Value of pulmonary function testing identifying progressive pulmonary disease in fibrotic sarcoidosis: results of a prospective feasibility study.
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ABSTRACT:
SUBMITTER: Baughman RP
PROVIDER: S-EPMC9437762 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Value of pulmonary function testing identifying progressive pulmonary disease in fibrotic sarcoidosis: results of a prospective feasibility study.
Baughman Robert P RP Gupta Rohit R Judson Marc A MA Lower Elyse E EE Birring Surinder S SS Stewart Jeffrey J Reeves Rebecca R Wells Athol U AU
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 20220629 2
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Project description:Investigate the differences between Sarcoidosis and Controls as well as between progressive and nonprogressive pulmonary sarcoidosis using 2D LC-MS/MS proteomics instrumentation and bronchoalveolar lavage samples. MaxQuant was used for database searches label free quantitation followed by Ingenuity Pathway Analysis to identify pathways of differentially expressed proteins and potential biomarkers.
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Project description:BackgroundPulmonary sarcoidosis is a rare granulomatous disease of unknown aetiology. Heterogeneity in the outcomes measured in trials of treatment for pulmonary sarcoidosis has impacted on the ability to systematically compare findings, contributing to research inefficiency. The FSR-SCOUT study has aimed to address this heterogeneity by developing a core outcome set that represents a patient and health professional consensus on the most important outcomes to measure in future research for the treatment of pulmonary sarcoidosis.Research design and methodssystematic review of trial registries, narrative synthesis of published qualitative literature on the patient experience and results of a patient survey contributed to the development of a comprehensive list of outcomes that were rated in a two round online Delphi survey. The Delphi survey was completed by patients/carers and health professionals and the results discussed and ratified at an online consensus meeting.Results259 patients/carers and 51 health professionals completed both rounds of the Delphi survey. A pre-agreed definition of consensus was applied and the results discussed at an online consensus meeting attended by 17 patients and 7 health professionals). Fifteen outcomes, across five domains (physiological/clinical, treatment, resource use, quality of life, and death), reached the definition of consensus and were included in the core outcome set.ConclusionsThe core outcome set represents a patient and health professional consensus on the most important outcomes for pulmonary sarcoidosis research. The use of the core outcome set in future trials, and efforts to validate its components, will enhance the relevance of trials to stakeholders and will increase the opportunity for the research to contribute to evidence synthesis.
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Project description:Pulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis-associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut-off values where transplant-free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant-free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan-Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut-off values where transplant-free survival was decreased. Decreased transplant-free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant-free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut-offs with decreased transplant-free survival in the SAPH population. Neither cut-off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant-free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.
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Project description:Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern surrounding the granulomas. Th1 to Th2 shift in environment along with angiogenesis is implicated in exuberant fibrosis. Clinical features include dyspnea, cough, and frequently with pulmonary function tests showing a mixed ventilatory defect with severely decreased diffusion capacity of carbon monoxide. Serologic markers including soluble interleukin 2 receptor, chitotriosidase and kern von den lunges 6, and chemokine ligand 18 are elevated and implicated in progression of disease. CT imaging shows fibrosis along bronchovascular bundles with reticulations, traction bronchiectasis and honeycombing predominantly in the upper and central distribution. Complications include sarcoidosis-associated pulmonary hypertension (SAPH) and chronic pulmonary aspergillosis. Treatment involves glucocorticoids and steroid-sparing agents in the presence of active granulomas. Anti-fibrotic agents such as pirfenidone and nintedanib have been shown to slow down pulmonary function decline in randomized clinical trials involving sarcoidosis-associated pulmonary fibrosis. Transplant workup is indicated in New York Heart Association class III or IV with similar success rates as in other lung transplant patients.
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Project description:Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma.Experimental Design: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed.Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations.Conclusions: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. Clin Cancer Res; 24(2); 295-305. ©2017 AACRSee related commentary by Wick and Kessler, p. 256.
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Project description:Although most of the progressive multifocal leukoencephalopathy cases in sarcoidosis patients are explained by the treatment with immunosuppressive drugs, it is also reported in treatment-naive sarcoidosis patients, which implies a general predisposition of sarcoidosis patients for progressive multifocal leukoencephalopathy. Indeed, it was shown that active sarcoidosis patients have increased regulatory T cell frequencies which could lead to a subsequent systemic immunosuppression. However, if sarcoidosis with systemic changes of T cell subsets frequencies constitute a risk factor for the development of progressive multifocal leukoencephalopathy, which could then be counteracted by sarcoidosis treatment, is not known. In this cohort study, we included, characterized and followed-up six patients with bioptically confirmed definite progressive multifocal leukoencephalopathy and definite or probable sarcoidosis presenting between April 2013 and January 2019, four of them had no immunosuppressive therapy at the time of developing first progressive multifocal leukoencephalopathy symptoms. Analysis of immune cell subsets in these patients revealed significant imbalances of CD4+ T cell and regulatory T cell frequencies. Due to the progression of progressive multifocal leukoencephalopathy in four patients, we decided to treat sarcoidosis anticipating normalization of immune cell subset frequencies and thereby improving progressive multifocal leukoencephalopathy. Notably, by treatment with infliximab, an antibody directed against tumour necrosis factor-α, three patients continuously improved clinically, JC virus was no longer detectable in the cerebrospinal fluid and regulatory T cell frequencies decreased. One patient was initially misdiagnosed as neurosarcoidosis and died 9 weeks after treatment initiation due to aspiration pneumonia. Our study provides insight that sarcoidosis can lead to changes in T cell subset frequencies, which predisposes to progressive multifocal leukoencephalopathy. Although immunosuppressive drugs should be avoided in progressive multifocal leukoencephalopathy, paradoxically in patients with sarcoidosis treatment with the immunosuppressive infliximab might restore normal T cell distribution and thereby halt progressive multifocal leukoencephalopathy progression.
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Project description:BackgroundFibrotic sarcoidosis patients often have acute events of increased cough and sputum production. We evaluated the impact of roflumilast in fibrotic sarcoidosis patients with repeated episodes of increased cough and sputum.MethodsSarcoidosis patients with pulmonary fibrosis and at least two acute episodes in the previous year were randomized to receive either roflumilast (ROF) or placebo (PLA) in a double blind, placebo controlled multi-center trial. Subjects were assessed initially and every three months for 12 months. At each visit, spirometry and health related quality of life questionnaires were completed. For each subject, the best forced expiratory volume at 1 second (FEV-1) was noted.ResultsOf the 38 subjects who enrolled in the study, 28 subjects (14 in each group) received at least three months of treatment and 10 in each arm completing all 12 months of study. During the treatment, patients treated with ROF were less likely to have visits in which the FEV-1 was less than 90% of the best FEV-1 (Odds ratio=0.34 (0.16 to 0.76 95% confidence interval, p=0.0073). At the end of treatment with ROF, patients had a significant improvement in their KSQ LUNG (Initial visit: 45.3 ± 6.89 (Mean ± S.D.); Last visit: 52.6± 7.91, p<0.05) with no change for PLA treated patients.ConclusionPatients treated with at least three months of roflumilast had fewer follow-up visits with an FEV-1 of less than 90% of best value. At the end of treatment, ROF treated patients had a better quality of life as assessed by KSQ LUNG.Clinical trial registrationNCT01830959.
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Project description:BackgroundMacrophages are pivotal cells in sarcoidosis. Monocytes-derived (MD) macrophages have recently been demonstrated to play a major role especially in pulmonary sarcoidosis. From inflammatory tissues to granulomas, they may be exposed to low oxygen tension environments. As hypoxia impact on sarcoidosis immune cells has never been addressed, we designed the present study to investigate MD-macrophages from sarcoidosis patients in this context. We hypothesized that hypoxia may induce functional changes on MD-macrophages which could have a potential impact on the course of sarcoidosis.MethodsWe studied MD-macrophages, from high active sarcoidosis (AS) (n=26), low active or inactive sarcoidosis (IS) (n=24) and healthy controls (n=34) exposed 24 hours to normoxia (21% O2) or hypoxia (1.5% O2). Different macrophage functions were explored: hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-kappa B (NF-κB) activation, cytokines secretion, phagocytosis, CD80/CD86/HLA-DR expression, profibrotic response.ResultsWe observed that hypoxia, with a significantly more pronounced effect in AS compared with controls and IS, increased the HIF-1α trans-activity, promoted a proinflammatory response (TNFα, IL1ß) without activating NF-κB pathway and a profibrotic response (TGFß1, PDGF-BB) with PAI-1 secretion associated with human lung fibroblast migration inhibition. These results were confirmed by immunodetection of HIF-1α and PAI-1 in granulomas observed in pulmonary biopsies from patients with sarcoidosis. Hypoxia also decreased the expression of CD80/CD86 and HLA-DR on MD-macrophages in the three groups while it did not impair phagocytosis and the expression of CD36 expression on cells in AS and IS at variance with controls.ConclusionsHypoxia had a significant impact on MD-macrophages from sarcoidosis patients, with the strongest effect seen in patients with high active disease. Therefore, hypoxia could play a significant role in sarcoidosis pathogenesis by increasing the macrophage proinflammatory response, maintaining phagocytosis and reducing antigen presentation, leading to a deficient T cell response. In addition, hypoxia could favor fibrosis by promoting profibrotic cytokines response and by sequestering fibroblasts in the vicinity of granulomas.
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