Netherlands

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which impaired healing to recurrent micro-injury is thought to lead to fibrosis. Recent findings hint to a role for B cells and autoimmunity in IPF pathogenesis. Increased expression of the signaling molecule Bruton’s tyrosine kinase (BTK) and an enhanced response to B cell receptor (BCR) stimulation was shown to be an over-arching observation in circulating B cells from patients with a systemic autoimmune disease. Recently, we showed that circulating B cells from a fraction of IPF patients, compared to healthy controls, also expressed increased levels of BTK. However, given the involvement of BTK in many different signaling pathways, it remains unclear if BCR signaling is altered in IPF. Here, we showed that the response to BCR stimulation was enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-Ig-induced phosphorylation of BTK and its substrate phospholipase Cy2 in naïve but not in memory B cells. In IPF naïve B cells, enhanced BCR signaling correlated with surface expression of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor). This was in contrast to healthy controls, where BCR signaling correlated with expression of the B cell activating factor (BAFF) receptor. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, and commonly used in IPF treatment, induced substantial changes in BCR signaling. These findings support the involvement of B cells and autoimmunity in IPF pathogenesis and suggest that targeting BCR signaling has potential value as treatment option.

Dutch Lung Congress

Aberrant B cell receptor signaling in naïve B cells from patients with idiopathic pulmonary fibrosis

autoimmunity

nintedanib

bruton's tyrosine kinase

b cell receptor signaling

idiopathic pulmonary fibrosis

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### **Welcome Message**

Welcome to the inaugural **Dutch Lung Congress.** We have all missed our opportunities to network and interact with our colleagues in the last twelve months or more. While our desire was to meet face to face once again, when it became evident that this would not be possible until much later in 2021 (or even into 2022) the hard working committee organizing the Dutch Lung Congress found, what we hope will be, an excellent alternative to facilitate our annual meeting.

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 **Janette Burgess
 Chair, DLC Organizing Committee**
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**More about the committee team:**:
[Barbro N. Melgert, PhD] (https://drive.google.com/file/d/1q_IIH3JvTivumCUzzsZGX7BgD41HxQmk/view?usp=sharing)
// [Bas Holverda, PhD] (https://drive.google.com/file/d/1QKXHmTTQjgs4OZVuM8doXU055S-fu_uU/view?usp=sharing)
// [Frits Franssen, PhD] (https://drive.google.com/file/d/1d7HRUJaqGuRFzkPN3SVgkbBfqFkDkWq2/view?usp=sharing)
// [Janette Burgess, PhD] (https://drive.google.com/file/d/1VHFlrEN6uCQGeeW3Lj4I8aTw7HsB0GFr/view?usp=sharing)
// [Michel van den Heuvel, PhD] (https://drive.google.com/file/d/1JeOEP8MHxiK_4lONr8UM2HaxdxpkAmA2/view?usp=sharing)
// [Patrick Bhairosing] (https://drive.google.com/file/d/1xI8ORq-g1bbVcrlRDviZ9NhAwanc4dFl/view?usp=sharing)
// [Gimano Amatngalim, PhD] (https://drive.google.com/file/d/1fyVDDKARLNjRk_JZk8_GyhGMjmp6DWHp/view?usp=sharing)
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Title: Long-term effects of multidisciplinary inpatient asthma treatment
Background For children with refractory difficult asthma achieving adequate control can be challenging. Previously we have shown that multidisciplinary inpatient treatment improves short-term asthma control and quality of life for patients that remain uncontrolled despite optimal outpatient treatment by paediatric pulmonologists.

Objective To evaluate the long-term effects of multidisciplinary inpatient treatment in paediatric patients with refractory difficult asthma.

Methods In this prospective observational study, 10 children (mean age 12.3 ± 2.3 years) hospitalised in Asthma Centre Merem, Netherlands (mean treatment duration 4.4 ± 0.5 weeks) were followed up for 12-24 months (mean 17.6 ± 4.3). Treatment focused on optimizing basic management by addressing four modules; asthma specific, physical health, chronical illness and system therapy. Evaluations were taken prior admission and post treatment. Statistical significance on intra-individual change in outcome variables was assessed using the Wilcoxon signed rank test.

Results Overall there was a significant reduction in hospital admissions (p. 0.018), emergency room visits (p. 0.021) and oral corticosteroid use (p. 0.007) comparing 12 months prior and post treatment. In addition treatment had positive effect on school attendance; children with < 1 month of school absenteeism increased from 10% (pre-treatment) to 90% (post-treatment). Improvements in asthma related quality of life (PAQLQ) exceeded the clinically minimal important difference; mean pre-treatment 5.5 ± 0.8 vs post treatment 6.5 ± 0.5.

Conclusion This small observational study shows that multidisciplinary inpatient treatment can have long-term effects in several aspects of asthma control and quality of life.

Long-term effects of multidisciplinary inpatient asthma treatment

Exposure of the human airways to cigarette smoke (CS) is the major etiological risk factor for developing devastating lung diseases such as Chronic Obstructive Pulmonary Disease (COPD). Although previous studies demonstrated aberrant mitochondrial morphology and impaired mitochondrial function in response to exposure of human airway epithelial cells to CS, to what extent the pathways regulating mitochondrial content and quality control are impacted is unknown. Therefore, we assessed the activity and abundance of key constituents of mitochondrial metabolic pathways, as well as transcript and protein levels of critical molecules regulating mitochondrial biogenesis and mitophagy in undifferentiated human primary bronchial epithelial cells (PBECs; provided by PLUC facility MUMC+, Maastricht) of COPD (n=5) and non-COPD (n=7) subjects, in undifferentiated PBECs of non-COPD subjects (n=4) exposed to CS extract (CSE) (0-1-2%), and in air-liquid interface differentiated PBECs of non-COPD subjects (n=4) exposed to CS (1 Marlboro Red cigarette) by machine smoking according to the Health Canadian Intense Regime. Evaluation of the abundance of prominent regulators controlling mitochondrial metabolic pathways revealed no outstanding differences at gene and protein level in PBECs of COPD versus non-COPD subjects. Although mitochondrial DNA copy number was unaltered, CSE exposure, dose- and time-dependently, downregulated mRNA levels of mitochondrial biogenesis markers and upregulated protein and transcript abundance of autophagy regulators in undifferentiated PBECs. Moreover, we observed increased metabolic enzyme activity in response to CSE exposure, respectively of hydroxyacyl-coenzyme A dehydrogenase and phosphofructokinase. These alterations were, at least in part, recapitulated in CS exposed differentiated PBECs. Collectively, these data show that CS(E) exposure disrupts the molecular regulation of mitochondrial metabolism in cells of the human airways.

Exposure to cigarette smoke disrupts the molecular regulation of mitochondrial metabolism in epithelial cells of the human airways

Background: In Adults long-COVID is a well-documented multisystem disease that
describes the 10% of COVID-19 infected with long-term sequelae persisting for more than 12
weeks. Far less is known about these long-term sequelae in children, as only recently this
disease has started to garner scientific literary attention. While COVID-19 in children is
characterised by a markedly mild disease phenotype during the (semi-)acute phase, the
spectrum of paediatric long-COVID might not parallel the child-sparing pattern of the initial
infection. Here, we report on the occurrence of long-COVID in children and characterise its
presentation as seen by paediatricians in the Netherlands.
Methods: We conducted a national survey among paediatricians in the Netherlands,
collecting information on initial infection characteristics, testing, the COVID-19 sequelae, and
their effect on the patients’ daily lives. We furthermore describe a case series of 6 children
with long-COVID to explore the clinical features in greater detail; medical histories, diagnostic
test results, along with treatment plans and their respective effects.
Results: With a response rate of 78% of Dutch paediatric departments, we identified 89
children, aged 2-18 years, suspected of long-COVID with various complaints. Of these, only
8% experienced no limitations in daily function. The most common complaints were fatigue,
dyspnoea, and concentration difficulties, with 87%, 55%, and 45%, respectively. Our case
series emphasises the non-specific nature, and the broad clinical manifestations of paediatric
long-COVID, as well as highlighting the current lack of a best practice diagnostic and
treatment plan.
Conclusion: Our study shows that long-COVID is also present in the paediatric population.
The main symptoms resemble those previously described in adults, and are just as
heterogeneous. This novel condition demands a multi-disciplinary approach, spanning all
patient age groups, with international awareness and consensus to aid early detection and
devise a rigorous evidence based diagnostic and treatment plan.


Pediatric Long-COVID: An overlooked
phenomenon?

BACKGROUND
Allergic bronchopulmonary aspergillosis (ABPA) is caused by allergic inflammation triggered by inhaled fungal spores. ABPA is characterized by high IgE levels and high eosinophil counts and is usually treated with systemic steroids and azoles. Dupilumab is an agent with IL-4 and IL-13 antagonistic properties, counteracting IgE production and eosinophils. Dupilumab efficacy in asthmatic ABPA has been suggested in small case series and retrospective analysis of the LIBERTY trial, showing improved FEV1, reduced exacerbation frequency and decreases in IgE and FeNO. 

METHODS
Retrospective case series. Patients provided written consent to collect data. Comparisons were made between 6 months prior and 6 months after first dupilumab dose. 

RESULTS
Baseline: Six patients were included. Median age 76 years (61-83 years), five were male. All patients had allergic asthma on ICS and bronchodilators. ABPA diagnosis (ISHAM 2013 criteria) was at least one year old, in two patients >10 years. Five patients were on maintenance prednisone (7.5-10mg/day). Five patients were previously treated with azoles, three patients with omalizumab. Median FEV1 before dupilumab was 76.5% (27-96.3%) and median total IgE was 1921 kU/L (66-4147 kU/L). Treatment: Dupilumab dose was 300mg/14 days. Efficacy: After start of dupilumab, five patients reported a subjective improvement. Four patients had a documented increase in FEV1. Exacerbations for which additional steroids were prescribed decreased with median 2.5 (1-4) exacerbations in six months before vs. median 0 exacerbations (range 0-1) in six months after dupilumab. Three patients had a documented fall in total IgE below 1000 kU/L. After six months, oral prednisone was discontinued in two out of five patients. Prednisone was continued in reduced dose in three out of five patients, of which one had steroid withdrawal syndrome and one had discontinued dupilumab. Safety: One patient discontinued dupilumab due to arthralgia.

CONCLUSIONS
In six patients with ABPA and asthma treated with dupilumab, improvements were observed in symptoms, exacerbations, FEV1, prednisone dose and total IgE. Retrospective data suggest dupilumab is an effective alternative to treat ABPA in selected asthmatic patients.

Case series: asthmatic patients with allergic bronchopulmonary aspergillosis (ABPA) treated with dupilumab

Background: COPD involves emphysema and small airway wall thickening. Chronic inflammation and aberrant repair processes play a role in both, but the exact mechanisms are unknown. Pulmonary fibroblasts are key regulators of repair and are affected by chronic inflammation. So far, a comprehensive analysis comparing COPD and control fibroblasts on protein level is lacking.
Aim: To identify COPD-related protein changes in lung fibroblasts using a shotgun proteomics approach.
Methods: Lung fibroblasts were isolated from 13 stage IV COPD patients and 10 matched controls. Isolated proteins were subjected to shotgun proteomic analysis using LC-MS/MS. Differential protein expression comparing COPD patients and controls was assessed using linear regression modeling correcting for age and sex. Differentially expressed proteins were cross-referenced with literature via high-throughput text-mining with TenWise KMAP-API to determine associations with COPD.
Results: After removal of lowly expressed proteins, we detected the expression of 774 proteins in primary lung fibroblasts of which 40 proteins were significantly differentially expressed between COPD and control fibroblasts, with the most significant being HNRNPA2B1 and FHL1 . 20 of the 40 proteins had significantly higher expression while the other 20 had lower expression in COPD fibroblasts compared to controls. The proteins were enriched for pathways relating to the immune system and protein folding, among others. Of the 40 proteins 13 were previously associated with COPD in literature cross-referencing, including FHL1 and GSTP1.
Conclusions: We identified 40 differentially expressed proteins in COPD stage IV compared to control fibroblasts, who are enriched for immune system pathways that suggest a role in chronic inflammation in COPD. These proteins include previously described COPD related proteins (e.g. FHL1 and GSTP1), validating their altered expression in COPD lung fibroblasts. But they also include new COPD research targets like HNRNPA2B1 ad CAPN2. Thus this study demonstrates the robustness of the proteomic approach and provides several intriguing new research foci for further functional studies in COPD.

Proteomics approach to identify COPD-related changes in pulmonary fibroblasts

"Introduction: The covid-19 pandemic has boosted the use of in FEV1 telemonitoring in pediatric asthma, while a consensus on its most efficient and effective implementation is still lacking. To find answers, it is important to study how such an intervention is perceived, experienced and used both by patients and healthcare professionals (HCP).

Objective: To provide perspectives on how FEV1 home monitoring should be used in pediatric asthma.

Methods: This is a qualitative multicenter prospective observational study which included asthma patients aged 6-16 years old and HCP. Primary outcomes were survey results of two surveys which were sent to all participants, one at study start and one after 3 to 4 months. Secondary outcomes consisted of FEV1 usage during four months after receiving the FEV1 device.

Results: 39 participants (26 patients and 13 HCP) were included in this study. Survey response rates were 97% at start and 87% at study end. Both patients and HCP were receptive to online FEV1 home monitoring and found it contributive to asthma control, self-management and disease perception. The main concerns were about reliability of the FEV1 device and validity of home-performed FEV1 maneuvers. 69% of included patients used their device regularly during the study period with a large inter-individual variation.

Conclusion: Patients and HCP are receptive towards online FEV1 home monitoring. Frequency of measurements varied largely among individuals, yet perceived benefits remained similar. This emphasizes that online FEV1 home monitoring strategies should be used as a means to reach individual goals, rather than being a goal on its own."
![](https://assets.underline.io/uploads/markdown_image/1/image/abdf8f2785aec73cb5ea6edda04edf5f.png)

It’s not just the FEV1 that matters, but the personal goals we reach along the way: Viewpoint article

Background: Hyaluronic acid (HA) is a key component of the extracellular matrix. HA and its metabolism are suggested to be altered in the lungs of patients with COPD. The present study explored systemic HA, and its metabolic regulators, in patients with COPD and smoking (SC) and non-smoking controls (NSC). Furthermore, associations of HA with acute exacerbations (AECOPD), airway-related hospitalizations, systemic inflammation and cardiovascular risk were studied.
Methods: HA was measured by ELISA in plasma of 192 patients with clinically stable COPD (GOLD II-IV), 84 SC (≥10 pack years) and 107 NSC (<10 pack years) enrolled in the ICE-Age study (Ciro, Horn, the Netherlands). mRNA expression of the enzymatic regulators HA-synthase 3 (HAS-3) and hyaluronidase 2 (HYAL-2) was assessed in PBMCs of a subset of subjects.
Results: Plasma HA was reduced in patients with COPD compared to NSC (p=0.033), but was comparable after adjusting for age and sex. Expression of HAS-3 did not differ between groups, but was substantially less detectable in more patients with COPD (56%) than SC (33.3%) and NSC (10%), p<0.001. Expression of HYAL-2 was enhanced in patients with COPD compared to SC (p=0.019) and NSC (p<0.001), also in the age- and sex- adjusted model (p<0.001). Plasma HA was not associated with AECOPD, airway related hospitalizations in the past year, or any of the inflammatory markers (WBCs, fibrinogen, IL-6, IL-8, TNF-α and CRP) in patients with COPD. Arterial pulse wave velocity explained some of the variance, i.e. <10%, in plasma HA (p=0.006). 
Conclusion: Overall, these results indicate that expression of HYAL-2, but not plasma HA nor HAS-3, is enhanced in patients with COPD compared to (non)smoking controls. Furthermore, HA was not associated with clinical outcomes, yet, cardiovascular risk might play a role in its systemic regulation in stable COPD. Case-control studies are indicated to establish the causality of our findings.

Alterations in plasma hyaluronic acid in patients with clinically stable COPD versus (non)smoking controls: a cross-sectional analysis

Introduction
The concept “the right care at the right place” in Severe Asthma (SA) demands regional collaboration with centralization of expertise and decentralization of care. Our Centre of Excellence for SA in South-West Netherlands (Franciscus Gasthuis & Vlietland hospital) has taken the initiative to design a blueprint to optimize regional care for SA patients together with their regional partners (11 hospitals so far and GP-network).

Project approach
The project team consisted of 3 pulmonologists and 1 respiratory nurse from the center of excellence (core team), 3 pulmonologists from referral centers, 1 GP specialized in asthma and 1 patient. First, 15 interviews were conducted with different stakeholders: health care professionals, pharmacists, insurer, patient association and patients to gather different perspectives and best practices in SA care. Then the outcomes were discussed in work sessions. 

Main findings and outcomes
The project team identified four area’s for optimal regional care that require agreement: SA diagnostics, referral processes, infrastructure for regional multidisciplinary consultation (MDC) and regional follow up on treatment. Designing a regional SA care pathway from GP to regional MDC may further improve the quality of care and the value of the regional MDC. The impact of this intervention will be monitored. Process parameters were formulated:
• % of SA patients treated with biologicals discussed in MDC, 
• % of SA patients with individual treatment plan, 
• % of treatment centers with pulmonologist specialized in severe asthma care
• % of SA patient included in the existing RAPSODI* register.

Next steps
The progress of this project will be evaluated monthly by the core team with updates shared in the MDC. The MDC meets every week to discuss patient cases with 3-4 hospital partners in each meeting. A baseline measurement will be conducted for the selected set of parameters and will be structurally discussed every 6 months in the regional MDC to monitor the impact of the interventions.

Conclusions
This blueprint can be used as practical guidance for implementation and further improvement of regional SA care, in particular the role of the regional MDC.

* Registry of Adult Patients with Severe asthma for Optimal DIsease management

This project was realized with the support of AstraZeneca. It is part of the wider PRECISION
project, which has been set up internationally with the aim of improving the quality of care for patients with severe asthma.


Roadmap to improve regional care for severe asthma patients in the Netherlands

Introduction: Sarcoidosis is a multisystemic disorder, characterized by the formation of non-caseating granulomas. the mTORC1 signaling pathway is suggested to play a role in granuloma formation. Recent studies demonstrated conflicting data on mTORC1 expression in patiens with sarcoidosis with either 33% or 100% of patients demonstrating mTORC1 activation within the granulomas. Therefore the aim of our study was to reevaluate the percentage of mTORC1 activation in sarcoidosis patients in a Dutch cohort. We also included Dutch patients with other granulomatous disorders of the lung to investigate whether mTORC1 activation can also be found in these diseases. 
Material and methods: This is a retrospective analysis of 74 patients with sarcoidosis and 39 patients with other pulmonary granulomatous disorders such as HP and vasculitiis. The activation of the mTORC1 signaling pathway was evaluated by immunohistochemical staining of its downstream effector p-S6 in tissue sections. 
Results: Active mTORC1 signaling was detected in 32 (43%) of the sarcoidosis patients and in 12 (31%) of the patients with other granulomatous disorders, demonstrating that this pathway is not specific for granuloma formation in sarcoidosis (p=0.628). 
Conclusion: Activation of mTORC1 can be found in a subgroup of patients with sarcoidoiss, as well as in patients with other granulomatous pulmonary disorders such as HP or vasculitis.

Expression of mTOR signaling can be found in a subgroup of Dutch patients with either sarcoidosis, hypersensitiviy pneumonitis or vasculitis

Background: Dysfunctional of alveolar microvascular endothelial cells drives microangiopathies in chronic obstructive pulmonary disease (COPD). Tobacco smoking and air pollution are two major causes of COPD. We hypothesized that cigarette smoke (CS) and diesel exhaust particles (DEP) might impact on pulmonary microvascular endothelial repair in vitro.
Methods: Immortalized human pulmonary microvascular endothelial cells (HPMECs) were starved for 24 h followed by treatments with either vehicle control, CS extract (CSE) (1%, 2.5%, 5%), DEP (50, 100, 200 µg/ml), or IL-1ß (0.1, 1ng/ml) for 24h. Post-analyses comprised PCR analysis and scratch wound healing assays. 
Results: In the wound healing assay, 83% closure was observed within the vehicle group at 12h, which was reduced to 76%, 59% and 57% by 1%, 2.5%, and 5% CSE respectively; 87%, 89% and 82% by 50-, 100-, and 200 µg/ml DEP respectively; and increased to 93% and 97% by IL-1ß (0.1-, 1ng/ml). After 24h treatments, the wound closed 96-100% in vehicle, IL-1ß (0.1-, 1ng/ml) and DEP (50-, 100 µg/ml) groups; however, the wound closed 95%, 85%, 73% and 91% by 1%, 2.5%, 5%CSE and DEP (200 µg/ml) respectively. The wound closed slower when cells were first pretreated for 24 h with DEP. The gene expression levels of the pro-inflammatory IL-6 and CXCL8/IL-8 were increased in HPMECs treated with DEP (100 µg/ml) or IL-1ß (0.1-, 1ng/ml) but not by CSE; the gene expression of the aging associated marker P16 decreased by CSE (2.5%, 5%) or DEP (50-, 200 µg/ml) whereas the expression of P21 increased by IL-1ß (0.1-, 1ng/ml). The expression level of the oxidative stress responsive gene MGST1 increased by CSE, DEP or IL-1ß in a concentration-dependent manner.
Conclusions: Both CSE and DEP exposure impair the wound repair function of pulmonary microvascular endothelial cells and this dysfunction was associated with changes in markers of oxidative stress, and to a lesser extent senescence and inflammation. 


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