Publications by authors named "Marlies S Wijsenbeek"

57 Publications

The use of online visual analogue scales in idiopathic pulmonary fibrosis.

Eur Respir J 2021 Jul 29. Epub 2021 Jul 29.

Department of Respiratory Medicine, Interstitial Lung Diseases Centre of Excellence, Erasmus Medical Center, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1183/13993003.01531-2021DOI Listing
July 2021

Patient-centered Outcomes Research in Interstitial Lung Disease: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 Jul;204(2):e3-e23

In the past two decades, many advances have been made to our understanding of interstitial lung disease (ILD) and the way we approach its treatment. Despite this, many questions remain unanswered, particularly those related to how the disease and its therapies impact outcomes that are most important to patients. There is currently a lack of guidance on how to best define and incorporate these patient-centered outcomes in ILD research. To summarize the current state of patient-centered outcomes research in ILD, identify gaps in knowledge and research, and highlight opportunities and methods for future patient-centered research agendas in ILD. An international interdisciplinary group of experts was assembled. The group identified top patient-centered outcomes in ILD, reviewed available literature for each outcome, highlighted important discoveries and knowledge gaps, and formulated research recommendations. The committee identified seven themes around patient-centered outcomes as the focus of the statement. After a review of the literature and expert committee discussion, we developed 28 research recommendations. Patient-centered outcomes are key to ascertaining whether and how ILD and interventions used to treat it affect the way patients feel and function in their daily lives. Ample opportunities exist to conduct additional work dedicated to elevating and incorporating patient-centered outcomes in ILD research.
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http://dx.doi.org/10.1164/rccm.202105-1193STDOI Listing
July 2021

Disease Behaviour During the Peri-Diagnostic Period in Patients with Suspected Interstitial Lung Disease: The STARLINER Study.

Adv Ther 2021 Jul 11;38(7):4040-4056. Epub 2021 Jun 11.

Department of Clinical and Experimental Medicine, Regional Referral Centre for Rare Lung Diseases, University Hospital Policlinico "G. Rodolico-San Marco", University of Catania, Via Santa Sofia 78, 95123, Catania, Italy.

Introduction: Disease behaviour may guide diagnosis and treatment decisions in patients with interstitial lung disease (ILD). STARLINER aimed to characterise disease behaviour in patients with suspected ILD during the peri-diagnostic period using real-time home-based assessments.

Methods: STARLINER (NCT03261037) was an international, multicentre study. Patients ≥ 50 years old with suspected ILD were followed throughout the peri-diagnostic period, consisting of a pre-diagnostic period (from enrolment to diagnosis) and a post-diagnostic period (from diagnosis to treatment initiation). Study length was variable (≤ 18 months). The primary endpoint was time-adjusted semi-annual forced vital capacity (FVC) change measured during the peri-diagnostic period using daily home spirometry in patients with idiopathic pulmonary fibrosis (IPF). Secondary outcomes included changes in FVC (home spirometry) in patients with non-IPF ILD, changes in FVC (site spirometry), changes in physical functional capacity measured by daily home accelerometry and site 6-min walk distance (6MWD), and changes in patient-reported outcomes (PROs) in IPF or non-IPF ILD.

Results: Of the 178 patients enrolled in the study, 68 patients were diagnosed with IPF, 62 patients were diagnosed with non-IPF ILD, 9 patients received a non-ILD diagnosis and 39 patients did not receive a diagnosis. Technical and analytical issues led to problems in applying the prespecified linear regression model to analyse the home FVC data. Time-adjusted median (quartile [Q]1, Q3) semi-annual FVC change during the peri-diagnostic period measured using home and site spirometry, respectively, was - 147.7 (- 723.8, 376.2) ml and - 149.0 (- 314.6, 163.9) ml for IPF and 19.1 (- 194.9, 519.0) ml and - 23.4 (- 117.9, 133.5) ml in non-IPF ILD. A greater decline in steps per day was observed for IPF versus non-IPF ILD, whereas an increase in 6MWD was observed for patients with IPF versus a decline in 6MWD for patients with non-IPF ILD. No clear patterns of disease behaviour were observed for IPF versus non-IPF ILD for PROs.

Conclusions: Despite home spirometry being feasible for most patients and centres, technical and analytical challenges in the home-based assessments prevented firm conclusions regarding disease behaviour. This highlights that further optimisation of the technology and analysis methods is required before widespread implementation.

Trial Registration: NCT03261037.
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http://dx.doi.org/10.1007/s12325-021-01790-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195454PMC
July 2021

Aberrant B Cell Receptor Signaling in Naïve B Cells from Patients with Idiopathic Pulmonary Fibrosis.

Cells 2021 May 26;10(6). Epub 2021 May 26.

Department of Pulmonary Medicine, Erasmus MC, University Medical Center, 3015 GD Rotterdam, The Netherlands.

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease in which an impaired healing response to recurrent micro-injuries is thought to lead to fibrosis. Recent findings hint at a role for B cells and autoimmunity in IPF pathogenesis. We previously reported that circulating B cells from a fraction of patients, compared with healthy controls, express increased levels of the signaling molecule Bruton's tyrosine kinase (BTK). However, it remains unclear whether B cell receptor (BCR) signaling is altered in IPF. Here, we show that the response to BCR stimulation is enhanced in peripheral blood B cells from treatment-naïve IPF patients. We observed increased anti-immunoglobulin-induced phosphorylation of BTK and its substrate phospholipase Cγ2 (PLCγ2) in naïve but not in memory B cells of patients with IPF. In naïve B cells of IPF patients enhanced BCR signaling correlated with surface expression of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) but not B cell activating factor receptor (BAFFR), both of which provide pro-survival signals. Interestingly, treatment of IPF patients with nintedanib, a tyrosine kinase inhibitor with anti-fibrotic and anti-inflammatory activity, induced substantial changes in BCR signaling. These findings support the involvement of B cells in IPF pathogenesis and suggest that targeting BCR signaling has potential value as a treatment option.
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http://dx.doi.org/10.3390/cells10061321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226954PMC
May 2021

The Value of the Surprise Question to Predict One-Year Mortality in Idiopathic Pulmonary Fibrosis: A Prospective Cohort Study.

Respiration 2021 May 27:1-6. Epub 2021 May 27.

Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease with a heterogeneous disease course. Timely initiation of palliative care is often lacking. The surprise question "Would you be surprised if this patient died within the next year?" is increasingly used as a clinical prognostic tool in chronic diseases but has never been evaluated in IPF.

Objective: We aimed to evaluate the predictive value of the surprise question for 1-year mortality in IPF.

Methods: In this prospective cohort study, clinicians answered the surprise question for each included patient. Clinical parameters and mortality data were collected. The sensitivity, specificity, accuracy, negative, and positive predictive value of the surprise question with regard to 1-year mortality were calculated. Multivariable logistic regression analysis was performed to evaluate which factors were associated with mortality. In addition, discriminative performance of the surprise question was assessed using the C-statistic.

Results: In total, 140 patients were included. One-year all-cause mortality was 20% (n = 28). Clinicians identified patients with a survival of <1 year with a sensitivity of 68%, a specificity of 82%, an accuracy of 79%, a positive predictive value of 49%, and a negative predictive value of 91%. The surprise question significantly predicted 1-year mortality in a multivariable model (OR 3.69; 95% CI 1.24-11.02; p = 0.019). The C-statistic of the surprise question to predict mortality was 0.75 (95% CI 0.66-0.85).

Conclusions: The answer on the surprise question can accurately predict 1-year mortality in IPF. Hence, this simple tool may enable timely focus on palliative care for patients with IPF.
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http://dx.doi.org/10.1159/000516291DOI Listing
May 2021

Management of Idiopathic Pulmonary Fibrosis.

Clin Chest Med 2021 06;42(2):275-285

Department of Respiratory Medicine, Centre for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, University Medical Centre Rotterdam, Dr. Molewaterplein 40, Rotterdam 3015, GD, the Netherlands.

Progress in the past 2 decades has led to widespread use of 2 medications to slow loss of lung function in patients with pulmonary fibrosis. Treatment of individual patients with currently available pharmacotherapies can be limited by side effects, and neither drug has a consistent effect on patient symptoms or function. Several promising new pharmacotherapies are under development. Comprehensive management of pulmonary fibrosis hinges on shared decision making. Patient and caregiver education, and early identification and management of symptoms and comorbidities, can help improve quality of life.
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http://dx.doi.org/10.1016/j.ccm.2021.03.004DOI Listing
June 2021

Loss of immune homeostasis in patients with idiopathic pulmonary arterial hypertension.

Thorax 2021 May 7. Epub 2021 May 7.

Department of Pulmonary Medicine, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands

Introduction: Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology.

Methods: Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Peripheral blood lymphocytes from patients with IPAH (n=13), connective tissue disease-associated PAH (CTD-PAH, n=9), congenital heart disease PAH (n=7), interstitial lung disease associated PH (n=17) and healthy controls (n=19) were characterised by 14-colour flow cytometry.

Results: Following pulmonary injury, BTK-overexpressing mice showed prolonged activation of B cells and CXCR5 follicular T-helper (Tfh) cells, as well as features of PH development. Patients with CTD-PAH and CHD-PAH displayed reduced proportions of circulating non-switched-memory B cells (p=0.03, p=0.02, respectively). Interestingly, we observed increased BTK protein expression in naive (p=0.007) and memory B-cell subsets of patients with IPAH and CTD-PAH. BTK was particularly high in patients with IPAH with circulating autoantibodies (p=0.045). IPAH patients had low frequencies of circulating CXCR5 Tfh cells (p=0.005). Hereby, the increased BTK protein expression in B cells was associated with high proportions of Tfh17 (p=0.018) and Tfh17.1 (p=0.007) cells within the circulating Tfh population.

Conclusions: Our study shows that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce PH symptoms in mice. In parallel, immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation, indicating that adaptive immune activation contributes to IPAH disease induction or progression.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215460DOI Listing
May 2021

Educational aspects of rare and orphan lung diseases.

Respir Res 2021 Mar 24;22(1):92. Epub 2021 Mar 24.

Department of Respiratory Medicine, Erasmus Medical Centre, University Hospital Rotterdam, Rotterdam, The Netherlands.

People with rare lung diseases often suffer the burden of delayed diagnosis, limited treatment options, and difficulties in finding expert physicians. One of the reasons for the delay in diagnosis is the limited training for healthcare practitioners on rare diseases. This review explores the main concerns and needs for education on rare lung diseases from the perspectives of both patients and professionals. Despite the increasing interest in rare lung disorders and some recent breakthrough developments on the management of several diseases, healthcare professionals, including general practitioners and hospital workers, receive little education on this topic. Nonetheless, many healthcare professionals show much interest in receiving further training, especially on diagnosis. Patients and families want easier access to high-quality education materials to help them manage their own disease. Well-educated patients are better equipped to deal with chronic diseases, but patient education can be challenging as patients' individual health issues, and diverse backgrounds can create significant barriers. Raising more awareness for rare lung diseases and further development of patient-centred international expert networks like the European Reference Network on Rare Lung Diseases (ERN-LUNG), which includes both experts and patient representatives, are essential for improving care and education on rare lung diseases. Initiatives such as the Rare Disease Day, have been successful in increasing awareness for rare conditions. The development of online tools for accessing information has had positive effects and should be further supported and extended in the future.
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http://dx.doi.org/10.1186/s12931-021-01676-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988372PMC
March 2021

Evaluation of a Home Monitoring Application for Follow Up after Lung Transplantation-A Pilot Study.

J Pers Med 2020 Nov 21;10(4). Epub 2020 Nov 21.

Department of Pulmonary Medicine, Erasmus Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.

Home spirometry after lung transplantation is common practice, to monitor graft function. However, there is little experience with online home monitoring applications with direct data transfer to the hospital. We evaluated the feasibility and patient experiences with a new online home monitoring application, integrated with a Bluetooth-enabled spirometer and real-time data transfer. Consecutive lung transplant recipients were asked to evaluate this home monitoring application for three months in a pilot study. Home spirometry measurements were compared with in-hospital lung function tests (the forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) at the end of the study. Ten patients participated. The home and hospital spirometry measurements showed a high correlation, for both the FEV1 ( = 0.99, < 0.01) and FVC ( = 0.99, < 0.01). The adherence and patient satisfaction were high, and the patients preferred the home monitoring application over the current home spirometer, with a difference of 1.4 ± 1.5 points on a scale from 0 to 10 ( = 0.02). Online home monitoring with direct data transfer is feasible and reliable after lung transplantation and results in high patient satisfaction. Whether the implementation of online home monitoring enables the earlier detection of lung function decline and improves patient and graft outcomes will be the subject of future research.
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http://dx.doi.org/10.3390/jpm10040240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711442PMC
November 2020

Feasibility of online home spirometry in systemic sclerosis-associated interstitial lung disease: a pilot study.

Rheumatology (Oxford) 2021 05;60(5):2467-2471

Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: Frequent monitoring of forced vital capacity at home may be of added value in patients with SSc-associated interstitial lung disease (SSc-ILD) to monitor disease progression and guide treatment decisions. The aim of this study was to evaluate the feasibility and optimal frequency of online home spirometry using a home monitoring application in patients with SSc-ILD.

Methods: This was a prospective, observational study in patients with SSc-ILD. Patients evaluated for 3 months the online home monitoring application ILD-online integrated with a Bluetooth-connected spirometer. Patients performed daily home spirometry for 6 weeks and weekly home spirometry for 6 weeks. In addition, patients completed an evaluation questionnaire after 3 months and online patient-reported outcomes at baseline and 3 months.

Results: Ten consecutive patients participated. Mean adherence to home spirometry was 98.8% (s.d. 1.5). Home and hospital spirometry were highly correlated. The mean coefficient of variation was lower for weekly [2.45% (s.d. 1.19)] than daily [3.86% (s.d. 1.45)] forced vital capacity measurements (P = 0.005). All patients considered the home monitoring application and spirometer easy to use and no patients considered home spirometry burdensome. All patients would recommend home monitoring to other patients with SSc.

Conclusions: Home spirometry using an online home monitoring application is feasible in patients with SSc-ILD, with high adherence and patient satisfaction. Larger long-term studies are needed to assess whether home spirometry can detect the progression of ILD in patients with SSc.
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http://dx.doi.org/10.1093/rheumatology/keaa607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121441PMC
May 2021

The effect of the walk-bike on quality of life and exercise capacity in patients with idiopathic pulmonary fibrosis: a feasibility study.

Sarcoidosis Vasc Diffuse Lung Dis 2020 30;37(2):192-202. Epub 2020 Jun 30.

Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of pulmonary function and exercise capacity, leading to loss of quality of life and often social isolation. A new walking aid, the walk-bike, showed an improvement in exercise performance in COPD patients. Aims of this pilot study were to evaluate feasibility of a homebased walk-bike intervention study in IPF patients and to explore the effect of the walk-bike on quality of life (QoL) and exercise capacity. Twenty-three patients with IPF were included in a randomized multicenter crossover study with 8 weeks of standard care and 8 weeks of walk-bike use at home. Ten patients completed both study phases. Study barriers included reluctance to participate and external factors (e.g. weather and road conditions) that hampered adherence. Patients' satisfaction and experience with the walk-bike varied greatly. After training with the walk-bike, health-related QoL (St. George's Respiratory and King's Brief Interstitial Lung Disease questionnaires) demonstrated a tendency towards improvement, exercise capacity did not. A clinically important difference was found between 6-minute walk test with the walk-bike and the standard test; median (range) respectively 602 m (358-684) and 486 m (382-510). Conclusions: Due to practical barriers a larger study with the walk-bike in patients with IPF seems not feasible. Individual patients may benefit from the use of a walk-bike as it improved action radius and showed a tendency towards improvement in QoL. No effect on exercise capacity was observed. .
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http://dx.doi.org/10.36141/svdld.v37i2.9433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569562PMC
November 2020

Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study.

BMC Pulm Med 2020 Oct 19;20(1):271. Epub 2020 Oct 19.

Department of Respiratory Medicine, Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, Rotterdam, the Netherlands.

Background: Treatment of pulmonary sarcoidosis is recommended in case of significant symptoms, impaired or deteriorating lung function. Evidence-based treatment recommendations are limited and largely based on expert opinion. Prednisone is currently the first-choice therapy and leads to short-term improvement of lung function. Unfortunately, prednisone often has side-effects and may be associated with impaired quality of life. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects.

Objective: The primary objective of this trial is to investigate the effectiveness and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared with prednisone. The primary endpoint of this study will be the change in hospital-measured Forced Vital Capacity (FVC) between baseline and 24 weeks. Secondary objectives are to gain more insights in response to therapy in individual patients by home spirometry and patient-reported outcomes. Blood biomarkers will be examined to find predictors of response to therapy, disease progression and chronicity, and to improve our understanding of the underlying disease mechanism.

Methods/design: In this prospective, randomized, non-blinded, multi-center, non-inferiority trial, we plan to randomize 138 treatment-naïve patients with pulmonary sarcoidosis who are about to start treatment. Patients will be randomized in a 1:1 ratio to receive either prednisone or methotrexate in a predefined schedule for 24 weeks, after which they will be followed up in regular care for up to 2 years. Regular hospital visits will include pulmonary function assessment, completion of patient-reported outcomes, and blood withdrawal. Additionally, patients will be asked to perform weekly home spirometry, and record symptoms and side-effects via a home monitoring application for 24 weeks.

Discussion: This study will be the first randomized controlled trial comparing first-line treatment of prednisone and methotrexate and provide valuable data on efficacy, safety, quality of life and biomarkers. If this study confirms the hypothesis that methotrexate is as effective as prednisone as first-line treatment for sarcoidosis but with fewer side-effects, this will lead to improvement in care and initiate a change in practice. Furthermore, insights into the immunological mechanisms underlying sarcoidosis pathology might reveal new therapeutic targets.

Trial Registration: The study was registered on the 19th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; ID NCT04314193 .
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http://dx.doi.org/10.1186/s12890-020-01290-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574228PMC
October 2020

ERS International Congress, Madrid, 2019: highlights from the Interstitial Lung Diseases Assembly.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Dept of Diseases of the Thorax, Ospedale GB Morgagni, Forli, Italy.

This article discusses a selection of the scientific presentations in the field of interstitial lung diseases (ILDs) that took place at the 2019 European Respiratory Society International Congress in Madrid, Spain. There were sessions from all four groups within Assembly 12: group 12.01 "Idiopathic interstitial pneumonias", group 12.02 "ILDs/diffuse parenchymal lung diseases (DPLDs) of known origin", group 12.03 "Sarcoidosis and other granulomatous ILDs/DPLDs" and group 12.04 "Rare ILDs/DPLDs". The presented studies brought cutting-edge developments on several aspects of these conditions, including pathogenesis, diagnosis and treatment. As many of the ILDs are individually rare, the sharing of experiences and new data that occur during the Congress are very important for physicians interested in ILDs and ILD patients alike.
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http://dx.doi.org/10.1183/23120541.00143-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533302PMC
October 2020

Exhaled breath analysis by use of eNose technology: a novel diagnostic tool for interstitial lung disease.

Eur Respir J 2021 01 5;57(1). Epub 2021 Jan 5.

Center of Excellence and European Reference Center for Interstitial Lung Disease and Sarcoidosis, Dept of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Introduction: Early and accurate diagnosis of interstitial lung diseases (ILDs) remains a major challenge. Better noninvasive diagnostic tools are much needed. We aimed to assess the accuracy of exhaled breath analysis using eNose technology to discriminate between ILD patients and healthy controls, and to distinguish ILD subgroups.

Methods: In this cross-sectional study, exhaled breath of consecutive ILD patients and healthy controls was analysed using eNose technology (SpiroNose). Statistical analyses were done using partial least square discriminant analysis and receiver operating characteristic analysis. Independent training and validation sets (2:1) were used in larger subgroups.

Results: A total of 322 ILD patients and 48 healthy controls were included: sarcoidosis (n=141), idiopathic pulmonary fibrosis (IPF) (n=85), connective tissue disease-associated ILD (n=33), chronic hypersensitivity pneumonitis (n=25), idiopathic nonspecific interstitial pneumonia (n=10), interstitial pneumonia with autoimmune features (n=11) and other ILDs (n=17). eNose sensors discriminated between ILD and healthy controls, with an area under the curve (AUC) of 1.00 in the training and validation sets. Comparison of patients with IPF and patients with other ILDs yielded an AUC of 0.91 (95% CI 0.85-0.96) in the training set and an AUC of 0.87 (95% CI 0.77-0.96) in the validation set. The eNose reliably distinguished between individual diseases, with AUC values ranging from 0.85 to 0.99.

Conclusions: eNose technology can completely distinguish ILD patients from healthy controls and can accurately discriminate between different ILD subgroups. Hence, exhaled breath analysis using eNose technology could be a novel biomarker in ILD, enabling timely diagnosis in the future.
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http://dx.doi.org/10.1183/13993003.02042-2020DOI Listing
January 2021

Desquamative interstitial pneumonia: a systematic review of its features and outcomes.

Eur Respir Rev 2020 Jun 23;29(156). Epub 2020 Jun 23.

Dept of Respiratory Diseases and Allergy, Center for Rare Lung Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Desquamative Interstitial Pneumonia (DIP) is a rare form of idiopathic interstitial pneumonia (IIP). Data on clinical features, aetiology, prognosis and effect of treatment strategies are limited. We aimed to collect all published cases to better characterise DIP.

Methods: A systematic literature search was performed for all original cases of adult patients with histopathologically-confirmed DIP. Individual patient data were extracted and summarised.

Results: We included 68 individual cases and 13 case series reporting on 294 cases. Most common presenting symptoms were dyspnoea and cough. Pulmonary function showed a restrictive pattern (71%) with decreased diffusion capacity. We found a high incidence (81%) of ever smoking in patients with DIP and 22% of patients had other (occupational) exposures. Characteristic features on high-resolution computed tomography (HRCT) scan were bilateral ground-glass opacities with lower lobe predominance (92%). Treatment and duration of treatment widely varied. Initial response to treatment was generally good, but definitely not uniformly so. A significant proportion of patients died (25% of individual cases) or experienced a relapse (18% of individual cases).

Conclusion: DIP remains an uncommon disease, frequently but not always related to smoking or other exposures. Furthermore, DIP behaves as a progressive disease more often than generally thought, possibly associated with different underlying aetiology.
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http://dx.doi.org/10.1183/16000617.0181-2019DOI Listing
June 2020

Managing Fatigue in Patients With Interstitial Lung Disease.

Chest 2020 11 7;158(5):2026-2033. Epub 2020 May 7.

Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address:

Fatigue is one of the most burdensome symptoms in interstitial lung disease (ILD) and can have a major impact on quality of life, social interactions, and work capacity. The cause of fatigue is complex; it is caused or aggravated by a combination of different predisposing, precipitating, and perpetuating factors. There is no uniform definition of fatigue, but it is often divided in physical and mental components. Several validated questionnaires can be used for structural assessment of fatigue in daily care. Although the high burden of fatigue in ILD is recognized increasingly, studies that have investigated pharmacologic and nonpharmacologic treatment options are scarce. Because fatigue in ILD is often a multifactorial problem, therapeutic interventions ideally should be aimed at different domains. One of the first steps is to optimize treatment of the underlying disease. Subsequently, treatable causes of fatigue should be identified and treated. Recently, an increasing number of studies showed that supportive measures have the potential to improve fatigue. However, evidence-based treatment guidelines are lacking, and more research is highly needed in this field. In clinical practice, a comprehensive, multidisciplinary, and individually tailored approach seems best fit to optimize treatment of fatigue in patients with ILD.
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http://dx.doi.org/10.1016/j.chest.2020.04.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674989PMC
November 2020

Home Monitoring in Patients with Idiopathic Pulmonary Fibrosis. A Randomized Controlled Trial.

Am J Respir Crit Care Med 2020 08;202(3):393-401

Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with increasingly impaired health-related quality of life (HRQOL). eHealth technologies facilitate collection of physiological outcomes and patient-reported outcomes at home, but randomized controlled trials (RCTs) on the effects of eHealth are scarce. To investigate whether a home monitoring program improves HRQOL and medication use for patients with IPF. We performed a multicenter RCT in newly treated patients with IPF. Patients were randomly assigned to standard care or a home monitoring program on top of standard care for 24 weeks. The home monitoring program included home spirometry, reporting of symptoms and side effects, patient-reported outcomes, information, a medication coach, and eConsultations. The primary endpoint was between-group difference in change in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) score at 24 weeks. A total of 90 patients were randomized (46 assigned to the home monitoring group and 44 to the standard care group). After 24 weeks, no statistically significant difference was found in K-BILD total score, with a 2.70-point increase in the home monitoring group (SD = 9.5) and a 0.03-point increase in the standard care group (SD = 10.4); between-group difference was 2.67 points (95% confidence interval [CI], -1.85 to 7.17;  = 0.24). Between-group difference in psychological domain score was 5.6 points (95% CI, -1.13 to 12.3;  = 0.10), with an increase of 5.12 points in the home monitoring group (SD = 15.8) and a decline of 0.48 points in the standard care group (SD = 13.3). In the home monitoring group, medication was more often adjusted (1 vs. 0.3 adjustments per patient; 95% CI, 0.2 to 1.3;  = 0.027). Patient satisfaction with the home monitoring program was high. Home-based spirometry was highly correlated with hospital-based spirometry over time. The results of this first-ever eHealth RCT in IPF showed that a comprehensive home monitoring program did not improve overall HRQOL measured with K-BILD but tended to improve psychological well-being. Home monitoring was greatly appreciated by patients and allowed for individually tailored medication adjustments.Clinical trial registered with www.clinicaltrials.gov (NCT03420235).
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http://dx.doi.org/10.1164/rccm.202002-0328OCDOI Listing
August 2020

Diurnal variation in forced vital capacity in patients with fibrotic interstitial lung disease using home spirometry.

ERJ Open Res 2020 Jan 6;6(1). Epub 2020 Apr 6.

Dept of Respiratory Medicine, Erasmus Medical Center, University Hospital Rotterdam, Rotterdam, The Netherlands.

http://bit.ly/37SQtBK.
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http://dx.doi.org/10.1183/23120541.00054-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132034PMC
January 2020

Comprehensive Care for Patients with Sarcoidosis.

J Clin Med 2020 Feb 1;9(2). Epub 2020 Feb 1.

Department of Respiratory Medicine, Erasmus Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.

Sarcoidosis is a multisystem granulomatous disease, associated with significant morbidity and impaired quality of life. Treatment is aimed at recovering organ function, reducing symptom burden and improving quality of life. Because of the heterogeneity and variable disease course, a comprehensive, multidisciplinary approach to care is needed. Comprehensive care includes not only pharmacological interventions, but also supportive measures aimed at relieving symptoms and improving quality of life. The purpose of this review is to summarize the most recent knowledge regarding different aspects of care and propose a structured approach to sarcoidosis management.
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http://dx.doi.org/10.3390/jcm9020390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074229PMC
February 2020

Results of the standard set for pulmonary sarcoidosis: feasibility and multicentre outcomes.

ERJ Open Res 2019 Oct 30;5(4). Epub 2019 Oct 30.

Interstitial Lung Diseases Center of Excellence, Dept of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands.

Our study presents findings on a previously developed standard set of clinical outcome data for pulmonary sarcoidosis patients. We aimed to assess whether changes in outcome varied between the different centres and to evaluate the feasibility of collecting the standard set retrospectively. This retrospective observational comparative benchmark study included six interstitial lung disease expert centres based in the Netherlands, Belgium, the UK and the USA. The standard set of outcome measures included 1) mortality, 2) changes in pulmonary function (forced vital capacity (FVC), forced expiratory volume in 1 s, diffusing capacity of the lung for carbon monoxide), 3) soluble interleukin-2 receptor (sIL-2R) change, 4) weight changes, 5) quality-of-life (QoL) measures, 6) osteoporosis and 7) clinical outcome status (COS). Data collection was considered feasible if the data were collected in ≥80% of all patients. 509 patients were included in the retrospective cohort. In total six patients died, with a mean survival of 38±23.4 months after the diagnosis. Centres varied in mean baseline FVC, ranging from 110 (95% CI 92-124)% predicted to 99 (95% CI 97-123)% pred. Mean baseline body mass index (BMI) of patients in the different centres varied between 27 (95% CI 23.6-29.4) kg·m and 31.8 (95% CI 28.1-35.6) kg·m. 310 (60.9%) patients were still on systemic therapy 2 years after the diagnosis. It was feasible to measure mortality, changes in pulmonary function, weight changes and COS. It is not (yet) feasible to retrospectively collect sIL-2R, osteoporosis and QoL data internationally. This study shows that data collection for the standard set of outcome measures for pulmonary sarcoidosis was feasible for four out of seven outcome measures. Trends in pulmonary function and BMI were similar for different hospitals when comparing different practices.
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http://dx.doi.org/10.1183/23120541.00094-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819983PMC
October 2019

Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis.

Respir Res 2019 Oct 24;20(1):232. Epub 2019 Oct 24.

Department of Pulmonary Medicine, Erasmus Medical Center, 's-Gravendijkwal 230, 3015, CE, Rotterdam, The Netherlands.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice.

Methods: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis.

Results: More IgA memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = - 0.50). Bruton's tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88).

Conclusion: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.
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http://dx.doi.org/10.1186/s12931-019-1195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814043PMC
October 2019

Gaps in care of patients living with pulmonary fibrosis: a joint patient and expert statement on the results of a Europe-wide survey.

ERJ Open Res 2019 Oct 21;5(4). Epub 2019 Oct 21.

Dept of Pneumology and Allergy, Ruhrlandklinik Medical Faculty, University of Duisburg-Essen, Essen, Germany.

Introduction: Pulmonary fibrosis (PF) and its most common form, idiopathic pulmonary fibrosis (IPF), are chronic, progressive diseases resulting in increasing loss of lung function and impaired quality of life and survival. The aim of this joint expert and patient statement was to highlight the most pressing common unmet needs of patients with PF/IPF, putting forward recommendations to improve the quality of life and health outcomes throughout the patient journey.

Methods: Two online surveys for patients and healthcare professionals (HCPs) were conducted by the European Idiopathic Pulmonary Fibrosis and Related Disorders Federation (EU-IPFF) in 14 European countries.

Results: The surveys were answered by 286 patients and 69 HCPs, including physicians and nurses. Delays in diagnosis and timely access to interstitial lung disease specialists and pharmacological treatment have been identified as important gaps in care. Additionally, patients and HCPs reported that a greater focus on symptom-centred management, adequate information, trial information and increasing awareness of PF/IPF is required.

Conclusions: The surveys offer important insights into the current unmet needs of PF/IPF patients. Interventions at different points of the care pathway are needed to improve patient experience.
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http://dx.doi.org/10.1183/23120541.00124-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801215PMC
October 2019

Cough, an unresolved problem in interstitial lung diseases.

Curr Opin Support Palliat Care 2019 09;13(3):143-151

Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

Purpose Of Review: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. Cough has a major impact on wellbeing, affecting both physical and psychological aspects of life. The pathophysiology of cough in ILDs is poorly understood and currently no good antitussive therapy exists.

Recent Findings: Research on cough in ILDs is increasing. A recent proof-of-concept study with nebulized sodium cromoglycate for patients with idiopathic pulmonary fibrosis (IPF)-related cough showed a promising effect on cough. Observational data suggest that antifibrotic pirfenidone might reduce cough in IPF. Studies on the effect of acid inhibition on cough in ILDs show contradicting results.

Summary: The first steps in analyzing new treatment options for chronic cough in patients with ILDs, especially in IPF, have been taken, but an effective treatment is still lacking.
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http://dx.doi.org/10.1097/SPC.0000000000000447DOI Listing
September 2019

Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study.

Lancet Respir Med 2019 08 20;7(8):657-664. Epub 2019 May 20.

Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study.

Methods: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24.

Findings: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224).

Interpretation: Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF.

Funding: Promedior.
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http://dx.doi.org/10.1016/S2213-2600(19)30172-9DOI Listing
August 2019

Feasibility of a Comprehensive Home Monitoring Program for Sarcoidosis.

J Pers Med 2019 May 5;9(2). Epub 2019 May 5.

Department of Respiratory Medicine, Erasmus Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands.

Sarcoidosis is a chronic, heterogeneous disease which most commonly affects the lungs. Currently, evidence-based and individually tailored treatment options in sarcoidosis are lacking. We aimed to evaluate patient experiences with a home monitoring program for sarcoidosis and assess whether home monitoring is a feasible tool to enhance personalized treatment. Outpatients with pulmonary sarcoidosis tested the home monitoring program "Sarconline" for one month. This is a secured personal platform which consists of online patient-reported outcomes, real-time wireless home spirometry, an activity tracker, an information library, and an eContact option. Patients wore an activity tracker, performed daily home spirometry, and completed patient-reported outcomes at baseline and after one month. Patient experiences were evaluated during a phone interview. Ten patients were included in the study. Experiences with the home monitoring program were positive; 90% of patients considered the application easy to use, none of the patients found daily measurements burdensome, and all patients wished to continue the home monitoring program after the study. Mean adherence to daily spirometry and activity tracking was, respectively, 94.6% and 91.3%. In conclusion, a comprehensive home monitoring program for sarcoidosis is feasible and can be used in future research and clinical practice.
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http://dx.doi.org/10.3390/jpm9020023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617326PMC
May 2019

Comprehensive Supportive Care for Patients with Fibrosing Interstitial Lung Disease.

Am J Respir Crit Care Med 2019 07;200(2):152-159

6 Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College, London, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201903-0614PPDOI Listing
July 2019

Serious adverse events in patients with idiopathic pulmonary fibrosis in the placebo arms of 6 clinical trials.

Respir Med 2019 04 13;150:120-125. Epub 2019 Mar 13.

University of Utah, Salt Lake City, UT, USA.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by irreversible loss of lung function and an unpredictable course of disease progression.

Methods: The safety data for patients with IPF who received placebo in 6 clinical trials were pooled to examine the categories and frequencies of serious adverse events (SAEs) in this population.

Results: In 1082 patients with IPF who received placebo, 673 SAEs were reported. Of these, 93 SAEs resulted in death (8.6% of patients). Respiratory-related conditions were the most frequently reported SAE (225 events, 16.33 per 100 patient-exposure years [PEY]), followed by infections and infestations (136 events, 9.87 per 100 PEY) and cardiac disorders (79 events, 5.73 per 100 PEY); these categories also had the most fatal outcomes (60, 10, and 10 deaths, respectively). The most frequently reported fatal respiratory-related SAEs were IPF and respiratory failure (38 and 11 patients, respectively), and the most frequently reported fatal infections and infestations and cardiac disorders were pneumonia (5 patients) and myocardial infarction (3 patients), respectively.

Conclusions: This pooled analysis has value as a comparator for safety in future studies of IPF and provides insights in the natural evolution of both IPF and common comorbidities.
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http://dx.doi.org/10.1016/j.rmed.2019.02.021DOI Listing
April 2019

First patient-centred set of outcomes for pulmonary sarcoidosis: a multicentre initiative.

BMJ Open Respir Res 2019 18;6(1):e000394. Epub 2019 Feb 18.

Department of Value-Based Healthcare, St. Antonius Hospital, Nieuwegein, The Netherlands.

Introduction: Routine and international comparison of clinical outcomes enabling identification of best practices for patients with pulmonary sarcoidosis is lacking. The aim of this study was to develop a standard set of outcome measures for pulmonary sarcoidosis, using the value-based healthcare principles.

Methods: Six expert clinics for interstitial lung diseases in four countries participated in a consensus-driven RAND-modified Delphi study. A mixed-method approach was applied for the identification of an outcome measures set and initial conditions for patients with pulmonary sarcoidosis. The expert team consisted of multidisciplinary professionals (n=14) from Cleveland Clinic, Cincinnati MC, Erasmus MC, Leuven UZ, Royal Brompton and St. Antonius Hospital. During a ranking process, participants were instructed to rank variables on a scale from 1 to 10 based on whether it has (1) impact of the outcome on quality of life, (2) impact of quality of care on the outcome and (3) the number of patients negatively affected by the outcome.

Results: An outcome measures set was defined consisting of seven outcome measures: mortality, pulmonary function, soluble interleukin-2 receptor change as an activity biomarker, weight gain, quality of life, osteoporosis and clinical outcome status.

Discussion: Collecting outcomes in pulmonary sarcoidosis internationally and the use of a broadly accepted set can enable international comparison. Differences in outcomes can potentially be used as a starting point for quality improvement initiatives.
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http://dx.doi.org/10.1136/bmjresp-2018-000394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424298PMC
April 2020

Research highlights from the 2018 ERS International Congress: interstitial lung diseases.

ERJ Open Res 2019 Feb 18;5(1). Epub 2019 Feb 18.

Dept of Diseases of the Thorax, Ospedale GB Morgagni, Forlì, Italy.

This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD).
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http://dx.doi.org/10.1183/23120541.00215-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378342PMC
February 2019
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