Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study.

BACKGROUND: Sepsis-associated destruction of the pulmonary microvascular endothelial glycocalyx (EGCX) creates a vulnerable endothelial surface, contributing to the development of acute respiratory distress syndrome (ARDS). Constituents of the EGCX shed into circulation, glycosaminoglycans and proteoglycans, may serve as biomarkers of endothelial dysfunction. We sought to define the patterns of plasma EGCX degradation products in children with sepsis-associated pediatric ARDS (PARDS), and test their association with clinical outcomes. METHODS: We retrospectively analyzed a prospective cohort (2018-2020) of children (≥1 month to <18 years of age) receiving invasive mechanical ventilation for acute respiratory failure for ≥72 h. Children with and without sepsis-associated PARDS were selected from the parent cohort and compared. Blood was collected at time of enrollment. Plasma glycosaminoglycan disaccharide class (heparan sulfate, chondroitin sulfate, and hyaluronan) and sulfation subtypes (heparan sulfate and chondroitin sulfate) were quantified using liquid chromatography tandem mass spectrometry. Plasma proteoglycans (syndecan-1) were measured through an immunoassay. RESULTS: Among the 39 mechanically ventilated children (29 with and 10 without sepsis-associated PARDS), sepsis-associated PARDS patients demonstrated higher levels of heparan sulfate (median 639 ng/mL [interquartile range, IQR 421-902] vs 311 [IQR 228-461]) and syndecan-1 (median 146 ng/mL [IQR 32-315] vs 8 [IQR 8-50]), both p = 0.01. Heparan sulfate subtype analysis demonstrated greater proportions of N-sulfated disaccharide levels among children with sepsis-associated PARDS (p = 0.01). Increasing N-sulfated disaccharide levels by quartile were associated with severe PARDS (n = 9/29) with the highest quartile including >60% of the severe PARDS patients (test for trend, p = 0.04). Higher total heparan sulfate and N-sulfated disaccharide levels were independently associated with fewer 28-day ventilator-free days in children with sepsis-associated PARDS (all p < 0.05). CONCLUSIONS: Children with sepsis-associated PARDS exhibited higher plasma levels of heparan sulfate disaccharides and syndecan-1, suggesting that EGCX degradation biomarkers may provide insights into endothelial dysfunction and PARDS pathobiology.

CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury.

Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.

Pulmonary sarcoidosis: A comprehensive review: Past to present.

Sarcoidosis is a sterile non-necrotizing granulomatous disease without known causes that can involve multiple organs with a predilection for the lung and thoracic lymph nodes. Worldwide it is estimated to affect 2-160/100,000 people and has a mortality rate over 5 years of approximately 7%. For sarcoidosis patients, the cause of death is due to sarcoid in 60% of the cases, of which up to 80% are from advanced cardiopulmonary failure (pulmonary hypertension and respiratory microbial infections) in all races except in Japan were greater than 70% of the sarcoidosis deaths are due to cardiac sarcoidosis. Scadding stages for pulmonary sarcoidosis associates with clinical outcomes. Stages I and II have radiographic remission in approximately 30%-80% of cases. Stage III only has a 10%-40% chance of resolution, while stage IV has no change of resolution. Up to 40% of pulmonary sarcoidosis patients progress to stage IV disease with lung parenchyma fibroplasia, bronchiectasis with hilar retraction and fibrocystic disease. These patients are at highest risk for the development of precapillary pulmonary hypertension, which may occur in up to 70% of these patients. Sarcoid patients with pre-capillary pulmonary hypertension can respond to targeted pulmonary arterial hypertension medications. Stage IV fibrocytic sarcoidosis with significant pulmonary physiologic impairment, >20% fibrosis on HRCT or pre-capillary pulmonary hypertension have the highest risk of mortality, which can be >40% at 5-years. First line treatment for patients who are symptomatic (cough and dyspnea) with parenchymal infiltrates and abnormal pulmonary function testing (PFT) is oral glucocorticoids, such as prednisone with a typical starting dose of 20-40 mg daily for 2 weeks to 2 months. Prednisone can be tapered over 6-18 months if symptoms, spirometry, PFTs, and radiographs improve. Prolonged prednisone may be required to stabilize disease. Patients requiring prolonged prednisone ≥10 mg/day or those with adverse effects due to glucocorticoids may be prescribed second and third line treatements. Second and third line treatments include immunosuppressive agents (e.g., methotrexate and azathioprine) and anti-tumor necrosis factor (TNF) medication; respectively. Effective treatments for advanced fibrocystic pulmonary disease are being explored. Despite different treatments, relapse rates range from 13% to 75% depending on the stage of sarcoid, number of organs involved, socioeconomic status, and geography. CONCLUSION: The mortality rate for sarcoidosis over a 5 year follow up is approximately 7%. Unfortunately, 10%-40% of patients with sarcoidosis develop progressive pulmonary disease, and >60% of deaths resulting from sarcoidosis are due to advance cardiopulmonary disease. Oral glucocorticoids are the first line treatment, while methotrexate and azathioprine are considered second and anti-TNF agents are third line treatments that are used solely or as glucocorticoid sparing agents for symptomatic extrapulmonary or pulmonary sarcoidosis with infiltrates on chest radiographs and abnormal PFT. Relapse rates have ranged from 13% to 75% depending on the population studied.

Efficacy and safety of an inhaled pan-Janus kinase inhibitor, nezulcitinib, in hospitalised patients with COVID-19: results from a phase 2 clinical trial.

BACKGROUND: The inhaled lung-selective pan-Janus kinase inhibitor nezulcitinib had favourable safety and potential efficacy signals in part 1 of a phase 2 trial in patients with severe COVID-19, supporting progression to part 2. METHODS: Part 2 was a randomised, double-blind phase 2 study (NCT04402866). Hospitalised patients aged 18-80 years with confirmed symptomatic COVID-19 requiring supplemental oxygen (excluding baseline invasive mechanical ventilation) were randomised 1:1 to nebulised nezulcitinib 3 mg or placebo for up to 7 days with background standard-of-care therapy (including corticosteroids). Efficacy endpoints included respiratory failure-free (RFF) days through day 28 as the primary endpoint. Secondary endpoints included safety and change from baseline oxygen saturation (SaO2)/fraction of inspired oxygen (FiO2) ratio on day 7, and 28-day mortality rate was a prespecified exploratory endpoint. RESULTS: Between June 2020 and April 2021, 205 patients were treated (nezulcitinib, 103; placebo, 102). There was no statistically significant difference between nezulcitinib versus placebo in the primary endpoint (RFF days; median, 21.0 vs 21.0; p=0.6137) or secondary efficacy endpoints. Nezulcitinib was generally well tolerated with a favourable safety profile. CONCLUSIONS: Although the prespecified primary, secondary and exploratory efficacy endpoints, including RFF through day 28, change from baseline SaO2/FiO2 ratio on day 7, and 28-day mortality rate, were not met, nezulcitinib was generally well tolerated and had a favourable safety profile. Further studies are required to determine if treatment with nezulcitinib confers clinical benefit in specific inflammatory biomarker-defined populations of patients with COVID-19.

Early posttransplant reductions in club cell secretory protein associate with future risk for chronic allograft dysfunction in lung recipients: results from a multicenter study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk. METHODS: We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD. RESULTS: Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p = 0.035). CONCLUSIONS: We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology.

Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis.

Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.

Cell saver blood transfusions may be associated with a decrease in inflammation and improved outcome measures in pediatric cardiac surgery patients.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite for correction of congenital heart disease by open-heart surgery and induces a systemic inflammatory response that can lead to complications such as acute lung injury and acute kidney injury. In addition, blood transfusions are commonly required for this type of surgery, and they may further exacerbate this inflammatory response and increase morbidity and mortality. We hypothesized that, in contrast to red blood cells, intraoperative cell saver (CS) blood transfusions attenuate the post-CPB proinflammatory cytokine response. METHODS: Serum cytokine concentrations of IL-10, IL-1RA, IL-6, IL-8, and TNF-α were measured at four time points (preoperatively and postoperatively on postoperative days 0, 1, and 2). RESULTS: Anti-inflammatory IL-10 levels were significantly lower in the CS group on POD 0 than in the control group (mean 1083.2 pg/mL vs 2080.2 pg/mL, 95%CI 357.4-1636.6, p = .0026). Of the clinical parameters measured, mean BUN and creatinine levels on POD 2 were significantly lower in the CS group (13.79 vs 21.88, p = .004 and 0.45 vs 0.55, p = .055, respectively). In addition, the duration of milrinone use decreased by 80% in the CS group (0.20, 95%CI 0.04, 0.94; p = .048), the median time to extubation in hours was significantly lower in the CS group (3.5 vs 6.5; 95%CI -38.00, -0.50; p = .026), and hospital length of stay was decreased by 60% in the CS group (p = .003). CONCLUSIONS: CS transfusions in children may lower postoperative anti-inflammatory IL-10 levels, possibly due to an overall decrease in proinflammatory state, and may be associated with improvements in renal and pulmonary functions.

NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension.

Introduction: Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21. Materials and methods: To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS). Results: By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail. Conclusion: This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.

Prognostic implications of and clinical risk factors for acute lung injury and organizing pneumonia after lung transplantation: Data from a multicenter prospective cohort study.

We determined prognostic implications of acute lung injury (ALI) and organizing pneumonia (OP), including timing relative to transplantation, in a multicenter lung recipient cohort. We sought to understand clinical risks that contribute to development of ALI/OP. We analyzed prospective, histologic diagnoses of ALI and OP in 4786 lung biopsies from 803 adult lung recipients. Univariable Cox regression was used to evaluate the impact of early (≤90 days) or late (>90 days) posttransplant ALI or OP on risk for chronic lung allograft dysfunction (CLAD) or death/retransplantation. These analyses demonstrated late ALI/OP conferred a two- to threefold increase in the hazards of CLAD or death/retransplantation; there was no association between early ALI/OP and these outcomes. To determine risk factors for late ALI/OP, we used univariable Cox models considering donor/recipient characteristics and posttransplant events as candidate risks. Grade 3 primary graft dysfunction, higher degree of donor/recipient human leukocyte antigen mismatch, bacterial or viral respiratory infection, and an early ALI/OP event were significantly associated with increased late ALI/OP risk. These data from a contemporary, multicenter cohort underscore the prognostic implications of ALI/OP on lung recipient outcomes, clarify the importance of the timing of these events, and identify clinical risks to target for ALI/OP prevention.

The safety profile of a protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe for interstitial lung disease.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) has emerged as a promising alternative to surgical lung biopsy for the diagnosis of interstitial lung disease. However, uncertainty remains regarding its overall complications due to a lack of procedural standardization including the size of cryoprobe utilized. METHODS: This is a prospective cohort study of a protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe. 201 consecutive subjects were enrolled at a single academic center. RESULTS: The average biopsy size was 106.2 ± 39.3 mm2. Complications included a total pneumothorax rate of 4.9% with 3.5% undergoing chest tube placement. Severe bleeding defined by the Nashville Working Group occurred in 0.5% of cases. There were no deaths at 30-days. DISCUSSION: A protocolized transbronchial cryobiopsy program utilizing a 2.4 mm cryoprobe in can achieve a high diagnostic yield with a favorable safety profile.

Plasma CXCL9 and CXCL10 at allograft injury predict chronic lung allograft dysfunction.

Histopathologic lung allograft injuries are putative harbingers for chronic lung allograft dysfunction (CLAD). However, the mechanisms responsible are not well understood. CXCL9 and CXCL10 are potent chemoattractants of mononuclear cells and potential propagators of allograft injury. We hypothesized that these chemokines would be quantifiable in plasma, and would associate with subsequent CLAD development. In this prospective multicenter study, we evaluated 721 plasma samples for CXCL9/CXCL10 levels from 184 participants at the time of transbronchial biopsies during their first-year post-transplantation. We determined the association between plasma chemokines, histopathologic injury, and CLAD risk using Cox proportional hazards models. We also evaluated CXCL9/CXCL10 levels in bronchoalveolar lavage (BAL) fluid and compared plasma to BAL with respect to CLAD risk. Plasma CXCL9/CXCL10 levels were elevated during the injury patterns associated with CLAD, acute rejection, and acute lung injury, with a dose-response relationship between chemokine levels and CLAD risk. Importantly, there were strong interactions between injury and plasma CXCL9/CXCL10, where histopathologic injury associated with CLAD only in the presence of elevated plasma chemokines. We observed similar associations and interactions with BAL CXCL9/CXCL10 levels. Elevated plasma CXCL9/CXCL10 during allograft injury may contribute to CLAD pathogenesis and has potential as a minimally invasive immune monitoring biomarker.

Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial.

BACKGROUND: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib. METHODS: Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial. RESULTS: A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients. CONCLUSIONS: The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety .

The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis.

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.

Diagnosis and Treatment of Pulmonary Sarcoidosis: A Review.

Importance: Sarcoidosis is an inflammatory granulomatous disease of unknown cause that affects an estimated 2 to 160 people per 100 000 worldwide and can involve virtually any organ. Approximately 10% to 30% of patients with sarcoidosis develop progressive pulmonary disease. Observation: Among patients with pulmonary sarcoidosis, the rate of spontaneous remission without serious sequelae ranges from 10% to 82%. However, lung disease progression occurs in more than 10% of patients and can result in fibrocystic architectural distortion of the lung, which is associated with a mortality rate of 12% to 18% within 5 years. Overall, the mortality rate for sarcoidosis is approximately 7% within a 5-year follow-up period. Worldwide, more than 60% of deaths from sarcoidosis are due to pulmonary involvement; however, more than 70% of deaths from sarcoidosis are due to cardiac involvement in Japan. Up to 70% of patients with advanced pulmonary sarcoidosis develop precapillary pulmonary hypertension, which is associated with a 5-year mortality rate of approximately 40%. Patients with sarcoidosis and precapillary pulmonary hypertension should be treated with therapies such as phosphodiesterase inhibitors and prostacyclin analogues. Although optimal doses of oral glucocorticoids for pulmonary sarcoidosis are unknown, oral prednisone typically starting at a dose of 20 mg/d to 40 mg/d for 2 to 6 weeks is recommended for patients who are symptomatic (cough, dyspnea, and chest pain) and have parenchymal infiltrates and abnormal pulmonary function test results. Oral glucocorticoids can be tapered over 6 to 18 months if symptoms, pulmonary function test results, and radiographs improve. Prolonged use of oral glucocorticoids may be required to control symptoms and stabilize disease. Patients without adequate improvement while receiving a dose of prednisone of 10 mg/d or greater or those with adverse effects due to glucocorticoids may be prescribed immunosuppressive agents, such as methotrexate, azathioprine, or an anti-tumor necrosis factor medication, either alone or with glucocorticoids combined with appropriate microbial prophylaxis for Pneumocystis jiroveci and herpes zoster. Effective treatments are not available for advanced fibrocystic pulmonary disease. Conclusions and Relevance: Sarcoidosis has a mortality rate of approximately 7% within a 5-year follow-up period. More than 10% of patients with pulmonary sarcoidosis develop progressive disease and more than 60% of deaths are due to advanced pulmonary sarcoidosis. Oral glucocorticoids with or without another immunosuppressive agent are the first-line therapy for symptomatic patients with abnormal pulmonary function test results and lung infiltrates. Patients with sarcoidosis and precapillary pulmonary hypertension should be treated with therapies such as phosphodiesterase inhibitors and prostacyclin analogues.

Serum markers of cardiac complications in a systemic sclerosis cohort.

Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21-0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52-7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08-3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11-2.50, p = 0.014, OR 1.86, 95% CI 1.25-2.77, p = 0.002, OR 0.32, 95% CI 0.15-0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22-2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.

Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.

The allograft injury marker CXCL9 determines prognosis of anti-HLA antibodies after lung transplantation.

Despite the common detection of non-donor specific anti-HLA antibodies (non-DSAs) after lung transplantation, their clinical significance remains unclear. In this retrospective single-center cohort study of 325 lung transplant recipients, we evaluated the association between donor-specific HLA antibodies (DSAs) and non-DSAs with subsequent CLAD development. DSAs were detected in 30% of recipients and were associated with increased CLAD risk, with higher HRs for both de novo and high MFI (>5000) DSAs. Non-DSAs were detected in 56% of recipients, and 85% of DSA positive tests had concurrent non-DSAs. In general, non-DSAs did not increase CLAD risk in multivariable models accounting for DSAs. However, non-DSAs in conjunction with high BAL CXCL9 levels were associated with increased CLAD risk. Multivariable proportional hazards models demonstrate the importance of the HLA antibody-CXCL9 interaction: CLAD risk increases when HLA antibodies (both DSAs and non-DSAs) are detected in conjunction with high CXCL9. Conversely, CLAD risk is not increased when HLA antibodies are detected with low CXCL9. This study supports the potential utility of BAL CXCL9 measurement as a biomarker to risk stratify HLA antibodies for future CLAD. The ability to discriminate between high versus low-risk HLA antibodies may improve management by allowing for guided treatment decisions.