correlate these to histology. METHODS: Patients with lung cancer, prior to lobectomy, underwent bronchoscopy including in-vivo OCT imaging. Ex-vivo OCT imaging was performed in the resected lung lobe after needle insertion for matching with histology. Airway wall layer perimeters and their corresponding areas were assessed by two independent observers. Airway wall layer areas (total wall area, mucosal layer area and submucosal muscular layer area) were calculated. RESULTS: 13 airways of 5 patients were imaged by OCT. Histology was matched with 51 ex-vivo OCT images and 39 in-vivo OCT images. A significant correlation was found between ex-vivo OCT imaging and histology, in-vivo OCT imaging and histology and ex-vivo OCT imaging and in-vivo OCT imaging for all measurements (p < 0.0001 all comparisons). A minimal bias was seen in Bland-Altman analysis. High inter-observer reproducibility with intra-class correlation coefficients all above 0.90 were detected. CONCLUSIONS: OCT is an accurate and reproducible imaging technique for identification and quantification of airway wall layers and can be considered as a promising minimal-invasive imaging technique to identify and quantify airway remodeling in obstructive lung diseases.