Plasminogen Degradation by Neutrophil Elastase in Pleural Infection, Not High Plasminogen Activator Inhibitor 1, Is the Cause of Intrapleural Lytic Failure.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of 0.05. RESULTS: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03583931; URL: www. CLINICALTRIALS: gov.

Understanding the systemic effects of intrapleural tPA and DNase by evaluating effects on coagulation.

Background: Complicated parapneumonic effusions and empyemas are common presentations that carry significant morbidity and mortality. Standard therapy includes antibiotics and chest tube placement. Due to the nature of the fluid, it is often difficult to drain completely using a chest tube. As outlined in multiple studies, intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) are effective at helping clear these effusions and the avoidance of surgery. Despite research to better understand the effectiveness of the treatment and possible side effects, there continues to be a lack of data on potential systemic effects. Methods: This prospective observational pilot study was conducted from May 2021 until June 2022. Basic demographics, complications, prothrombin time, activated partial thromboplastin time, D-Dimer, fibrinogen, and thromboelastography scans were measured both before and after infusion of chest tube tPA and DNase to assess for differences in coagulation using Signed Rank tests. Results: A total of 17 patients were enrolled in the study. Two patients were excluded due to protocol deviations. The median change score for lysis of clot at 30 minutes (Ly30), our primary outcome of interest, was 0 (P=0.88). There were no significant changes in other coagulation measures when comparing pre and post treatment. One patient (5.9%) had intrapleural bleeding associated with therapy. Three patients (17.6%) underwent surgical intervention to further treat their complicated pleural effusion. Conclusions: This is the first study to evaluate measurable changes in systemic coagulation after intrapleural tPA and DNase. Our data demonstrates no significant difference in coagulation after intrapleural tPA and DNase infusion, suggesting that there may not be clinically significant absorption.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

Extracting forced vital capacity from the electronic health record through natural language processing in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE: To develop a natural language processing (NLP) tool to extract forced vital capacity (FVC) values from electronic health record (EHR) notes in patients with rheumatoid arthritis-interstitial lung disease (RA-ILD). METHODS: We selected RA-ILD patients (n = 7485) in the Veterans Health Administration (VA) between 2000 and 2020 using validated ICD-9/10 codes. We identified numeric values in proximity to FVC string patterns from clinical notes in the EHR. Subsequently, we performed processing steps to account for variability in note structure, related pulmonary function test (PFT) output, and values copied across notes, then assigned dates from linked administrative procedure records. NLP-derived FVC values were compared to values recorded directly from PFT equipment available on a subset of patients. RESULTS: We identified 5911 FVC values (n = 1844 patients) from PFT equipment and 15 383 values (n = 4982 patients) by NLP. Among 2610 date-matched FVC values from NLP and PFT equipment, 95.8% of values were within 5% predicted. The mean (SD) difference was 0.09% (5.9), and values strongly correlated (r = 0.94, p < 0.001), with a precision of 0.87 (95% CI 0.86, 0.88). NLP captured more patients with longitudinal FVC values (n = 3069 vs. n = 1164). Mean (SD) change in FVC %-predicted per year was similar between sources (-1.5 [30.0] NLP vs. -0.9 [16.6] PFT equipment; standardized response mean = 0.05 for both). CONCLUSIONS: NLP of EHR notes increases the capture of accurate, longitudinal FVC values by three-fold over PFT equipment. Use of this NLP tool can facilitate pharmacoepidemiologic research in RA-ILD and other lung diseases by capturing this critical measure of disease severity.

Enhancing the identification of rheumatoid arthritis-associated interstitial lung disease through text mining of chest computerized tomography reports.

OBJECTIVES: Algorithms have been developed to identify rheumatoid arthritis-interstitial lung disease (RA-ILD) in administrative data with positive predictive values (PPVs) between 70 and 80%. We hypothesized that including ILD-related terms identified within chest computed tomography (CT) reports through text mining would improve the PPV of these algorithms in this cross-sectional study. METHODS: We identified a derivation cohort of possible RA-ILD cases (n = 114) using electronic health record data from a large academic medical center and performed medical record review to validate diagnoses (reference standard). ILD-related terms (e.g., ground glass, honeycomb) were identified in chest CT reports by natural language processing. Administrative algorithms including diagnostic and procedural codes as well as specialty were applied to the cohort both with and without the requirement for ILD-related terms from CT reports. We subsequently analyzed similar algorithms in an external validation cohort of 536 participants with RA. RESULTS: The addition of ILD-related terms to RA-ILD administrative algorithms increased the PPV in both the derivation (improvement ranging from 3.6 to 11.7%) and validation cohorts (improvement 6.0 to 21.1%). This increase was greatest for less stringent algorithms. Administrative algorithms including ILD-related terms from CT reports exceeded a PPV of 90% (maximum 94.6% derivation cohort). Increases in PPV were accompanied by a decline in sensitivity (validation cohort -3.9 to -19.5%). CONCLUSIONS: The addition of ILD-related terms identified by text mining from chest CT reports led to improvements in the PPV of RA-ILD algorithms. With high PPVs, use of these algorithms in large data sets could facilitate epidemiologic and comparative effectiveness research in RA-ILD.

Peripheral Blood Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Systematic Review.

BACKGROUND: Biomarkers have been proposed as tools to aid in the identification and prognostication of interstitial lung disease (ILD) in rheumatoid arthritis (RA). We performed a systematic review of studies evaluating peripheral blood biomarkers and their association with RA-ILD and its prognosis. METHODS: Medline, Embase, the Cochrane Library, and Scopus were queried for relevant studies, with the final search update on July 12, 2021. We included studies evaluating peripheral blood biomarkers for the identification and/or prognostication of RA-ILD, extracting the performance of individual biomarkers for identifying RA-ILD, and predicting prognosis. Modified versions of the Quality Assessment of Diagnostic Accuracy Studies 2 and the Quality in Prognosis Studies tools were used for quality assessment. RESULTS: Seventy studies met eligibility criteria. Study and patient characteristics, analytical methods, strength and consistency of associations, and study quality were heterogeneous. A total of 92 biomarkers were positively associated and 12 were negatively associated with RA-ILD among patients with RA in one or more report. Only a small number of biomarkers were evaluated in multiple cohorts using adjusted analyses. Biomarkers most strongly associated with RA-ILD overlapped with those identified for idiopathic pulmonary fibrosis. Few prognostic biomarkers of RA-ILD were identified. CONCLUSION: Several peripheral blood biomarkers are associated with the presence of RA-ILD, but few have been assessed in multivariable models, have been externally validated, have discriminated RA-ILD from other lung disease, or have prognosticated the disease course. High-quality studies investigating and validating peripheral biomarkers in RA-ILD are needed before they can be employed in clinical care.

Pulmonary Tumor Embolism and Pulmonary Tumor Thrombotic Microangiopathy Causing Rapidly Progressive Respiratory Failure: A Case Series.

Pulmonary tumor embolism (PTE) and pulmonary tumor thrombotic microangiopathy (PTTM) are rare etiologies for rapidly progressive dyspnea in the setting of undiagnosed metastatic cancer. They occur most frequently in association with adenocarcinomas, with PTE being most frequently associated with hepatocellular carcinoma and PTTM being most commonly reported with gastric adenocarcinoma. Pulmonary tumor embolism and PTTM appear to be a disease spectrum where PTTM represents an advanced form of PTE. Pulmonary tumor embolism and PTTM are mostly identified postmortem during autopsy as the antemortem diagnosis remains a clinical challenge due to the rapidly progressive nature of these rare diseases. We report 2 cases of rapidly progressive respiratory failure leading to death, due to tumoral pulmonary hypertension resulting from PTE and PTTM, diagnosed postmortem. Both of the patients were middle-aged females, nonsmokers, and had a gastrointestinal source of their primary malignancy.

A Case of Guillain-Barré Syndrome Associated With COVID-19.

A novel member of human RNA coronavirus, which is an enveloped betacoronavirus, has been termed severe acute respiratory syndrome coronavirus-2 (SARS COV-2). The illness caused by SARS COV-2 is referred to as the coronavirus disease 2019 (COVID-19). It is a highly contagious disease that has resulted in a global pandemic. The clinical spectrum of COVID-19 ranges from asymptomatic illness to acute respiratory distress syndrome, septic shock, multi-organ dysfunction, and death. The most common symptoms include fever, fatigue, dry cough, dyspnea, and diarrhea. Neurological manifestations have also been reported. However, the data on the association of Guillain-Barré syndrome (GBS) with COVID-19 are scarce. We report a rare case of a COVID-19-positive 36-year-old immunocompromised male who presented with clinical features of GBS. His clinical examination showed generalized weakness and hyporeflexia. The cerebrospinal fluid (CSF) analysis showed albuminocytological dissociation. Intravenous immunoglobulin (IVIG) was administered based on the high clinical suspicion of GBS. The patient's neurological condition worsened with progression to bulbar weakness and ultimately neuromuscular respiratory failure requiring mechanical ventilation. His nerve conduction studies were consistent with demyelinating polyneuropathy. He received five plasma exchange treatments and was successfully weaned from mechanical ventilation. A brain and cervical spine magnetic resonance imaging was obtained to rule out other causes, which was normal. COVID-19 is believed to cause a dysregulated immune system, which likely plays an important role in the neuropathogenesis of GBS.

Management issues in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE OF REVIEW: Summarize recent evidence on the identification and management of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). RECENT FINDINGS: Clinical and subclinical interstitial lung disease (ILD) are frequent extra-articular manifestations of rheumatoid arthritis (RA). Better means of identifying and treating RA-ILD are needed to improve the prognosis, with a median survival of only 3-7 years after diagnosis. Several serum biomarkers are currently being evaluated for their ability to detect RA-ILD. Thorough evaluation and multidisciplinary discussion remains the gold standard for establishing the diagnosis of RA-ILD. Management is challenging with most RA disease-modifying antirheumatic drugs (DMARDs) linked to pneumonitis. Methotrexate is typically avoided in clinically significant ILD, although alternative therapies including leflunomide and biologic DMARDs also carry risks in RA-ILD. Antifibrotics appear to slow the progression of ILD, and a large phase II trial exclusively in RA-ILD is underway. In addition, smoking cessation, pulmonary rehabilitation, oxygen therapy, managing comorbidities, and lung transplantation evaluation are vital to improving patient outcomes in RA-ILD. SUMMARY: With little high-quality evidence to guide the management of RA-ILD, multidisciplinary teams with expertise in RA-ILD are highly valuable for diagnosing and treating RA-ILD. Clinical and translational research in RA-ILD is needed to fill the many evidence gaps.