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.

Dutch Lung Congress

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

immunohistochemical staining

mtorc1

sarcoidosis

[![](https://assets.underline.io/uploads/markdown_image/1/image/261902fdf187a88bfa74da226ff77186.png)](https://drive.google.com/file/d/1gUViQJJHCSgM38OhwpDoTdN89evCsZ-7/view?usp=sharing)
[![](https://assets.underline.io/uploads/markdown_image/1/image/1605292c232e6f185c7f87ee38e8502a.png)](https://drive.google.com/file/d/1kPkznVX_6cx-n846z_pUtyVDZql9KImc/view?usp=sharing)


### **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.

The Dutch Lung Congress aims to bring together everyone interested in research related to pulmonary diseases in the Netherlands.  We hope this event will provide opportunities for multidisciplinary interactions to enhance our approaches for addressing these challenging diseases.  Each session will include input from patients, clinical and basic and/or translational scientists discussing the latest information around the central themes chosen by the organizing committee.  One advantage of holding our congress as a virtual event this year is that we will have the opportunity to hear from world leading experts from all over the globe.  We hope you enjoy the programme the organizing committee have put together and will engage in dynamic discussions with all the speakers.

One highlight of our congress will be the Young Investigator Session.  Remember to join us for this exciting session when we will hear from the presenters who submitted the top scoring abstracts.  This promises to be a session full of exciting science that will display the strengths that constitute the future talent in our field.

When we are not listening to these great presentations we can all meet in Gathertown.  Within this interactive platform you will be able to meet colleagues and friends for networking. Enjoy a private chat over a virtual coffee, visit the booths of our sponsors and other parties, chat with the Young Investigator Board members or take some timeout in the relaxation spaces.  While in Gathertown take the opportunity to visit all the diverse posters on display. Chat live with the presenters or leave them a question on the discussion board for them to engage with you.  Make sure you check for any messages each time you enter Gathertown to make the most of your networking opportunities.

We look forward to seeing you during the DLC and the great scientific (and other) discussions we are anticipating during our 2021 meeting.

On behalf of the DLC organizing Committee
<br>**Janette Burgess
<br>Chair, DLC Organizing Committee**
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)



### Special Session: Publieksmiddag
![](https://assets.underline.io/uploads/markdown_image/1/image/77e768dd500e6205175e5cafba59abdc.png)






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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)
// [Peter Kunst, PhD] (https://drive.google.com/file/d/1QhtB4nQezpAjbfUAcBnINc-Bm3Shy2Lf/view?usp=sharing)
// [Dr. Michel van den Heuvel, Prof., MD, PhD] (https://drive.google.com/file/d/1JBdNEBXZCEikEZhJ6MoD5DhQfXMz3bP6/view?usp=sharing)
![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)

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poster

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

Background Pharmacotherapy is key in asthma control, including preventing lung function decline, in primary care. However, patients’ physical functioning (e.g., physical capacity, PC (=can do) and physical activity, PA (=do do)) correlates poorly with lung function. Therefore, a better insight in the physical function of patients with asthma is needed, using the “can do, do do” concept. 
Objective To explore the “can do, do do” concept in adult asthma patients at referral for the first time to an outpatient consultation of a pulmonologist. 
Methods PC was measured using the six-minute walk test (6MWT). PA by using an accelerometer. Patients were classified into quadrants: low PC (6MWD <70% predicted), low PA (<7000 steps/day, "can't do, don't do"); preserved PC, low PA ("can do, don't do”); low PC, preserved PA ("can't do, do do"); or preserved PC, preserved PA ("can do, do do").
Results 479 asthma patients had a median (IQR) 6MWD of 74 (66–82) % predicted, and walked 6829 (4593–9075) steps/day. Only 29% was classified as "can do, do do", while 30% was classified as “can’t do, don’t do”. The Asthma Control Questionnaire and the Asthma Quality of Life Questionnaire were worst in the “can’t do” groups. 
Conclusion Low PC and/or PA was found in a majority of asthma patients at the index referral to a pulmonologist. An impaired PC is accompanied by a significantly reduced asthma control and disease-specific quality of life. This justifies further studies on safety and efficacy of non-pharmacological interventions, such as physiotherapy.

"Can do" versus "do do" in patients with asthma at first referral to a pulmonologist

Introduction: Sarcoidosis is a granulomatous disease that can affect any organ. Diagnosis can be challenging and often requires tissue sampling; a non-invasive diagnostic method is lacking. Electronic nose (eNose) analysis is an emerging method for profiling exhaled volatile organic compounds. We aimed to evaluate whether eNose data could distinguish between sarcoidosis, other interstitial lung diseases (ILDs) and healthy controls, and between different phenotypes or clinical characteristics of sarcoidosis patients.
Methods: In this cross-sectional single centre study, exhaled breath of outpatients with sarcoidosis was analysed using an eNose (SpiroNose). Clinical characteristics were collected from medical files. eNose sensor data were analysed with partial least square discriminant and ROC analysis. Regression analysis was conducted to correlate sIL-2R values with the main principal component.
Results: 569 patients were included (252 with sarcoidosis, 317 with ILD) and 48 healthy controls. The mean age of sarcoidosis patients was 53.1±11.4 years, 53.2% was male, 61% never smoked, and 88.9% had pulmonary involvement. eNose data could distinguish sarcoidosis patients from healthy controls (AUC 1.00; Figure 1) and ILD patients (AUC 0.89). There were no differences in eNose data between sarcoidosis patients with or without fibrosis (AUC 0.60), immunosuppressive treatment (AUC 0.59), or pulmonary involvement (AUC 0.64). eNose data did differentiate the 1st and 4th sIL-2R quartiles (AUC 0.83; Figure 2). A moderate correlation of eNose data with individual sIL-2R values (r=0.32, p<0.05) was found.
Conclusion: Exhaled breath analysis using eNose technology may be a novel diagnostic tool for sarcoidosis. No differences were found between different phenotypes of sarcoidosis.

Use of electronic nose technology in sarcoidosis

"Objectives: The COVID-19 pandemic has spread across the world, leading to government measures such as national lockdowns and social distancing which are associated with a negative impact on mental health. This study evaluated the impact of COVID-19 on anxiety, depression and resilience in Dutch individuals with CF or PCD and their caregivers during the second wave of the pandemic.
Methods: Adolescents (12-18 years), adults and caregivers of children (0-18 years) with CF or PCD completed questionnaires on anxiety (GAD-7), depression (PHQ-9), and resilience (BRS) from Sept 2020-Febr 2021. The psychosocial impact of COVID-19 was measured by the Exposure and Family Impact Survey (CEFIS) Part 2, which was translated into Dutch using EMA guidelines. Results from the GAD-7 and PHQ-9 were compared to participants’ pre-pandemic scores.
Results: 110 participants (CF: 62, PCD: 48. Patients: 41, caregivers: 69) showed a high prevalence of anxiety and depression (scores ≥ 5 on the GAD-7 and/or PHQ-9) during the pandemic: 31% & 36% respectively for CF, 44% & 33% PCD, 53% & 35% patients, 30% & 35% caregivers, but did not differ from pre-pandemic scores (all p-values > 0.05). Resilience was within the normal range (mean for CF: 3.3; PCD: 3.3; patients: 3.5; caregivers: 3.3). Mean CEFIS scores corresponded to a normal impact (patients: 24.7; caregivers: 21.6), 0 patients and 3 caregivers tested positive for COVID-19. 
Conclusion: The prevalence of elevated symptoms of anxiety and depression during the pandemic was high and there was no detected change in these symptoms compared to pre-pandemic. These results do still emphasize the need for psychological care in individuals with CF or PCD and their caregivers."
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Anxiety, depression and resilience during COVID-19 in Dutch individuals with cystic fibrosis (CF) or primary ciliary dyskinesia (PCD) and their caregivers

"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: 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. 


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

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Long-term effects of multidisciplinary inpatient asthma treatment

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