Background/Objective: SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study, we present the results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS and to determine if any patient subgroups appeared to present a diagnostic challenge for the test. Methods: (1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. (2) Principal component analysis and k-means clustering analysis to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables. Results: No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response. Conclusions: We conclude that for this patient cohort, SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis.

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0–15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1–5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4–15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86–0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission.

Differentiating sepsis from the systemic inflammatory response syndrome (SIRS) in critical care patients is challenging, especially before serious organ damage is evident, and with variable clinical presentations of patients and variable training and experience of attending physicians. Our objective was to describe and quantify physician agreement in diagnosing SIRS or sepsis in critical care patients as a function of available clinical information, infection site, and hospital setting.

Objective: To determine long-term survival of visceral pleural invasion (VPI) and parenchymal invasion (PAI) (angiolymphatic and/or vascular) on survival of NSCLCs less than 30 mm in maximum diameter. Methods: Kaplan-Meier survivals for NSCLCs, with and without VPI and/or PAI, were determined for a prospective cohort of screening participants stratified by pathologic tumor size (<= 10 mm, 11-20 mm, and 21-30 mm) and nodule consistency. Log-rank test statistics were calculated. Results: The frequency of PAI versus VPI was significantly lower in patients with subsolid nodules than in those with solid nodules (4.9% versus 27.7% [p < 0.0001]), and correspondingly, Kaplan-Meier lung cancer survival was significantly higher among patients with subsolid nodules (99.1% versus 91.3% [p = 0.0009]). Multivariable Cox regression found that only tumor diameter (adjusted hazard ratio [HR] = 1.07, 95% confidence interval [CI]: 1.01-1.14, p = 0.02) and PAI (adjusted HR = 3.15, 95% CI: 1.25-7.90, p = 0.01) remained significant, whereas VPI was not significant (p = 0.15). When clinical and computed tomography findings were included with the pathologic findings, Cox regression showed that the risk of dying of lung cancer increased 10-fold (HR = 10.06, 95% CI: 1.35-75.30) for NSCLCs in patients with solid nodules and more than twofold (by a factor of 2.27) in patients with moderate to severe emphysema (HR = 2.27, 95% CI: 1.01-5.11), as well as with increasing tumor diameter (HR = 1.06, 95% CI: 1.01-1.13), whereas PAI was no longer significant (p = 0.19). Conclusions: Nodule consistency on computed tomography was a more significant prognostic indicator than either PAI or VPI. We propose that patients with NSCLC with VPI and a maximum tumor diameter of 30 mm or less not be upstaged to T2 without further large, multicenter studies of NSCLCs, stratified by the new T status and that classification be considered separately for patients with subsolid or solid nodules. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Bell, Brandon; Vondracek, Hugh; Gurka, David; Yoder, Mark; Panos, Nicholas; Nowell, Horace; Kleinpell, Ruth Author Information

With the recent shortage of venom extract, we had 25 patients who required stopping of venom immunotherapy (VIT). The March 2017 task force recommendation focused on prolonging existing supplies, but gave limited insight into retesting or restarting VIT, after prolonged periods without a maintenance injection. Our clinic’s venom extract supply was exhausted by December 2016. Using our list of patients previously on VIT we attempted to contact them for follow up and consideration for restarting VIT, retesting, or judicious stopping of VIT based on the 2016 practice parameter changes. This was done as a quality improvement project, and we also established a practice policy/guideline for restarting VIT in these patients. Our patients had an average of 168 days off of VIT. We successfully achieved maintenance in 5 of our patients by restarting a weekly buildup using 0.05 of the red vial as the initial dose. We experienced no systemic reactions. We also noted a significant percentage of patients who, although restarting VIT was warranted based on current practice parameter recommendations, were unwilling to reinitiate VIT. With the venom extract shortage apparently ending we present a cohort of patients who were successfully restarted on VIT. A large percentage of our cohort also appears to have lost interest in VIT, even though it is now available.

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands (www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. Measurements and Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82‐0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0‐10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502)

SESSION TITLE: Diffuse Lung Disease 1 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: The usual interstitial pneumonia (UIP) pattern of radiographic and histologic findings is commonly associated with idiopathic pulmonary fibrosis (IPF), although it can be associated with secondary interstitial lung diseases (ILD). Based on the radiographic findings, ILD can be classified as “UIP, “possible UIP”, or “inconsistent with UIP.” The purpose of this study is to analyze and compare treatment patterns and responsiveness between UIP and possible UIP radiographic patterns. METHODS: 220 patients seen and evaluated at Rush University Medical Center and/or Rush Oak Park Hospital for newly diagnosed interstitial lung disease were identified. Patients with previous workup, incomplete workup, or with an “inconsistent with UIP” pattern on radiography were excluded (180 patients). Patients were then split into the categories “UIP” or “possible UIP” based on the radiologist’s read of high-resolution CT. The rates of use of immunosuppressants and other medications (including anti-fibrotic agents, such as pirfenidone and nintedanib) were compared between the two groups. Response to treatment was also analyzed based on PFT data, using a cutoff of a 10% change in VC, TLC, or DLCO. Fisher’s exact tests compared frequencies between groups. RESULTS: 40 patients met inclusion criteria. There were 11 total pulmonologists who evaluated these patients. 13 patients had the UIP pattern and 27 patients had possible UIP, based on the radiologist’s read of a high-resolution CT scan. 8 UIP patients were treated with immunosuppressants, compared to 11 possible UIP patients (p = 0.3140); 2 UIP patients were treated with other medications, compared to 7 possible UIP patients (p = 0.6904). In UIP patients, 2 had improved VC, 5 had stable VC, and 3 had a worsened VC, compared to 1 improved, 12 stable, and 9 worsened VCs in possible UIP patients (p = 0.406). 1 UIP patient demonstrated improvement in TLC, 5 showed stable TLC, and 2 had a worsened TLC, compared to 2 improved, 13 stable, and 7 worsened TLCs in possible UIP patients (p = 0.999). Finally, for UIP, 1 patient had improved DLCO, 3 had stable DLCOs, and 4 had worsened DLCO, compared to 4 improved, 7 stable, and 11 worsened DLCOs in possible UIP (p = 0 .999). There were no statistically significant changes in PFTs when comparing UIP patients treated with immunosuppressants or other medications to those not treated; similarly, there were no statistically significant changes in PFT data comparing treated possible UIP pattern patients to those not treated. 3 out of the 13 typical UIP patients had a biopsy, compared to 8 of the 27 possible UIP patients (p = 1.000). CONCLUSIONS: Patients with both UIP and possible UIP patterns on radiographic imaging are more commonly treated with immunosuppressants. Despite this, there is no statistically significant improvement or prevention of decline in treated or untreated patients. CLINICAL IMPLICATIONS: Possible UIP and typical UIP patients tend to have similarly poor response to treatment with antifibrotic agent and immunosuppresants. When treating ILD with a UIP pattern, providers should carefully weigh subjective benefits against the risks of immunosuppressant or antifibrotic therapies. DISCLOSURE: The following authors have nothing to disclose: Krishnan Warrior, Mark Yoder No Product/Research Disclosure Information

We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.

Purpose Asthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids. Methods Eight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry. Results LPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X). Conclusions The increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.

Purpose In human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced. Methods Primary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 h, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloproteinase-1 (MMP-1). Results VEGF stimulation of NHBE for 1 or 6 h, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2-selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE. Conclusions Our findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury.

OBJECTIVE. Appropriate radiologic interpretation of screening CT can minimize unnecessary workup and intervention. This is particularly challenging in the baseline round. We report on the quality assurance process we developed for the International Early Lung Cancer Action Program.MATERIALS AND METHODS. After initial training at the coordinating center, radiologists at 10 participating institutions and at the center independently interpreted the first 100 baseline screenings. The radiologist at the institutions had access to the center interpretations before issuing the final reports. After the first 100 screenings, the interpretations were jointly discussed. This report summarizes the results of the initial 100 dual interpretations at the 10 institutions.RESULTS. The final institution interpretations agreed with the center in 895 of the 1000 interpretations. Compared with the center, the frequency of positive results was higher at eight of the 10 institutions. The most frequent reason of discrepant interpretations was not following the protocol (n = 55) and the least frequent was not identifying a nodule (n = 3).CONCLUSION. The quality assurance process helped focus educational programs and provided an excellent vehicle for review of the protocol with participating physicians. It also suggests that the rate of positive results can be reduced by such measures.

SESSION TYPE: Lung Cancer Posters I

SESSION TYPE: Lung Cancer Posters I

The present study reports on a 72-year-old female initially treated as a presumed chronic obstructive pulmonary disease (COPD) exacerbation, but she was ultimately discovered to have Aspergillus tracheobronchitis. Bronchoscopic findings were characteristic, revealing diffuse plaque-like inflammatory lesions extending from midtrachea into the mainstem bronchi. Evidence suggests that the rise in cases is attributable to the growing number of individuals who are immunocompromised secondary to underlying disease, combined with the expanding number of patients receiving glucocorticoids and immunomodulating medications to treat chronic, nonmalignant disorders. The present observations emphasize the importance of including Aspergillus tracheobronchitis in the differential diagnosis for patients receiving medications with immunosuppressive potential that present with dyspnea, cough, or fever and who fail to improve with empiric antimicrobial therapy.

The optimum septic shock vasopressor support strategy is currently debated. This study was performed to evaluate the efficacy and safety of norepinephrine (NE) and dopamine (DA) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol. A prospective, randomized, open-label, clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock. If the maximum dose of the initial vasopressor was unable to maintain the hemodynamic goal, then fixed-dose vasopressin was added to each regimen. If additional vasopressor support was needed to achieve the hemodynamic goal, then phenylephrine was added. The primary efficacy end point was all-cause 28-day mortality. Secondary end points included organ dysfunction, hospital and intensive care unit length of stay, and safety (primarily occurrence of arrhythmias). The 28-day mortality rate was 50% (67/134) with DA as the initial vasopressor compared with 43% (51/118) for NE treatment (P = 0.282). There was a significantly greater incidence of sinus tachycardia with DA (24.6%; 33/134) than NE (5.9%; 7/118) and arrhythmias noted with DA treatment (19.4%; 26/134) compared with NE treatment (3.4%; 4/118; P < 0.0001), respectively. Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score (P < 0.0001) and arrhythmia (P < 0.015) as significant predictors of outcome. In this protocol-directed vasopressor support strategy for septic shock, DA and NE were equally effective as initial agents as judged by 28-day mortality rates. However, there were significantly more cardiac arrhythmias with DA treatment. Patients receiving DA should be monitored for the development of cardiac arrhythmias (NCT00604019).