Predominance of M2 macrophages in organized thrombi in chronic thromboembolic pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68+ macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair. Currently, the phenotype of macrophages and their localization within thrombotic lesions of CTEPH are largely unknown. In our study, we subclassified thrombotic lesions of CTEPH patients into developing fresh thrombi (FT) and organized thrombi (OT), based on the degree of fibrosis and remodeling. We used multiplex immunofluorescence histology to identify immune cell infiltrates in thrombotic lesions of CPTEH patients. Utilizing software-assisted cell detection and quantification, increased proportions of macrophages were observed in immune cell infiltrates of OT lesions, compared with FT. Strikingly, the proportions with a CD206+INOS- M2 phenotype were significantly higher in OT than in FT, which mainly contained unpolarized macrophages. Taken together, we observed a shift from unpolarized macrophages in FT toward an expanded population of M2 macrophages in OT, indicating a dynamic role of macrophages during CTEPH pathogenesis.

Two-year diffusion capacity trajectory in COVID-19 pneumonia survivors.

Reduced diffusion capacity (DLCO) after COVID 19 pneumonia was reported in hospitalised patients after discharge. Here, we studied the restoration of DLCO over a 24 months period in COVID-19 pneumonia survivors (n = 317), who were categorised into "moderate" cases (no oxygen supply; no need for hospitalisation), "severe" cases (respiratory frequency > 30/min and/or peripheral oxygen SpO2 < 93%), and "critical" cases (respiratory failure and admission into the intensive care unit). COVID-19 pneumonia survivors with a decreased DLCO (<80%) at 3 months (n = 133) were invited for 6- and 24-months follow-up. At 3 months, impairment of DLCO was more severe in critical case (p < .01). Over time, the subgroups showed a similar level of improvement; and, there was no difference in recovery over time between the subgroups. At 24 months, the DLCO did not differ between the subgroups, with a mean DLCO of 73% for all patients. At 24 months, 65% of patients still had a DLCO < 80%, and in 40% of patients DLCO was <70% of predicted. Regardless the initial disease severity, all COVID-19 survivors showed improvement in DLCO during follow-up; however, DLCO had not normalised in the majority of patients with a DLCO <80% 3 months after hospital discharge.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

Pulmonary function and Quality of Life in a prospective cohort of (non-) hospitalized COVID-19 pneumonia survivors up to six months.

OBJECTIVES: A decrease of both diffusion capacity (DLCO) and Quality of Life (QoL) was reported after discharge in hospitalized COVID-19 pneumonia survivors. We studied three and 6 month outcomes in hospitalized and non-hospitalized patients. METHODS: COVID-19 pneumonia survivors (n = 317) were categorized into non-hospitalized "moderate" cases (n = 59), hospitalized "severe" cases (n = 180) and ICU-admitted "critical" cases (n = 39). We studied DLCO and QoL (Short Form SF-36 health survey) 3 and 6 months after discharge. Data were analyzed using (repeated measures) ANOVA, Kruskal-Wallis or Chi-square test (p < .05). RESULTS: At 3 months DLCO was decreased in 44% of moderate-, 56% of severe- and 82% of critical cases (p < .003). Mean DLCO in critical cases (64±14%) was lower compared to severe (76 ± 17%) and moderate (81±15%) cases (p < .001). A total of 159/278 patients had a decreased DLCO (<80%), of whom the DLCO improved after 6 months in 45% (71/159). However the DLCO did not normalize in the majority (89%) of the cases (63 ± 10% vs 68±10%; p < .001). At 3 months, compared to critical cases, moderate cases scored lower on SF-36 domain "general health" (p < .05); both moderate and severe cases scored lower on the domain of "health change" (p < .05). At 6 months, there were no differences in SF-36 between the subgroups. Compared to 3 months, in all groups "physical functioning" improved; in contrast all groups scored significantly lower on "non-physical" SF-36 domains. CONCLUSION: Three months after COVID-19 pneumonia, DLCO was still decreased in the more severely affected patients, with an incomplete recovery after 6 months. At 3 months QoL was impaired. At 6 months, while "physical functioning" improved, a decrease in "non-physical" QoL was observed but did not differ between the moderate and severely affected patients.

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

Rationale: 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.Objectives: To investigate whether a home monitoring program improves HRQOL and medication use for patients with IPF.Methods: 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.Measurements and Main Results: 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; P = 0.24). Between-group difference in psychological domain score was 5.6 points (95% CI, -1.13 to 12.3; P = 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; P = 0.027). Patient satisfaction with the home monitoring program was high. Home-based spirometry was highly correlated with hospital-based spirometry over time.Conclusions: 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).

Rationale and design of the PRAETORIAN-COVID trial: A double-blind, placebo-controlled randomized clinical trial with valsartan for PRevention of Acute rEspiraTORy dIstress syndrome in hospitAlized patieNts with SARS-COV-2 Infection Disease.

There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking. METHODS: The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020). SUMMARY: The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

Idiopathic Pulmonary Fibrosis: Best Practice in Monitoring and Managing a Relentless Fibrotic Disease.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease that is, by definition, progressive. Progression of IPF is reflected by a decline in lung function, worsening of dyspnea and exercise capacity, and deterioration in health-related quality of life. In the short term, the course of disease for an individual patient is impossible to predict. A period of relative stability in forced vital capacity (FVC) does not mean that FVC will remain stable in the near future. Frequent monitoring using multiple assessments, not limited to pulmonary function tests, is important to evaluate disease progression in individual patients and ensure that patients are offered appropriate care. Optimal management of IPF requires a multidimensional approach, including both pharmacological therapy to slow decline in lung function and supportive care to preserve patients' quality of life.

Digital versus analogue chest drainage system in patients with primary spontaneous pneumothorax: a randomized controlled trial.

BACKGROUND: Patients with a primary spontaneous pneumothorax (PSP) who are treated with chest tube drainage are traditionally connected to an analogue chest drainage system, containing a water seal and using a visual method of monitoring air leakage. Electronic systems with continuous digital monitoring of air leakage provide better insight into actual air leakage and changes in leakage over time, which may lead to a shorter length of hospital stay. METHODS: We performed a randomized controlled trial comparing the digital with analogue system, with the aim of demonstrating that use of a digital drainage system in PSP leads to a shorter hospital stay. RESULTS: In 102 patients enrolled with PSP we found no differences in total duration of chest tube drainage and hospital stay between the groups. However, in a post-hoc analysis, excluding 19 patients needing surgery due to prolonged air leakage, hospital stay was significantly shorter in the digital group (median 1 days, IQR 1-5 days) compared to the analogue group (median 3 days, IQR 2-5 days) (p 0.014). Treatment failure occurred in 3 patients in both groups; the rate of recurrence within 12 weeks was not significantly different between groups (16% in the digital group versus 8% in the analogue group, p 0.339). CONCLUSION: Length of hospital stay was not shorter in patients with PSP when applying a digital drainage system compared to an analogue drainage system. However, in the large subgroup of uncomplicated PSP, a significant reduction in duration of drainage and hospital stay was demonstrated with digital drainage. These findings suggest that digital drainage may be a practical alternative to manual aspiration in the management of PSP. TRIAL REGISTRATION: Registered 22 September 2013 - Retrospectively registered, Trial NL4022 (NTR4195).

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Long-Term Outcome of Patients With Chronic Thromboembolic Pulmonary Hypertension: Results From an International Prospective Registry.

BACKGROUND: Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. METHODS AND RESULTS: A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90-95), 91% (95% CI, 87-93), and 89% (95% CI, 86-92) in operated patients (n=404), and only 88% (95% CI, 83-91), 79% (95% CI, 74-83), and 70% (95% CI, 64-76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension-targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49-11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76-12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95-1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20-1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36-6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18-3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension-targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. CONCLUSIONS: The long-term prognosis of operated patients currently is excellent and better than the outcome of not-operated patients.

Expression of inhibitory regulators of innate immunity in patients with active tuberculosis.

BACKGROUND: Tuberculosis (TB) is an important cause of morbidity and mortality worldwide. Toll-like-receptors (TLRs) are important for the recognition of the causative agent Mycobacterium tuberculosis. Negative regulation of TLRs is necessary to control deleterious inflammatory damage, but could provide a means of immune evasion by M. tuberculosis as well. METHODS: To obtain insight in the extent of expression of inhibitory regulators of immunity in patients with active TB, peripheral-blood-mononuclear-cells (PBMCs) and plasma were obtained from 54 TB patients and 29 healthy blood donors from Chittagong, Bangladesh. Bilateral alveolar macrophages were obtained from an infected versus a contralateral normal lung segment of 9 patients. Statistical analyses were performed using Mann-Whitney U and Wilcoxon matched pairs testing. Correlations were calculated using the Spearman rho test. RESULTS: PBMCs harvested from TB patients demonstrated increased mRNA expression of IL-1-receptor-associated-kinase-M, suppressor-of-cytokine-signalling-3 and Toll-interacting-protein. Flow cytometry revealed enhanced expression of IL-1-receptor-like-1 (ST2) on lymphocytes. Plasma soluble ST2 was elevated in patients with TB and correlated with established TB biomarkers, most strongly with soluble interleukin-2 receptor subunit α and interleukin-8. Alveolar macrophage mRNA expression of negative TLR regulators did not differ between the infected and contralateral lung side. CONCLUSION: These results show enhanced expression of distinct negative regulators of innate immunity in PBMCs of patients with TB and identify plasma soluble ST2 as a potential novel biomarker for TB disease activity.

Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients.

Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty-four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V'O2 -peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2 -peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R = -0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better.

Pulmonary vascular limitation to exercise and survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is frequently observed in advanced idiopathic pulmonary fibrosis (IPF) and is associated with poor prognosis. Cardiopulmonary exercise testing (CPET) can be used to detect less advanced pulmonary vascular impairment, and therefore may be of prognostic use. We studied the predictive value of non-invasive exercise parameters that were associated with elevated systolic pulmonary artery pressure (sPAP) for survival in IPF patients. METHODS: From our interstitial lung disease database, we reviewed records of consecutive patients with IPF in whom CPET and echocardiography were performed within 2 weeks (n = 38). RESULTS: Eleven patients (29%) had increased sPAP (≥40 mm Hg). From all non-invasive CPET parameters, only the ventilatory equivalent for CO2 (V'E /V'CO2 ) at anaerobic threshold differed significantly between patients with and without sPAP ≥ 40 mm Hg. The receiver-operator characteristic curve for V'E /V'CO2 resulted in areas under the curve of 0.77 (95% CI: 0.569-0.970; P = 0.026), with a cut-off value for predicting sPAP ≥ 40 mm Hg of >45.0. Patients with V'E /V'CO2 > 45.0 had significantly worse survival compared with patients with V'E /V'CO2 ≤ 45.0 (P = 0.001). In contrast, sPAP did not predict survival. CONCLUSIONS: V'E /V'CO2 , the only CPET parameter associated with elevated sPAP, appears a potentially useful non-invasive marker for early detection of pulmonary vascular impairment, and therefore may be of use for a more accurate prognostic assessment in IPF patients.

An observational study ascertaining the prevalence of bullae and blebs in young, healthy adults and its possible implications for scuba diving.

Introduction: Intrapulmonary air-filled cavities, e.g., bullae, blebs, and cysts, are believed to contribute topulmonary barotrauma (PBT) and arterial gas embolism (AGE) in divers. However, literature is unclear about the prevalence of bullae in healthy adults, ranging from 2.3-33.8%. While this could in part be explained due to increasing quality of radiologic imaging, such as computed tomography (CT) scans, other methodological factors may also affect these findings. This study aims to ascertain the prevalence of bullae in young and healthy adults. Methods: This single-center cross-sectional observational study re-assessed the CT scans of adults (aged 18-40) performed for a clinical suspicion for pulmonary embolism, from 1 January 2016 to 1 March 2020. Presence of bullae was recorded in an electronic database. Chi-square and Fisher exact tests were used for statistical analyses. Additionally, a multivariate logistic regression analysis was performed to study the independent predictive value of identified risk factors. Results: A total of 1,014 cases were identified, of which 836 could be included. Distribution amongst age groups (18-25, 26-30, 31-35, and 36-40) was almost equally, however, 75% of the population was female. Of the male proportion, 41% smoked, compared to 27% in females. In 7.2% (95% CI 5.6-9.1) bullae were identified. The prevalence increased with increasing age (p < 0.001), with odd ratios up to 5.347 (95% CI 2.164-13.213, p < 0.001) in the oldest age group. Males and smokers had higher odds ratios for bullae of 2.460 (95% CI 1.144-4.208; p = 0.001) and 3.406 (95% CI 1.878-6.157, p < 0.001), respectively. Similar results were seen in the multivariate logistic regression analysis, where age, male sex and smoking were all statistically significant independent risk factors for bullae. Discussion: Bullae were seen in 7.2% of a healthy population up to 40 years old. Increasing age, smoking, and being male were identified as statistically significant risk factors, both in independent and in multivariate logistic regression analyses. Our observations may warrant a re-evaluation of the contribution of bullae to PBT and AGE, as the latter two occur very rarely and bullae appear to be more frequently present than earlier assumed.

Patients with CTEPH and mild hemodynamic severity of disease improve to a similar level of exercise capacity after pulmonary endarterectomy compared to patients with severe hemodynamic disease.

The correlation between hemodynamics and degree of pulmonary vascular obstruction (PVO) is known to be poor in chronic thromboembolic pulmonary hypertension (CTEPH), which makes the selection of patients eligible for pulmonary endarterectomy (PEA) challenging. It can be postulated that patients with similar PVO but different hemodynamic severity have different postoperative hemodynamics and exercise capacity. Therefore, we aimed to assess the effects of PEA on hemodynamics and exercise physiology in mild and severe CTEPH patients. We retrospectively studied 18 CTEPH patients with a mild hemodynamic profile (mean pulmonary arterial pressure [mPAP] between 25 and 30 mmHg at rest) and CTEPH patients with a more severe hemodynamic profile (mPAP > 30 mmHg), matched by age, gender, and PVO. Cardiopulmonary exercise testing parameters were evaluated at baseline and 18 months following PEA. At baseline, exercise capacity, defined as oxygen uptake, was less severely impaired in the mild CTEPH group compared to the severe CTEPH group. After PEA, in the mild CTEPH group, ventilatory efficiency and oxygen pulse improved significantly (p < 0.05), however, the change in ventilatory efficiency and oxygen pulse was smaller compared to the severe CTEPH group. Only in the severe CTEPH group exercise capacity improved significantly (p < 0.001). Hence, in the present study, postoperative hemodynamic outcome and the CPET-determined recovery of exercise capacity in mild CTEPH patients did not differ from a matched group of severe CTEPH patients.

Organ involvement in newly diagnosed sarcoidosis patients in the Netherlands: The first large European multicentre prospective study.

BACKGROUND: Clinical presentation and prevalence of organ involvement is highly variable in sarcoidosis and depends on ethnic, genetic and geographical factors. These data are not extensively studied in a Dutch population. AIM: To determine the prevalence of organ involvement and the indication for systemic immunosuppressive therapy in newly diagnosed sarcoidosis patients in the Netherlands. METHODS: Two large Dutch teaching hospitals participated in this prospective cohort study. All adult patients with newly diagnosed sarcoidosis were prospectively included and a standardized work-up was performed. Organ involvement was defined using the WASOG instrument. RESULTS: Between 2015 and 2020, a total of 330 patients were included, 55% were male, mean age was 46 (SD 14) years. Most of them were white (76%). Pulmonary involvement including thoracic lymph node enlargement was present in 316 patients (96%). Pulmonary parenchymal disease was present in 156 patients (47%). Ten patients (3%) had radiological signs of pulmonary fibrosis. Cutaneous sarcoidosis was present in 74 patients (23%). Routine ophthalmological screening revealed uveitis in 29 patients (12%, n = 256)). Cardiac and neurosarcoidosis were diagnosed in respectively five (2%) and six patients (2%). Renal involvement was observed in 11 (3%) patients. Hypercalcaemia and hypercalciuria were observed in 29 (10%) and 48 (26%, n = 182) patients, respectively. Hepatic involvement was found in 6 patients (2%). In 30% of the patients, systemic immunosuppressive treatment was started at diagnosis. CONCLUSIONS: High-risk organ involvement in sarcoidosis is uncommon at diagnosis. Indication for systemic immunosuppressive therapy was present in a minority of patients.

Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses.

Intravenous administration of activated protein C (APC) inhibits coagulation and inflammation in the lungs of humans and animals. Investigations in rodents demonstrated that direct intrapulmonary delivery of APC also exerts anticoagulant and anti-inflammatory effects. The effect of intrabronchial administration of recombinant human (rh)APC on lipopolysaccharide (LPS)-induced haemostatic and inflammatory alterations in the bronchoalveolar space of humans was studied. Eight subjects received rhAPC via intrabronchial instillation by bronchoscope, while in a contralateral subsegment subjects received saline; all subjects were challenged bilaterally with LPS in the same lung subsegments. Four additional subjects received rhAPC (75 µg), with saline as a control in the contralateral subsegment, while they were bilaterally "challenged" with saline. After 6 h a bronchoalveolar lavage was performed and coagulation and inflammatory parameters were measured. rhAPC enhanced LPS-induced coagulation activation in the bronchoalveolar space, when compared with the control side. In addition, rhAPC amplified LPS-induced pro-inflammatory responses, as indicated by higher concentrations of cytokines and chemokines. rhAPC alone did not have procoagulant or pro-inflammatory effects. Locally administered rhAPC has unexpected procoagulant and pro-inflammatory effects in LPS-challenged lung subsegments. These data argue against a role for intrapulmonary delivery of rhAPC as a treatment strategy for lung inflammatory disorders in humans.

Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. METHODS AND RESULTS: The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%- 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension-targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. CONCLUSIONS: Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension-targeted treatments.

Gene expression profiles in alveolar macrophages induced by lipopolysaccharide in humans.

Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo, we conducted a study in eight healthy humans, in which we instilled sterile saline into a lung segment by bronchoscope, followed by instillation of LPS into the contralateral lung. Six hours later, a bilateral bronchoalveolar lavage was performed and whole-genome transcriptional profiling was done on purified alveolar macrophages, comparing cells exposed to saline or LPS from the same individuals. LPS induced differential expression of 2,932 genes in alveolar macrophages; 1,520 genes were upregulated, whereas 1,440 genes were downregulated. A total of 26 biological functions were overrepresented in LPS-exposed macrophages; 44 canonical pathways affected by LPS were identified, among which the genes associated with the role of pattern recognition receptors in recognition of bacteria and viruses represented the top pathway. Other pathways included cellular immune response, signaling by tumor necrosis factor (receptor) family members, cytokine signaling and glucocorticoid receptor signaling. These results reveal for the first time a large number of functional pathways influenced by the biologically relevant challenge provided by LPS administered into the airways. These data can assist in identifying novel targets for therapeutic intervention in pulmonary diseases associated with LPS exposure, including pneumonia, asthma and chronic obstructive pulmonary disease.