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Objectives The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. Methods Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. Results Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. Conclusion In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use.

The clinical features of COVID-19 have a considerable range from a mild illness to severe disease. Underlying pathophysiological mechanisms of the rapidly progressive, and often fatal, pulmonary disease frequently observed in COVID-19 need to be elucidated, in order to develop new treatment strategies for different disease endotypes. Fatal cases can display features of a cytokine storm, which may be related to hemophagocytic lymphohistiocytosis. Also, a spectrum of vascular changes, including microvascular damage, is known to accompany severe COVID-19. In this paper, we describe the co-occurrence of hemophagocytic lymphohistiocytosis and extensive pulmonary microvascular damage with thrombosis and its sequelae in a patient with fatal COVID-19. We believe these response patterns may be linked by common mechanisms involving hypercytokinemia and require further investigation as a fatal constellation in COVID-19, to generate appropriate treatment in patients who display these combined features.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.OBJECTIVES: By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis.PATIENTS/METHODS: In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis.RESULTS: COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18).CONCLUSIONS: Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk.

Introduction The term progressive fibrosing interstitial lung disease (ILD) describes patients with fibrotic ILDs who, irrespective of the aetiology of the disease, show a progressive course of their disease despite current available (and non-licensed) treatment. Besides in idiopathic pulmonary fibrosis, little is known about management and the burden of patients with fibrotic ILD, particularly those with a progressive behaviour. Methods Using the Delphi method, 40 European experts in ILD management delivered information on management of (progressive) fibrosing ILD and on the impact of the disease on patients’ quality of life (QoL) and healthcare resource utilisation (HCRU). Annual costs were calculated for progressive and non-/slow-progressive fibrosing ILD for diagnosis, follow-up management, exacerbation management, and end-of-life care based on the survey data. Results Physicians reported that progression in fibrosing ILD worsens QoL in both patients and their caregivers. Progression of fibrosing ILD was associated with a greater use of HCRU for follow-up visits and maintenance treatment compared with the non-/slow progression. The number of patients who suffered at least one acute exacerbation was reported to be more than three times higher in progressive fibrosing ILD patients than in patients with non-/slow-progressive fibrosing ILD. On average, annual estimated costs of progressive fibrosing ILD per patient were 1.8 times higher than those of the non-/slow-progressive form of the disease. Conclusions Progression in fibrosing ILD causes a significant impact on QoL and HCRU and costs. These survey data underline the need for safe and effective therapies to slow the disease progression. Electronic supplementary material The online version of this article (10.1007/s12325-020-01384-0) contains supplementary material, which is available to authorized users.

ObjectivesDevelop simple and valid models for predicting mortality and need for intensive care unit (ICU) admission in patients who present at the emergency department (ED) with suspected COVID-19.DesignRetrospective.SettingSecondary care in four large Dutch hospitals.ParticipantsPatients who presented at the ED and were admitted to hospital with suspected COVID-19. We used 5831 first-wave patients who presented between March and August 2020 for model development and 3252 second-wave patients who presented between September and December 2020 for model validation.Outcome measuresWe developed separate logistic regression models for in-hospital death and for need for ICU admission, both within 28 days after hospital admission. Based on prior literature, we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. We assessed model performance by the area under the receiver operating characteristic curve (AUC) and by calibration plots.ResultsOf 5831 first-wave patients, 629 (10.8%) died within 28 days after admission. ICU admission was fully recorded for 2633 first-wave patients in 2 hospitals, with 214 (8.1%) ICU admissions within 28 days. A simple model—COVID outcome prediction in the emergency department (COPE)—with age, respiratory rate, C reactive protein, lactate dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well calibrated and showed good discrimination for mortality in second-wave patients (AUC in four hospitals: 0.82 (95% CI 0.78 to 0.86); 0.82 (95% CI 0.74 to 0.90); 0.79 (95% CI 0.70 to 0.88); 0.83 (95% CI 0.79 to 0.86)). COPE was also able to identify patients at high risk of needing ICU admission in second-wave patients (AUC in two hospitals: 0.84 (95% CI 0.78 to 0.90); 0.81 (95% CI 0.66 to 0.95)).ConclusionsCOPE is a simple tool that is well able to predict mortality and need for ICU admission in patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.

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 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.

Mycobacterium microti belongs to the Mycobacterium tuberculosis complex (MTBC). It can cause pulmonary and extrapulmonary tuberculosis in humans. Compared to M. tuberculosis , which is the most prevalent subspecies of the MTBC, M. microti infection has a different etiology. Moreover, establishing the diagnosis with conventional bacteriology can be difficult. We will illustrate this with a case of an extrapulmonary tuberculosis of the hip caused by M .microti in an immunocompetent patient in 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.

Background and aimCOVID-19 is putting extraordinary pressure on emergency departments (EDs). To support decision making in the ED, we aimed to develop a simple and valid model for predicting mortality and need for intensive care unit (ICU) admission in suspected COVID-19 patients.MethodsFor model development, we retrospectively collected data of patients who were admitted to 4 large Dutch hospitals with suspected COVID-19 between March and August 2020 (first wave of the pandemic). Based on prior literature we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. Logistic regression analyses with post-hoc uniform shrinkage was used to obtain predicted probabilities of in-hospital death and of the need for ICU admission, both within 28 days after hospital admission. We assessed model performance (Area Under the ROC curve (AUC); calibration plots) with temporal validation in patients who presented between September and December 2020 (second wave). We used multiple imputation to account for missing values.ResultsThe development data included 5,831 patients, of whom 629 (10.8%) died and 5,070 (86.9%) were discharged within 28 days after admission. ICU admission was fully recorded for 2,633 first wave patients in 2 hospitals, with 214 (8%) ICU admissions within 28 days. A simple model – COVID Outcome Prediction in the Emergency Department (COPE) – with age, respiratory rate, C-reactive protein, lactic dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well-calibrated and showed good discrimination in 3,252 second wave patients (AUC in 4 hospitals: 0.82 [0.78; 0.86]; 0.82 [0.74; 0.90]; 0.79 [0.70; 0.88]; 0.83 [0.79; 0.86]). COPE was also able to identify patients at high risk of needing IC in 706 second wave patients with complete information on ICU admission (AUC: 0.84 [0.78; 0.90]; 0.81 [0.66; 0.95]). The models are implemented in web-based and mobile applications.ConclusionCOPE is a simple tool that is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making.CONTRIBUTION TO THE LITERATUREWhat is already known on this topicPrediction models have the potential to support decision making about hospital admission of patients presenting to the emergency department with suspected COVID-19Most currently available models that were independently assessed contain a high risk of biasPromising models were developed in different patient selections and included predictors that are not quickly and objective obtainable in emergency departmentsWhat this study addsA simple and objective tool (“COPE”) is well able to predict mortality and need for ICU admission for patients who present to the ED with suspected COVID-19COPE may support ED physicians to identify high-risk patients – i.e. those at high risk of deterioration and/or death – requiring treatment in the ICU, intermediate-risk patients requiring admission to the clinical ward, and low-risk patients who can potentially be sent home

Introduction Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterised by microvascular damage, immune dysregulation and fibrosis, affecting the skin, joints and internal organs. Interstitial lung disease (ILD) is frequently associated with systemic sclerosis (SSc-ILD), leading to a poor prognosis and a high mortality rate. The aim of the BUILDup study (BUrden of Interstitial Lung Disease Consensus Panel) was to investigate the overall disease management and to estimate the social and economic burden of SSc-ILD across 8 European countries. Methods A modified Delphi method was used to obtain information on the management of SSc-ILD patients among 40 specialists (panellists) from 8 European countries. Average annual costs per patient and country were estimated by means of a direct cost-analysis study. Results The panellists had managed 805 SSc-ILD patients in the last year, 39.1% with limited (L-SSc-ILD) and 60.9% with extensive (E-SSc-ILD) disease. Of these, 32.8% of the panellists started treatment at diagnosis, 42.3% after signs of deterioration/progression and 24.7% when the disease had become extensive. The average annual cost of SSc-ILD per patient ranged from €6191 in Greece to €25,354 in Sweden. Main cost drivers were follow-up procedures, accounting for 80% of the total annual costs. Hospitalisations were the most important cost driver of follow-up costs. Healthcare resource use was more important for E-SSc-ILD compared to L-SSc-ILD. Early retirement was taken by 40.4% of the patients with an average of 11.9 years before the statutory retirement age. Conclusions SSc-ILD entails not only a clinical but also a social and economic burden, and is higher for E-SSc-ILD. Electronic supplementary material The online version of this article (10.1007/s12325-020-01541-5) contains supplementary material, which is available to authorized users.

Purpose of review Sarcoidosis is a complex granulomatous disease of unknown cause. Corticosteroids and immune suppressants are often given long term in chronic disease, which may result in substantial toxicity. Validated strategies for selecting patients at risk for disease progression, who might benefit from early and targeted treatment, are lacking. Consequently, the unmet need for new treatment options in sarcoidosis is high. In this review, we critically discuss potential therapeutic targets and ongoing clinical trials in sarcoidosis. Recent findings Despite the heterogeneous clinical manifestations and the lack of a reliable animal model, our knowledge and understanding of the pathogenesis of sarcoidosis has improved in recent years, which has resulted in the identification of several potential therapeutic strategies. They include the inhibition of cytokines involved in maturation of macrophages, activation of dendritic cells, and maturation and activation of pathogenic T-lymphocytes. The inflammasome and the autophagy are additional areas for future research. Antifibrotic therapy might also be a reasonable choice in selected patients, although the best treatment strategy in progressive fibrotic sarcoidosis remains undetermined. Summary In this article, we review novel approaches to sarcoidosis treatment and potential therapeutic targets.

Structured abstract for full paperBackgroundAfter recovery from COVID-19, most patients have anti-SARS-CoV-2 neutralizing antibodies. Their convalescent plasma could be an inexpensive and widely available treatment for COVID-19.MethodsThe Convalescent-plasma-for-COVID (ConCOVID) study was a randomized trial comparing convalescent plasma with standard of care therapy in patients hospitalized for COVID-19 in the Netherlands. Patients were randomized 1:1 and received 300ml of plasma with anti-SARS-CoV-2 neutralizing antibody titers of at least 1:80. The primary endpoint was day-60 mortality and key secondary endpoints were hospital stay and WHO 8-point disease severity scale improvement on day 15.ResultsThe trial was halted prematurely after 86 patients were enrolled. Although symptomatic for only 10 days (IQR 6-15) at the time of inclusion, 53 of 66 patients tested had anti-SARS-CoV-2 antibodies at baseline. A SARS-CoV-2 plaque reduction neutralization test showed neutralizing antibodies in 44 of the 56 (79%) patients tested with median titers comparable to the 115 donors (1:160 vs 1:160, p=0.40). These observations caused concerns about the potential benefit of convalescent plasma in the study population and after discussion with the data safety monitoring board, the study was discontinued. No difference in mortality (p=0.95), hospital stay (p=0.68) or day-15 disease severity (p=0.58) was observed between plasma treated patients and patients on standard of care.ConclusionMost COVID-19 patients already have high neutralizing antibody titers at hospital admission. Screening for antibodies and prioritizing convalescent plasma to risk groups with recent symptom onset will be key to identify patients that may benefit from convalescent plasma. Clinicaltrials.gov:NCT04342182

Objectives Sarcoidosis is a chronic, multisystem disease with often a major impact on quality of life. Information on unmet needs of patients and their partners is lacking. We assessed needs and perceptions of sarcoidosis patients and their partners. Methods During patient information meetings in 2015 and 2017 in the Erasmus University Medical Center, we interviewed patients and partners using interactive voting boxes. Patients responded anonymously to 17 questions. Answers were projected directly on the screen in the room. Results 210 patients and 132 partners participated. Sarcoidosis has a subjective significant impact on lives of both patients and partners. The vast majority of patients and partners feel regularly misunderstood because of the general unawareness of sarcoidosis. Many patients and partners experience anxiety. Three-quarters of patients would like to see more attention and support for their psychological problems. Additionally, more supportive care for partners of sarcoidosis patients is warranted. Interactive interviewing was considered educational (91%) and pleasant (84%). Discussion This study improves awareness of needs and perceptions of patients with sarcoidosis and their partners. Sarcoidosis leads to anxiety and psychological distress and impairs well-being of patients and their partners. Attention for psychological support, better disease education, and more supportive care for partners is warranted.

Case Presentation A 79-year-old woman presented to the ED with complaints of gradually worsening exertional dyspnea, dizziness, and chest discomfort. For several weeks she had not been able to perform light household work. The patient's medical history mentioned pulmonary embolism following immobilization (2012), several fractures after trauma, an ischemic cerebral vascular accident (2014), and curative treatment for breast cancer (1995). Her current medication included esomeprazole, clopidogrel, simvastatin, calcium/vitamin D, amitriptyline, and acetaminophen.

BACKGROUND: The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases. METHODS: A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden's Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis. RESULTS: In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p

Adopting the new Global Lung Function Initiative TLCOreference values may positively impact clinical trial eligibility for IPF patientshttp://ow.ly/bOMn30n2YOP

In idiopathic pulmonary fibrosis (IPF), home monitoring experiences are limited, not yet real-time available nor implemented in daily care. We evaluated feasibility and potential barriers of a new home monitoring program with real-time wireless home spirometry in IPF. Ten patients with IPF were asked to test this home monitoring program, including daily home spirometry, for four weeks. Measurements of home and hospital spirometry showed good agreement. All patients considered real-time wireless spirometry useful and highly feasible. Both patients and researchers suggested relatively easy solutions for the identified potential barriers regarding real-time home monitoring in IPF.

__SIR,__ Renal crisis is a major complication in patients with SSc but so far has not been described in other systemic autoimmune diseases. Here we describe the first case of a scleroderma-like renal crisis in a patient with anti-threonyl-tRNA synthetase (anti-PL7)-associated antisynthetase syndrome. [...]

Thin-slices multi-detector computed tomography (MDCT) plays a key role in the differential diagnosis of interstitial lung disease (ILD). However, thin-slices MDCT has a limited ability to detect active inflammation, which is an important target of newly developed ILD drug therapy. Magnetic resonance imaging (MRI), thanks to its multi-parameter capability, provides better tissue characterisation than thin-slices MDCT.Our aim was to summarise the current status of MRI applications in ILD and to propose an ILD-MRI protocol. A systematic literature search was conducted for relevant studies on chest MRI in patients with ILD.We retrieved 1246 papers of which 55 original papers were selected for the review. We identified 24 studies comparing image quality of thin-slices MDCT and MRI using several MRI sequences. These studies described new MRI sequences to assess ILD parenchymal abnormalities, such as honeycombing, reticulation and ground-glass opacity. Thin-slices MDCT remains superior to MRI for morphological imaging. However, recent studies with ultra-short echo-time MRI showed image quality comparable to thin-slices MDCT. Several studies demonstrated the added value of chest MRI by using functional imaging, especially to detect and quantify inflammatory changes.We concluded that chest MRI could play a role in ILD patients to differentiate inflammatory and fibrotic changes and to assess efficacy of new ILD drugs.

RATIONALE Automated quantitative imaging may assess disease course and response to therapy in idiopathic pulmonary fibrosis (IPF). However, effort-dependent variability in inspiration impacts measurements. Spirometry-guided high-resolution computed tomography (SG-HRCT) may reduce this variability. Furthermore, it is unknown to what extent quantitative imaging correlates with pulmonary function or exercise tolerance. METHODS In …

Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time., The needs of patients with pulmonary fibrosis and partners, and the value of interactive interviewing http://ow.ly/M02t307jdEh