Netherlands

Human lung function is intricately linked to the mechanics of breathing, but how breathing mechanics influence lung epithelial cell functioning is incompletely understood. While respiration-related strains and fluid flows have been suggested to promote alveolar epithelial cell function, the study of such fundamental mechanisms in the airway epithelium has been hindered by the lack of suitable in vitro airway models.

Here, we developed a well-differentiated primary cell culture model of the human airway epithelium on a commercial organs-on-chips platform that enables the application of breathing-associated airflow and cyclic strain, and features optional endothelial cell co-culture to allow for crosstalk with the vascular compartment.

Using this model, we evaluated the impact of airflow and physiological levels of cyclic strain on airway epithelial cell differentiation and function. Our findings suggest that breathing-associated mechanical stimulation changes epithelial cell type composition, reduces secretion of IL-8, and downregulates gene expression of matrix metalloproteinase 9, fibronectin, and other extracellular matrix (remodeling) factors.

These results indicate that breathing-associated forces might be important modulators of airway epithelial cell composition and function and that their fine-tuned application could generate models of specific epithelial phenotypes and pathologies. 


Dutch Lung Congress

Breathing on Chip: studying the effect of biomechanical forces on airway epithelial cell biology using a modular Airway Lung-Chip

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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.

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)






![](https://assets.underline.io/uploads/markdown_image/1/image/f461fb275d9667fb2a76a30813388e90.png)
**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

Background: To complement telephone or video consultations during the ongoing COVID-19 pandemic we provided our children with cystic fibrosis (CF) a smartphone connected home spirometer (Spirobank® Smart (Medical International Research, Roma, Italy)). During lockdown, or when children cannot attend the hospital, they perform a pulmonary function test (PFT) guided by the lung function technician via a video connection, before the doctor’s e-consult. Via the smartphone app (version: 1.1) a pdf of the results is sent to the hospital. The children brought the Spirobank with them at their first live hospital visit to get extra training and instructions.
Aim: To test the reliability of spirometry results with the home spirometer Spirobank compared to conventional PFT in the hospital.
Methods: Children with CF (n=16) with median age 11.5 yrs. (IQR: 5) and a 50/50 male/ female ratio were included. At their live visit children performed conventional PFT (MasterScreen™ PFT (Vyaire medical, Würzburg, Germany)) and subsequently Spirobank spirometry guided by the lung function technician, with the same instruction as during video guided consultations. Wilcoxon signed-rank test was used to test the differences between percent predicted (pp)FVC, ppFEV1 and ppMFEF25-75 of both measurements.
Results: Median (IQR) of ΔppFVC, ΔppFEV1, and ΔppMFEF25-75 were 2% (6.25), 2.5% (4.25) and 4% (4.75) respectively. ppFEV1 of Spirobank was significantly lower compared to PFT (p = 0.049), whereas ppFVC (p = 0.73) and ppMFEF25-75 (p= 0.10) were not.
Conclusions: We showed a statistically significant lower ppFEV1 measured by the home spirometer Spirobank compared to conventional PFT, however with a median difference of 2% this was in most cases not a clinically significant difference. We conclude that the Spirobank is a useful home spirometer with reliable results that are slightly lower compared to conventional PFT, when it is performed under (video)guidance of a lung function technician.

Funded by: Sophia foundation & Yaren Foundation

Reliability of a home spirometer for monitoring children with cystic fibrosis during the COVID-19 pandemic.

Introduction: Adult-onset asthma (AOA) is usually more severe compared to childhood onset asthma (CoA). Given the increasing evidence that AoA is associated with obesity, we investigated the relationship of other related metabolic comorbid conditions with AoA compared to CoA. 
Study design and methods: This cross-sectional study compared the metabolic syndrome and lipid derived inflammatory markers in patients with AoA, CoA and age- and sex-matched control subjects without asthma. Participants were asthma patients visiting the outpatient clinic of two teaching hospitals in Rotterdam, The Netherlands. All participants underwent lung function tests, blood tests and physical activity tracking. AoA was defined as asthma age of onset after the age of 18. Metabolic syndrome was defined according to the international joint interim statement criteria.
Results: Eighty-one participants were included (27 AoA, 25 CoA, 29 controls). AoA was associated with the metabolic syndrome (Odds Ratio=4.04 95% CI (1.04-15.68) p=0.028, Nagelkerke R2=0.268), adjusted for age, sex, body mass index and smoking habits. AoA patients had higher median serum IL-6 and leptin-adiponectin (LA) ratio compared to controls (IL-6 (pg/mL): 3.10 [1.11-4.30] vs. 1.13 [0.72-1.58], p=0.002 and LA ratio (pg/mL): 6.21 [2.45-14.11] vs. 2.24 [0.67-4.71], p=0.0390). This was not observed in CoA and controls. 
Conclusion: AoA was associated with the metabolic syndrome and its related pro-inflammatory endocrine and cytokine status. This may suggest lipid inflammatory markers play a role in the pathophysiology of AoA.

Adult but not childhood onset asthma is associated with the metabolic syndrome, independent from body mass

Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown. 
Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment. 
Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year, were included. The intervention regimen consisted of OM-85/placebo for ten consecutive days per month for six months during two winter seasons. Primary endpoint was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent.
Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68-1.69], p=0.77). With the use of OM-85, FEV1% increased with 3.81% (p=0.04) compared to placebo. Nasopharyngeal swabs taken during RTIs, detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p=0.02).
In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR=0.71, 95%CI [0.39-1.26], p=0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T-cells, did not show differences between the groups. 
Conclusion: Although OM-85 may have immune modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post-hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Prevention of exacerbations in moderate-severe asthma by bacterial lysate add-on therapy: a randomized controlled trial

Early CF lung disease is characterized by neutrophil influx. Airway macrophages (Mφ) are also presentin the lumen to scavenge pathogens and clear apoptotic cells. Pulmonary inflammation can cause long-term Mφ paralysis, and Mφ dysfunction has also been described in CF lungs. We hypothesized that Mφdysfunction in early CF lung disease results from an altered expression of scavenging receptors. Weassessed the expression of key scavenging receptors (CD163, CD91, CD36, CD16) and of SIRPα, aninhibitor of phagocytosis, and its ligand CD47.

Broncho-alveolar lavage fluid (BALF) cells were collected from 19 CF infants of the I-BALL cohort(Erasmus MC), at ages 1, 3 or 5, and analyzed using flow cytometry. The neutrophil-to-macrophage(N/Mφ) ratio was calculated. Surface marker expression levels on Mφ were compared between agegroups and N/Mφ ratio quartiles. Findings were validated in 36 CF patients within the 1-5 age range fromthe AREST-CF cohort (Telethon Kids Institute).

Mean BALF N/Mφ ratios showed a positive correlation with age (Spearman ρ= 0.59, p = 0.008). WhileCD16, CD36 and CD91 levels remained consistent, CD163 expression was decreased in 5 year oldscompared to 1 year olds (p = 0.04). Expression of both CD47 and SIRPα trended towards a decreaseacross age groups. In the AREST-CF cohort, reduced Mφ scavenger receptor expression correlated with high BALF N/Mφ ratios rather than age. Expression levels of CD163 (p=0.03), CD47 (p = 0.03) andSIRPα (p = 0.004) were significantly lower in the top BALF N/Mφ ratio quartile.

Our data show that the BALF N/Mφ ratio in CF infants increases with age. Expression of severalscavenger receptors is decreased at the age of 5 in the I-BALL cohort, and in subjects with high N/Mratios in the AREST-CF cohort. We propose that the N/Mφ ratio provides an age-independent indicatorof inflammation severity. Prolonged low SIRPα expression has been linked to poor phagocytosis. Thesedata suggest that in early CF lung disease, Mφ become functionally paralyzed, which may contribute toan increasingly neutrophil-dominated milieu that incites structural damage.

Airway macrophages in early CF lung disease show signs of immune paralysis

Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mediated decay (NMD) and CFTR protein modulation. Rescue of PTC CFTR protein was assessed by the forskolin-induced swelling of 12 intestinal organoid cultures, homozygous or compound heterozygous for distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function. We anticipate that this novel approach can strongly contribute to the development of CFTR modulating treatments for pwCF that currently have no CFTR modulating treatments available.

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Background
Fatigue is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, the difference in fatigue perceptions for these patients is unknown and this may be important to better understand what fatigue means to the individual patient. 
Methods 
This cross-sectional quantitative study aims to determine the different perceptions of fatigue as ‘frustrating’, ’exhausting’, ‘pleasant’, ‘frightening’ using the Fatigue Quality List and to assess determinants related to these perceptions of fatigue.
Beside the fatigue quality connotations, demographics, lung function, fatigue severity (Checklist Individual Strength subscale Fatigue), dyspnea (modified-Medical Research Council), fatigue catastrophizing (Fatigue Catastrophizing Scale), anxiety/depression (Hospital Anxiety and Depression Scale) and general health status (EuroQoL 5-dimension 5-level) were assessed.
Results
Mean frequency score of fatigue-related perceptions in patients with IPF was 3.4 points and in patients with sarcoidosis 4.0 points. Severely fatigued patients with IPF reported their fatigue less ‘pleasant’ significantly more often than patients without severe fatigue. Fatigue severity, dyspnea, catastrophizing and general health were significantly correlated with the negative connotations categories of the Fatigue Quality List in patients with IPF. Severely fatigued sarcoidosis patients reported their fatigue perceptions significantly more often as ‘frustrating’, ’exhausting’, ‘frightening’ and less ‘pleasant’ than patients without severe fatigue. Moreover, in patients with sarcoidosis fatigue severity, dyspnea, catastrophizing and depression were significantly associated with all four categories of the Fatigue Quality List that describe the experienced fatigue (p<0.05).
Conclusions
The current findings of experiences of fatigue in patients with IPF or pulmonary sarcoidosis provide insights for professionals treating these patients. Although similarities were found in the several experiences of fatigue across non-severely and severely fatigued patients, differences were also evident and could be mapped for IPF and sarcoidosis.


Perceptions of Fatigue in Patients With Idiopathic Pulmonary Fibrosis or Sarcoidosis

Background
Self-management is considered important in the management of patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, data about the degree of activation for self-management is lacking.
Objectives
To determine the degree of activation for self-management in patients with IPF or sarcoidosis using the patient activation measure (PAM) and to evaluate the association between PAM scores, clinical characteristics and health-related outcomes. 
Study Design and Methods
This cross-sectional prospective study assessed besides the PAM also demographics, lung function, dyspnea (modified-Medical Research Council (mMRC)), fatigue (Checklist Individual Strength-Fatigue (CIS-Fatigue)), anxiety/depression (Hospital Anxiety and Depression Scale (HADS-A/HADS-D)) and generic health status (EuroQol five-dimensional-five-level (EQ-5D-5L)).
Results 
Mean PAM was 55.0 (9.1) points in patients with IPF (n=59), and low levels of patient activation for self-management (PAM ≤55.1 points) were present in 56% of the patients. PAM Scores correlated significantly (p<0.05) with mMRC (ρ =-0.476), HADS-A (ρ =-0.326), HADS-D (ρ =-0.459) and EQ-5D-5L (ρ =0.393). In patients with sarcoidosis (n=59) the mean PAM score was 55.7 (11.0) points, and 46% of the patients reported low PAM levels. Significant correlations were found with mMRC (ρ =-0.356), HADS-A (ρ =-0.394), HADS-D (ρ =-0.478) and EQ-5D-5L (ρ =0.313). 
Conclusion
About half of the outpatients with IPF or sarcoidosis have a low degree of activation for self-management, and these patients generally report more dyspnea, anxiety, depression and a lower health status. Whether patients with a low degree of activation can be successful in self-managing their disease remains to be determined.

Patient Activation for Self Management Idiopathic Pulmonary Fibrosis or Sarcoidosis 

Background
The COVID-19 pandemic has a large worldwide societal impact. Restrictive measures have aimed to restrain the burden on the healthcare systems. However, while early treatment to prevent hospitalization is still urgently needed, the role of primary care in the treatment is limited. Home-based monitoring of oxygen saturation and disease status makes it possible to monitor patients who show early signs of worsening COVID-19 and to identify those patients who further deteriorate and may need to be referred to hospital or can be treated. This strategy may thus be a promising measure to prevent or delay hospital admission.

Objective
To evaluate a home-based platform for monitoring of oxygen saturation and assess its added value in preventing or delaying hospital admission of patients with COVID-19 in primary care.

Study design
The COVID-19 Primary care Platform for Early treatment and Recovery (COPPER) study includes adult patients who consult their general practitioner for COVID-19 symptoms. Patients who are not immediately referred to a hospital are monitored at home for 28 days by measuring pulse oxygen saturation 3 times daily in rest and after the 1-minute sit-to-stand exercise. In addition, patients answer questions on symptoms and signs that may indicate worsening of disease once per day. The results of the daily measurements are monitored by a medical call center who alert the general practitioner when necessary.

Results
Although not enough data have been collected to show hospitalization effects, the platform showed to be an effective way of monitoring disease progression. Measurements that might indicate the need for clinical intervention, like low pulse oxygen saturation and chest pain, triggered warnings to the remote caretakers who could contact and reassess patients accordingly.

Conclusion
A distant monitoring platform appears to be a useful tool for monitoring of patients with pulmonary diseases. In the context of the COVID-19 pandemic it may lower the burden placed on healthcare workers during a straining time such as this one.

Home-based monitoring and early treatment of COVID-19 to reduce hospital admissions and improve outcomes: the COPPER studies.

Background: Airway neuroplasticity occurs in asthma and contributes to airway hyperresponsiveness (AHR). Corticosteroids, an established asthma therapy, are known to reduce airway inflammation and improve lung function. However, their effect on airway neuroplasticity has not been described yet.

Aim: To investigate the effects of corticosteroids on airway neuroplasticity.

Methods: BALB/cByJ (Jax-strain) mice were sensitized and challenged to ovalbumin (OVA) for 4 weeks. Budesonide was administered before every OVA challenge. 24 hours after the last challenge, lungs were collected for immunohistochemistry.
To elucidate the direct effect of corticosteroids on airway cholinergic neurons, we exposed human pluripotent stem cells (hPSCs)-derived airway cholinergic neurons to dexamethasone for 5 days. 

Results: In the murine asthma model, budesonide inhibited the OVA induced expression of the neuronal marker β-III-tubulin (p<0.05). The anti-inflammatory effect of budesonide was shown by its ability to supress eosinophil infiltration into the airway (p<0.05). The eosinophil count correlated with β-III-tubulin expression irrespective of treatment arm (p<0.0001). hPSCs-derived airway cholinergic neurons that were exposed to dexamethasone showed significant reductions in choline acetyltransferase (ChAT) and β-III-tubulin double-positive staining.

Conclusions: Corticosteroids inhibit airway neuroplasticity in a murine chronic asthma model and prevent hPSCs-derived airway cholinergic neuronal differentiation. Therefore, both indirect (anti-inflammatory effects) and direct inhibition of neuronal marker expression may contribute to the effects.


Corticosteroid effects on airway neuroplasticity in experimental models of asthma

Introduction
Following the recent Covid-19 lockdown, a reduction of infectious diseases was reported. Social distancing is known to reduce the spread of viral respiratory tract infections. Since asthma exacerbations (AE) are often caused by viral RTI, we hypothesized that AE frequency would decrease during the Covid-19 social distancing measures in The Netherlands.

Methods
This study comprises a follow-up from a recent finished randomized controlled trial, in moderate severe asthma patients, treated according to GINA 4, and controls in The Netherlands. AE in this cohort were monitored between 2017-2019. Participants (67 asthma patients and 27 controls) were invited to fill out a short survey. AE frequencies in 2020 and Q1 2021 were verified with medical records, pharmacies and patient interviews.

Results
Asthma patients were comparable in terms of asthma control and did not differ in terms of age, BMI and sex from controls. The mean number of AE in 2020 was lower compared to prior years, χ2(3)=19.06, p<0.001.
Mean number of AE in quarter 2 (Q2), Q3 and Q4 was significantly lower in 2020 compared to prior years (Q2: χ2(3) = 9.91, p=0.019; Q3: χ2(3) = 8.79, p=0.032; Q4: χ2(3) = 15.94, p=0.001). Mean number of AE in Q1 of 2021 was also lower compared to prior years χ2(4)=23.55, p<0.001 (Figure 1). 
Asthma patients were more likely to avoid (38.8% vs. 0.0%, p<0.01) or delay (24.5% vs. 0.0%, p=0.02) essential medical visits due to fear of SARS-CoV2 infection at medical facilities compared to controls. In case of AE, most patients used e-consults (83.3%).

Conclusion
AE frequency was significantly reduced in 2020 compared to previous years. We suggest the frequency of AE is reduced by social distancing and hygiene measures during the lockdown. Also, asthma patients showed more anxiety towards acquiring Covid-19 disease at medical facilities, therefore it is important to encourage asthma patients to contact their practitioner in case of need.


Breathing on Chip: studying the effect of biomechanical forces on airway epithelial cell biology using a modular Airway Lung-Chip

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Reliability of a home spirometer for monitoring children with cystic fibrosis during the COVID-19 pandemic.

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