Netherlands

Nasal high-flow therapy (NHFT) appears to be a suitable treatment in COVID-19 patients, but healthcare professionals are reluctant to use the therapy on the ward. This observational study included 86 COVID-19 patients in whom NHFT was initiated on the ward. As a control group, 43 patients were retrospectively included. In patients with a restricted medical policy, 51% of the patients in the NHFT group recovered compared to 20% in the control group. In patients with a full medical policy, ICU admission was 71% in the NHFT group compared to 46% in the control group. Overall, NHFT did not lead to increased or delayed intubations. Furthermore, the overall mortality rate and the mortality rate after intubation is similar in both groups (control 15%, NHFT 17%). The study shows that NHFT on the ward is feasible and effective in both patients with a full medical policy and in patients with a restricted policy.

Dutch Lung Congress

The effectiveness of nasal high-flow therapy on the COVID-19 ward

pulmonary ward

effectiveness

nasal high-flow therapy

covid-19

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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.

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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**
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### Special Session: Publieksmiddag
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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)
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Introduction Small fiber neuropathy (SFN) may presents as complication in amongst others sarcoidosis.1 SFN can potentially result into a large range of symptoms with a high impact on quality of life.2 Although treatment of the underlying disease of SFN is advised for the past decades, little research has been performed to investigate SFN improvement as consequence of sarcoidosis treatment. This retrospective study investigates treatment effects of Infliximab on SFN symptoms.
Methods The Small Fiber Neuropathy Screening List (SFNSL) was used to identify changes in SFN symptoms. Maximal standardized uptake value (SUVmax) from Fluordeoxyglucose Positron Emission Tomography (FDG-PET) was used as inflammatory activity measure. To investigate the effects of Infliximab on inflammatory activity, a subdivision was made defined as improved, stable and worsened SFNSL-score.
Results 45 sarcoidosis patients were eligible for analysis. SFNSL-score showed a mean decrease of -3 points (p = 0.207). SUVmax did improve with a mean of 3.44 (p=<0.001). When looking at the subdivision based on the change in SFNSL, only in the group with worsening of SFN-related symptoms, no clinical relevant improvement of sarcoidosis inflammatory activity was induced.
Discussion In patients with active inflammatory sarcoidosis defined by FDG-PET, Infliximab treatment showed an improvement of the SFNSL-score in 47% of patients. In this subgroup we found a significant decrease of sarcoidosis inflammation measured by FDG-PET. In patients without improvement of SFNSL, the SUVmax did not improve clinically relevant. These data could open a discussion about whether persistent inflammation in sarcoidosis can be detrimental to symptoms of SFN.


Effects of Infliximab on small fiber neuropathy symptoms in sarcoidosis patients


Particulate matter is a widespread pollutants, consisting of a complex mixture of organic and inorganic substances. Epidemiological and experimental exposure studies have clearly associated chronic exposure of airborne particulate matter (PM) with increased respiratory diseases. Although several in vitro studies have been performed to elucidate toxicological effect of particulate matter on airway epithelial cells, the majority of studies do not represent the correlation and applicability to realistic in vivo systems. In the current study, we developed and implemented an in vitro model to assess the chronic PM exposure with lower concentrations in order to provide more realistic exposure condition and illuminate the implications of chronic PM exposure. This model was further used to study how chronic PM exposure might predispose to the development of allergy or allergic reactions. Human bronchial epithelial cells 16HBE cells were exposed to increasing concentrations of diesel exhaust particles (12.5-800 µg/ml) for 96h followed by 24h exposure to house dust mite. Afterwards, effect on cell cytotoxicity and barrier integrity were investigated. When 16HBE cells were exposed to 12.5 µg/ml DEP, we determined that chronically exposed cells showed an augmented stress and modified functionality in comparison to acute exposed cells. The current study shows that chronic exposure to low concentrations of PM (12.5 ug/ml) leads to loss of airway barrier integrity compared to 24h exposure. Moreover, in this study we showed that pre-exposure to DEP (12.5 and 25µg/ml) aggravated the HDM-induced loss of TEER and an increased flux of LY to the basolateral compartment compared to HDM or DEP alone. Pre-exposure to DEP additionally increased increased HDM-induced IL-6 and CCL-22. In summary, in the current study we provided for the first an in vitro chronic model which might be helpful for further understanding of the interplay between allergens and chronic PM exposure.

Repeated exposure of bronchial epithelial cells to particular matter increases allergen-induced cytokine release and permeability 

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. 


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

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

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.


The effectiveness of nasal high-flow therapy on the COVID-19 ward

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