Baseline C-reactive Protein Research Articles

Early changes in laboratory parameters are predictors of mortality and ICU admission in patients with COVID-19: a systematic review and meta-analysis

Despite the growing knowledge of the clinicopathological features of COVID-19, the correlation between early changes in the laboratory parameters and the clinical outcomes of patients is not entirely understood. In this study, we aimed to assess the prognostic value of early laboratory parameters in COVID-19. We conducted a systematic review and meta-analysis based on the available literature in five databases. The last search was on July 26, 2020, with key terms related to COVID-19. Eligible studies contained original data of at least ten infected patients and reported on baseline laboratory parameters of patients. We calculated weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) with 95% confidence intervals. 93 and 78 studies were included in quantitative and qualitative syntheses, respectively. Higher baseline total white blood cell count (WBC), C-reactive protein (CRP), lactate-dehydrogenase (LDH), creatine kinase (CK), D-dimer and lower absolute lymphocyte count (ALC) (WMDALC = − 0.35 × 109/L [CI − 0.43, − 0.27], p < 0.001, I2 = 94.2%; < 0.8 × 109/L, ORALC = 3.74 [CI 1.77, 7.92], p = 0.001, I2 = 65.5%) were all associated with higher mortality rate. On admission WBC, ALC, D-dimer, CRP, LDH, and CK changes could serve as alarming prognostic factors. The correct interpretation of laboratory abnormalities can guide therapeutic decisions, especially in early identification of potentially critical cases. This meta-analysis should help to allocate resources and save lives by enabling timely intervention.

Abstract 16122: Comparative Risk of Incident Coronary Heart Disease Across Multiple Chronic Inflammatory Diseases

Introduction: Inflammation plays an important role in the pathogenesis of coronary heart disease (CHD). Chronic inflammatory diseases (CIDs) may serve as models to provide insights into the relationships between immune dysfunction, inflammation, and CHD. To investigate this further, we analyzed the risk of incident CHD across different CIDs. Methods: We created a cohort of individuals with CIDs and non-CID controls (frequency-matched on demographics and CHD risk factors), free of baseline CHD, receiving regular outpatient care in a large medical system from 2000 to 2019. CIDs included psoriasis, rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV), and inflammatory bowel disease (IBD). CHD was defined as myocardial infarction (MI), angina, or coronary revascularization. We used adjusted hazards models to determine incident CHD risk for each CID relative to controls. We also analyzed incident CHD risk by severity of inflammation (baseline C-reactive protein) or immune dysfunction (baseline CD4 T cell level in HIV). Results: Of 18,129 individuals with CIDs and 18,988 controls, there were 1,011 incident CHD events over a median of 3.5 years. After adjusting for demographics and CHD risk factors, CHD risk was significantly elevated in SLE [hazard ratio (HR) 2.85, 95% confidence interval (CI) 2.19-3.71, p&lt;0.01], SSc (HR 2.14, 95% CI 1.54-2.99, p&lt;0.01), HIV (HR 1.38, 95% CI 1.12-1.69, p&lt;0.01), and RA (HR 1.22, 95% CI 1.00-1.49, p=0.05). Findings were similar with MI as the lone outcome. When CIDs were categorized by inflammation or immune dysfunction, there was a pattern of higher CHD risk with higher levels of inflammation/immune dysfunction across CIDs (Figure). Conclusions: Our results show that SLE, SSc, HIV, and RA were associated with significantly elevated risks of incident CHD and MI. Higher levels of inflammation or immune dysfunction were associated with heightened CHD risk within CIDs.

Abstract 12909: Usefulness of Sarcopenia Index for Predicting Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement

Introduction: Sarcopenia, a marker of biological senescence, is a robust prognostic indicator of outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS). However, there are no serum markers routinely available for estimating skeletal muscle mass (SMM). The present study aimed to describe a new sarcopenia index (SI, serum creatinine value/cystatin C value x 100) and investigate its association with outcomes after TAVR. Methods: The study cohort comprised 100 patients ≥ 65 years of age (mean 83.9±5.7; 36% men) who underwent transfemoral TAVR at Hospital Italiano de Buenos Aires, Argentina from 2016 to 2018. The mean Society of Thoracic Surgeons (STS) score was 3.3±1.7. Sarcopenia was defined according to ROC curve for SI (AUC 0.731, CI 95% 0.599-0.863, p-value=0.001) for predicting the primary endpoint. Both all-cause mortality and/or readmissions for congestive heart failure (CHF) were defined as the primary endpoint within the first year after TAVR. Results: According to SI cutoff, half of the study population (SI ≤66) was sarcopenic before TAVR. The 30-day mortality increased significantly in the lowest SI tertile (sarcopenia+) group (12, 3, and 0%, p=.05, respectively). SI strongly correlated with timed-up and go and gait speed but not with body mass index and baseline C-reactive protein levels. Overall survival was worse (Log-rank test= p=0.02) and CHF readmissions were more prevalent in the lowest SI tertile (Log-rank test=p=0.01). On Cox regression analysis, a low SI (SI ≤66) had a significantly higher risk of the primary endpoint (adjusted hazard ratio: 4.01, 95% CI: 1.31-12.27, p=.015). Conclusions: SI, a novel-non-invasive method for assessing SMM was able to predict mid-term mortality and CHF readmissions. We suggest careful consideration of sarcopenia prior to TAVR in order to decide the best treatment approaches.

Oral Health, Oral Microbiota, and Incidence of Stroke-Associated Pneumonia-A Prospective Observational Study.

Stroke-associated pneumonia is a major cause for poor outcomes in the post-acute phase after stroke. Several studies have suggested potential links between neglected oral health and pneumonia. Therefore, the aim of this prospective observational study was to investigate oral health and microbiota and incidence of pneumonia in patients consecutively admitted to a stroke unit with stroke-like symptoms. This study involved three investigation timepoints. The baseline investigation (within 24 h of admission) involved collection of demographic, neurological, and immunological data; dental examinations; and microbiological sampling (saliva and subgingival plaque). Further investigation timepoints at 48 or 120 h after baseline included collection of immunological data and microbiological sampling. Microbiological samples were analyzed by culture technique and by 16S rRNA amplicon sequencing. From the 99 patients included in this study, 57 were diagnosed with stroke and 42 were so-called stroke mimics. From 57 stroke patients, 8 (14%) developed pneumonia. Stroke-associated pneumonia was significantly associated with higher age, dysphagia, greater stroke severity, embolectomy, nasogastric tubes, and higher baseline C-reactive protein (CRP). There were trends toward higher incidence of pneumonia in patients with more missing teeth and worse oral hygiene. Microbiological analyses showed no relevant differences regarding microbial composition between the groups. However, there was a significant ecological shift over time in the pneumonia patients, probably due to antibiotic treatment. This prospective observational study investigating associations between neglected oral health and incidence of SAP encourages investigations in larger patient cohorts and implementation of oral hygiene programs in stroke units that may help reducing the incidence of stroke-associated pneumonia.

Macrophage Activation Syndrome-like Manifestations (MAS-L) Following BCMA-Directed CAR T-Cells in Multiple Myeloma

Introduction Chimeric antigen receptor (CAR) T-cells can induce a rapid disease response but are frequently associated with immunologic toxicities. In addition to cytokine release syndrome (CRS), macrophage activation syndrome-like manifestations (MAS-L), characterized by uncontrolled immune activation, have been described (Shah et al, 2020). Traditional MAS definitions are challenging to apply in patients receiving CAR T cells, due to overlapping signs and symptoms with lymphodepletion and CRS. Therefore, we sought to develop novel criteria to characterize MAS-L following CAR T cells and used these criteria to identify risk factors for developing MAS-L. Methods We conducted a retrospective review of 55 patients who received B cell maturation antigen-directed CAR T cells for multiple myeloma from 11/1/17 - 5/1/20. Based on the labs readily available in our patient population, we defined MAS-L using the following criteria: 1) rate of ferritin rise ³ 100 mg/L/hour within a 24 hour period and2) minimum fibrinogen &amp;lt; 150 mg/dL or maximum LDH &amp;gt; 2 times the upper limit of normal. In developing these simplified criteria, we considered multiple laboratory markers of inflammation (ferritin, LDH, soluble interleukin receptor-2, natural killer cell activity) and end organ damage. Infection was defined as any culture positivity, febrile neutropenia, or clinical suspicion such that a new antimicrobial was started in the 30 days prior to CAR T cells. Wilcoxon rank-sums and Fisher's exact test were used to compare continuous and categorical variables, respectively. Overall (OS) and progression-free survival (PFS) were compared using log-rank tests. Results Of the 55 patients, 12 (21.8%) met the above criteria for MAS-L with similar disease trajectories. Following CAR T cells, all 12 patients first developed CRS, characterized by an elevated C-reactive protein (CRP) and administration of tocilizumab, and subsequently developed MAS-L, characterized by decrease in fibrinogen and rapid rise of ferritin and LDH (Figure 1). Compared to the 45 patients who did not develop MAS-L, patients with MAS-L had similar baseline patient and disease characteristics (Table 1); however, a significantly higher proportion of patients with MAS-L had an infection prior to receiving CAR T cells (75% vs 9.3%, p &amp;lt; 0.001.) Patients with MAS-L also had higher peak ferritin (median 20,707 vs 573 ug/L, p &amp;lt; 0.001), D-dimer (14,000 vs 3,010 ng/mL, p &amp;lt; 0.001), aspartate aminotransferase (AST; 153 vs 48 U/L:, p &amp;lt; 0.001) and a trend towards higher alanine aminotransferase (ALT; 76 vs 50 U/L, p = 0.08). In contrast, patients with MAS-L had a lower peak C-reactive protein (CRP; 29.8 vs 60 mg/L, p = 0.03). Compared to patients who did not develop MAS-L, a similar proportion of MAS-L patients developed any CRS (100% vs 84%, p = 0.33) and ³ grade 2 CRS (50% vs 50%, p = 1). Neurotoxicity was more common in patients with MAS-L (42% vs 14%, p = 0.05). A greater proportion of patients with MAS-L received tocilizumab (100% vs 70%, p = 0.05), systemic steroids (92% vs 27%, p &amp;lt; 0.001), and anakinra (83% vs 2.3%, p &amp;lt; 0.001). Anakinra was given per clinician discretion and not per study protocol. Following CAR T cell therapy, patients with MAS-L had longer hospitalizations (21 vs 19 days, p = 0.009) and a greater proportion required ICU-level care (27% vs 2%, p = 0.02). OS and PFS between the two groups were similar (p = 0.15 and 0.63, respectively), with a 1-year OS of 65.2% vs 90.6% and PFS of 35.4% vs 54.7% for patients with vs without MAS-L, respectively. In univariate logistic regression of baseline patient factors, disease characteristics, and ferritin, CRP, and D-dimer prior to receiving CAR T cells, only a history of documented infection in the 30 days prior to CAR T cells predicted MAS-L development (Hazard Ratio 29.2, 95% CI 5.54 - 154, p &amp;lt; 0.001). Conclusions In this analysis, we developed novel criteria for defining MAS-L following CAR T cell therapy and used these criteria to define the unique laboratory profile and clinical trajectory of patients with MAS-L. We also identify pre-existing infection as a strong risk factor for MAS-L development. Although patients with MAS-L frequently require prolonged monitoring, this immunologic toxicity can be mitigated with steroids, anakinra, and supportive care, and patients ultimately have similar survival compared to patients without MAS-L. Larger studies are needed to prospectively validate these novel criteria. Disclosures Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin:Sanofi, Amgen, Seattle Genetics, JNJ - Janssen: Research Funding; Legend Biotech: Consultancy. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Wong:Bristol Myers Squibb: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding; GSK: Research Funding.

Assessing Early Mortality in Intensively-Treated Acute Myeloid Leukemia in a Developing Country: Genetic, Laboratory Findings, and Comorbidities Add Prognostic Information

Background: Early death (ED) during first-line therapy for acute myeloid leukemia (AML) is acknowledged as a pending issue worldwide. Few pivotal studies from developed countries have identified baseline characteristics related to poor outcome. Retrospective reports from Brazil and Mexico indicate alarming ED rates from real-world data, raising the question of which factors contribute towards this finding in low-income centers. In this study, we aimed to identify risk factors for ED in AML to increase the prediction power of previously known tools such as Charlson's Comorbidity Index (CCI) as well as to examine the role of anti-infective prophylaxis in our cohort. Methods: This is a retrospective cohort study involving adult patients (pts) newly diagnosed with AML treated at Instituto do Cancer do Estado de Sao Paulo, Brazil between June 2011 and June 2020. Only pts receiving the classic "7+3" regimen were included. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). The primary endpoint was ED rate, calculated by the Kaplan-Meier method. A Cox regression model selected by a stepwise method was used to find risk factors. Post-chemotherapy events (secondary endpoints) constituted any documented infection, bleeding, thrombosis, and acute kidney injury (AKI) during the first 30 days. Results: Overall, 206 out of 337 pts (61%) entered in the analysis. The median age was 54 years (range,17-74) and 50.5% were male. The median time between symptoms' onset and hospital admission was 7 weeks (0-48). Thirteen pts (6.3%) presented with leukostasis, of which 9 proceeded leukapheresis. At the presentation, clinical tumor lysis syndrome was seen in 12% of patients (associated with extramedullary disease [p&amp;lt;0.001], among other factors). Other baselines clinical and laboratory findings are summarized in table 1. Pre-chemotherapy infection was found in 67% of patients (positive blood culture: 26.3%). 45-day mortality was 23.8% (95% CI 17.8-29.4) (Figure 1), being 39.8% in pts above 60y. Dose reductions for liver or kidney dysfunction were not, per si, associated with higher ED. Multivariable Cox regression models examined the utility of baseline markers in predicting ED in our cohort and the best-fitted model by Akaike information criteria (AIC) is outlined in a forestplot (Figure 2). Briefly, in a model controlled for age, adding phenotype, genetic risk, platelets and C-reactive protein (CRP) to CCI resulted in improved prediction in our cohort (AIC 479 vs 542). CRP, AGR, and CCI were independently associated with short-term survival in AML (figure 3, 4, and 5). Noticeably, 13/20 diabetic patients died during the first 45 days (unadjusted HR 4.29 [95% CI 2.33-7.92]). Only antibacterial prophylaxis with quinolone was associated with decreased ED (unadjusted HR 0.38 [95% CI 0.15-0.95]), while the use of fluconazole or anidulafungin did not affect survival. Colonization during hospitalization occurred in 71% (mainly vancomycin-resistant Enterococcus [77%] and carbapenemase-producing Enterobacteriaceae [44%]). Any sort of colonization was associated with ED (OR 4.41 [95% CI 1.89-12.08]). Thromboembolic events were registered in 11.9% (95% CI 7.9-17.4, mostly catheter-related) and were marginally associated with central nervous system disease (OR 4.31 [95% CI 0.84-18.25) and diabetes mellitus (DM) (OR 3.24 [95% CI 0.94-9.82) 20.8 vs 7.9%, p=0.097). Bleeding was observed in 17.6% and was associated with monocytic AML subtypes, tumor lysis, and DM. Complete response was attained in 50.5% (95% CI 43.4- 57.5). Presumed or confirmed invasive fungal infection was diagnosed during induction in 26.6%, but empirical amphotericin was prescribed in 60.2%. 66.5% of subjects developed any grade of AKI, with the need for hemodialysis in 10.3%. Conclusion: This is the first Brazilian study to evaluate risk factors for ED in newly diagnosed AML in the public setting, as well as to address which events explain such higher mortality in comparison to American and European reports. In line with the literature, age itself was not associated with mortality when adjusted for other variables such as CCI and genetic stratification. Interestingly, we found that the baseline CRP levels are significantly correlated with ED, highlighting the role of infection and inflammation at the AML diagnosis. Disclosures No relevant conflicts of interest to declare.

Early Inflammatory Markers are Associated With Inadequate Post-Induction Infliximab Trough in Pediatric Crohn's Disease.

In pediatric Crohn's disease, infliximab trough concentrations after standard weight-based induction therapy are commonly below 7 μg/mL. Clinical treatment outcomes are associated with post-induction infliximab trough concentration. Markers of inflammation are associated with low infliximab concentrations during maintenance dosing. We sought to determine if early markers of disease activity are associated with inadequate post-induction infliximab trough concentrations in pediatric Crohn's disease. We performed a retrospective single-center case-control study of pediatric Crohn's disease patients to assess the association between baseline and week-2 biomarkers (albumin, C-reactive protein, and erythrocyte sedimentation rate) and inadequate post-induction infliximab trough concentration (<7 μg/mL) in patients treated with standard 5 mg/kg dosing. Baseline and week-2 biomarker values were coded as dichotomous variables at clinically useful thresholds. Univariable logistic regression was used to calculate odds ratios of developing an inadequate infliximab trough concentration for each threshold, as well as thresholds in combination. Fifty-five patients were evaluated. Early biomarker thresholds significantly associated with inadequate post-induction infliximab trough concentrations included baseline C-reactive protein >1 mg/dL (odds ratio [OR] 4.58; 95% confidence interval [CI] 1.24--17.01), both baseline C-reactive protein >0.5 mg/dL and albumin <3.5 g/dL (OR 8.31; 95% CI 1.99--34.63), and week-2 C-reactive protein >0.5 mg/dL or albumin <3.5 mg/dL or erythrocyte sedimentation rate >25 mm/hour (OR 11.08; 95% CI 2.14--57.22). Routine baseline and week-2 markers of disease activity at clinically useful thresholds were associated with inadequate post-induction infliximab trough concentration in pediatric Crohn's disease patients receiving standard weight-based induction dosing.

Prognostic impact of elevated baseline CRP levels in primary PCI-treated patients with residual cholesterol risk

Abstract Background Recent large randomized studies have indicated the potential of anti-inflammatory therapies to reduce adverse cardiovascular events in patients with myocardial infarction, with the most pronounced benefit in patients with baseline elevated C-reactive protein (CRP). Purpose Our aim was to assess the association of CRP levels with 30-day and 1-year mortality in patients with acute myocardial infarction treated with primary PCI and with residual cholesterol risk. Methods The study included 1531 patients admitted for primary PCI, with the residual cholesterol risk, i.e. low-density lipoprotein cholesterol (LDL-C) levels of &amp;gt;1.80 mmol/l (70 mg/dl), from a prospectively kept electronic registry of a high-volume tertiary center, for whom in-hospital CRP measurements were available. Elevated CRP was defined as ≥5 mg/l (local laboratory cut off value), measured during index hospitalization. Cox regression models were constructed to assess the impact of elevated CRP on 30-day and 1-year mortality. Results 72% of the included patients with LDL-C &amp;gt;1.80 mmol/l had elevated in-hospital CRP (n=1107). Compared with patients with CRP levels within reference limit, elevated CRP was associated with older age (62 vs. 60, p&amp;lt;0.001), higher rates of diabetes (25.8% vs. 18.5%, p=0.002), renal failure (6.4% vs. 2.1%, p&amp;lt;0.001) and Killip class &amp;gt;1 at presentation (22.5% vs. 12.3%, p&amp;lt;0.001), as well as lower EF (44% vs. 48%, p&amp;lt;0.001) and lower haemoglobin on admission (13.9 g/dl vs. 14.2 g/dl, p&amp;lt;0.001). Crude mortality rates were increased in patients with CRP ≥5mg/l at both 30 days (6.0% vs. 2.4%, p=0.003) and 1 year (13.2% vs. 6.3%, p&amp;lt;0.001) (Figure). After adjusting for the observed baseline differences, CRP ≥5mg/l remained an independent predictor of mortality at 1 year (HR 1.691, 95% CI: 1.050–2.724, p=0.03), but not at 30 days (HR 1.690, 95% CI: 0.859–3.324, p=0.13). Conclusion In primary PCI-treated patients with residual cholesterol risk, elevated in-hospital CRP was independently associated with 1-year mortality. Our findings may thus suggest a potential window of opportunity, for anti-inflammatory therapies to improve outcomes beyond the acute phase. Figure 1 Funding Acknowledgement Type of funding source: None

A second C-reactive protein (CRP) test to detect inflammatory burst in patients with acute bacterial infections presenting with a first relatively low CRP.

A first C-reactive protein (CRP) test, as often performed by clinicians during the presentation of patients with an acute bacterial infection, might be misleading. The aim of our study was to explore the dynamic between a second CRP test taken within 12 hours from admission CRP test in a cohort of patients diagnosed with acute bacterial infection in comparison to CRP in a control group of apparently healthy individuals.This was a historical cohort study comprised of all patients admitted to the Sourasky Tel-Aviv Medical Center, Israel, between July 2007 and March 2016. The study cohort included adult patients who were diagnosed as having an infection, assumed to be of bacterial etiology (cellulitis and erysipelas, pneumonia, cholecystitis, pyelonephritis, or septicemia), who had a CRP test during the first 6 hours of hospital admission (baseline CRP), and a successive CRP test up to 12 hours from the first one (recurrent CRP). The control group was of healthy subjects who attended our medical center for a routine annual check-up.The study included 950 patients. Baseline CRP ranged from 0.04 to 454 mg/L. The median CRP velocity was 0.53 mg/L/h. Patients were grouped by baseline CRP into 4 groups (CRP < 10, 10–74.9, 75–199.9, ≥200). There was an increase in median CRP velocity between the first (0.48 mg/L/h) and the second (0.93 mg/L/h) groups, which then was decreased in the next 2 groups (0.46 and −2.58 mg/L/h, respectively). In 45 of 103 (44%) patients of the group of baseline CRP concentration less than 10 mg/dL with bacterial diagnosis, there was a complete overlap with CRP values of apparently healthy individuals during their routine annual checkup.A first single low CRP result cannot exclude the presence of a significant bacterial infection. Patients with acute bacterial infection might present with a relatively low CRP value that at times correspond to normal limit CRP concentrations. A second test, obtained within 12 hours of admission, might serve as an important tool to identify patient with an evolving inflammatory burst commonly seen during acute bacterial infection.

Association between clinical characteristics and pain relief in patients with axial spondyloarthritis treated with non-steroidal anti-inflammatory drugs.

Objectives The aim of this study was to evaluate pain relief in axial spondyloarthritis (axSpA) patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) and to investigate the relation of the demographic, clinical, and psychological characteristics with pain relief.Patients and methods Between February 2017 and December 2019, a total of 94 patients (61 males, 33 females; mean age: 28.3±8.1 years; range, 14 to 54 years) who were diagnosed with axSpA and treated with NSAIDs were included. The patients were assessed at baseline and at three months. A reduction of 30% in the Numeric Rating Scale (NRS) indicates a clinically meaningful improvement. The patients were divided into the relief group (≥30% improvement in NRS) and non-relief group (<30% improvement). Potential influential factors for pain relief such as neuropathic pain (NP), disease activity, function, pain catastrophizing, and pain self-efficacy were assessed. The relationship between patients’ characteristics and pain relief was analyzed.Results Seventy-two (76.6%) patients achieved pain relief. These patients had significantly higher baseline erythrocyte sedimentation rate, C-reactive protein, and lower percentage of NP. There was no significant difference between the two groups in function, pain catastrophizing, and pain self-efficacy. Multiple logistic regression analysis revealed that patients with NP were less likely to achieve pain relief (odds ratio [OR]: 3.531, 95% confidence interval [CI]: 1.155-10.789; p=0.027).Conclusion Pain relief is still insufficient in some axSpA patients, despite the administration of NSAIDs. The presence of NP is significantly associated with poor pain relief. Alternative medications instead of NSAIDs are needed to achieve optimal pain relief, when NP is diagnosed.

Neutrophil to lymphocyte ratio predicts glucocorticoid resistance in polymyalgia rheumatica.

Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) correlate with disease activity in several rheumatic diseases; however, their utility in polymyalgia rheumatica (PMR) remains unclear. This study evaluated their relationship with disease activity and glucocorticoid resistance in PMR. Data for disease activity (PMR-AS) and full blood examination was obtained from a prospective observational cohort comprising newly diagnosed, steroid-naïve PMR patients treated with low-dose glucocorticoid therapy. Glucocorticoid resistance was defined as non-response to prednisolone 15mg/d or initial response followed by flare (PMR-AS≥9.35 or ∆ ≥6.6) upon weaning to 5mg/d. Univariable Bayesian linear regression analysis of the relationship between PMR-AS (baseline and mean) and NLR and PLR was performed. Predictors of glucocorticoid resistance were identified using a multivariable outcome model, with variables derived from Bayesian model selection. Of the 32 included patients, 16 (50%) fulfilled the primary outcome measure of glucocorticoid resistance. These participants were older, typically female, and had higher baseline C-reactive protein than their glucocorticoid-responsive counterparts. A statistically significant relationship was identified between PMR-AS and both NLR (odds ratio [OR] 28.1; 95% CI 1.6-54.7) and PLR (OR 40.6; 95% CI 10.1-71.4) at baseline, with PLR also found to correlate with disease activity during follow-up (OR 15.6; 95% CI 2.7-28.2). Baseline NLR proved a statistically significant predictor of glucocorticoid-resistant PMR (OR 14.01; 95% CI 1.49-278.06). Baseline NLR can predict glucocorticoid resistance in newly diagnosed PMR patients. Both NLR and PLR may be reliable biomarkers of disease activity in PMR.

Utilization of serum procalcitonin as a biomarker in the diagnosis and treatment of children with bacterial hospital-acquired pneumonia.

Hospital-acquired pneumonia (HAP) is one of the common infections in hospitalized patients. Early and prompt diagnosis of HAP is important because it aids in the appropriate selection of antibiotics and decreases the mortality and morbidity of patients. The investigation on serum procalcitonin (PCT) levels in pediatric patients is limited. Herein we aimed to evaluate the role of PCT in the early diagnosis of children with bacterial HAP. The study enrolled 264 children (< 14 years old) who were radiographically detected by pulmonary condensation chest X-rays. The HAP patients were stratified by patterns of microbiological detection of pathogens. Baseline white blood cell (WBC) count, neutrophil proportion, PCT, and C-reactive protein (CRP) were measured on admission. The laboratory findings and microbiological findings were analyzed and compared among groups. The median PCT concentration of patients with typical bacterial pathogens (3.95 ± 3.75 ng/mL) was significantly higher than the one of the patients with other pathogen types (median lower than 1.20 ng/mL). Correlation analysis indicated a significant correlation between PCT concentrations and the main inflammation makers including WBC count, neutrophil proportion, and CRP. PCT level was significantly decreased to 0.86 ± 1.46 ng/mL in post-treatment patients (p < 0.001). This cohort study with 264 pediatric HAP patients demonstrated the reliability of PCT level as a biomarker in patients with typical bacterial pathogens. Specifically, PCT cutoffs of 2 ng/mL accurately identified HAP children with typical bacterial pathogens. This finding suggested that PCT may serve as a reliable biomarker for the early diagnosis and treatment indicator of children with HAP.

Can Use of Silymarin Improve Inflammatory Status in Patients with β-Thalassemia Major? A Crossover, Randomized Controlled Trial

Background: In β-thalassemia major (β-TM) patients, iron overload is one of the main causes of inflammation. This study investigated whether use of silymarin could improve inflammatory status in patients with β-TM and iron overload, through a placebo-controlled, crossover study. Methods: Silymarin (140 mg, 3 times a day) or placebo were prescribed to all patients (n = 82) for 12 weeks, and after a 2-week washout period, patients were crossed over to the other group. The efficacy of silymarin was assessed by measuring serum C-reactive protein (CRP) (mg/dL), interleukin (IL)-6 (pg/mL), and IL-10 (pg/mL). Results: Sixty-nine patients completed the study. Data analysis showed that compared to the placebo, silymarin could decrease CRP, IL-6, and raise IL-10 significantly (the p values for all variables were <0.001). Cohen’s d for CRP adjusted according to the baseline CRP value was –1.72, the 95% confidence interval (CI) –2.12 to –1.33. The adjusted Cohen’s d equal to –1.12, 95% CI –1.48 to –0.76, and 0.78, 95% CI 0.43–1.12, were also estimated for IL-6 and IL-10, respectively. Conclusion: The results of the current study demonstrate that the combination of iron chelation therapy with silymarin can improve inflammatory status in patients with β-TM in the clinical setting.

Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicentre cohort study

ObjectivesTocilizumab has been proposed as a candidate therapy for patients with severe coronavirus disease 2019 (COVID-19), especially among those with higher systemic inflammation. We investigated the association between receipt of tocilizumab and mortality in a large cohort of hospitalized patients. MethodsIn this cohort study of patients hospitalized with COVID-19 in Spain, the primary outcome was time to death and the secondary outcome time to intensive care unit (ICU) admission or death. We used inverse probability weighting to fit marginal structural models adjusted for time-varying covariates to determine the causal relationship between receipt of tocilizumab and outcome. ResultsData from 1229 patients were analysed, with 261 patients (61 deaths) in the tocilizumab group and 969 patients (120 deaths) in the control group. In the adjusted marginal structural models, a significant interaction between receipt of tocilizumab and high C-reactive protein (CRP) levels was detected. Tocilizumab was associated with decreased risk of death (adjusted hazard ratio 0.34, 95% confidence interval 0.16–0.72, p 0.005) and ICU admission or death (adjusted hazard ratio 0.39, 95% confidence interval 0.19–0.80, p 0.011) among patients with baseline CRP >150 mg/L but not among those with CRP ≤150 mg/L. Exploratory subgroup analyses yielded point estimates that were consistent with these findings. ConclusionsIn this large observational study, tocilizumab was associated with a lower risk of death or ICU admission or death in patients with higher CRP levels. While the results of ongoing clinical trials of tocilizumab in patients with COVID-19 will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials.

Inflammatory and cardiometabolic markers at presentation with first episode psychosis and long-term clinical outcomes: A longitudinal study using electronic health records

Approximately one third of patients presenting with a first episode of psychosis need long-term support, but there is a limited understanding of the sociodemographic or biological factors that predict this outcome. We used electronic health records from a naturalistic cohort of consecutive patients referred to an early intervention in psychosis service to address this question. We extracted data on demographic (age, sex, ethnicity and marital status), immune (differential cell count measures and C-reactive protein (CRP)) and metabolic (cholesterol, triglycerides, glucose, glycated haemoglobin, blood pressure, body mass index (BMI)) factors at baseline, and subsequent need for long-term secondary (specialist) psychiatric care. Of 749 patients with outcome data available, 447 (60%) had a good outcome and were discharged to primary care, while 302 (40%) required follow-up by secondary mental health services indicating a worse outcome. The need for ongoing secondary mental healthcare was associated with high triglyceride levels (adjusted odds ratio/OR = 7.32, 95% CI 2.26–28.06), a low basophil:lymphocyte ratio (adjusted OR = 0.14, 95% CI 0.02–0.58), and a high monocyte count (adjusted OR = 2.78, 95% CI 1.02–8.06) at baseline. The associations for baseline basophil (unadjusted OR = 0.27 per SD, 95% CI 0.10–0.62) and platelet counts (unadjusted OR = 2.88, 95% CI 1.29–6.63) attenuated following adjustment for BMI. Baseline CRP levels or BMI were not associated with long-term psychiatric outcomes. In conclusion, we provide evidence that triglyceride levels and several blood cell counts measured at presentation may be clinically useful markers of long-term prognosis for first episode psychosis in clinical settings. These findings will require replication.

Interleukin-6 receptor blockade or TNF\u03b1 inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

BackgroundDiabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes.MethodsData were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes.ResultsPatients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p < 0.0001) and − 0.42 (− 0.54, − 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was − 0.13 (− 0.22, − 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA.ConclusionsIn post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings.Trial registrationClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

Early C-reactive protein kinetics predict survival of patients with advanced urothelial cancer treated with pembrolizumab.

To assess the prognostic and predictive ability of early C-reactive protein (CRP) kinetics, dynamic changes in CRP levels, in patients with advanced urothelial cancer treated with pembrolizumab. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab in second-line or later settings. Patients were divided into three early CRP kinetics groups: non-elevated (baseline CRP < 5mg/L), responder (baseline CRP ≥ 5mg/L and CRP decreased below baseline at least once within 30days), and non-responder (baseline CRP ≥ 5mg/L and CRP never decreased to baseline within 30days). Association between early CRP kinetics and pembrolizumab efficacy including objective response rate (ORR), disease control rate (DCR), and overall survival (OS) were evaluated. Based on early CRP kinetics, 40, 27, and 30 patients were classified as non-elevated, responder, and non-responder, respectively. ORR and DCR were 33% and 60% in non-elevated, 30% and 48% in responder, and 17% and 40% in non-responder; without a statistically significant difference. OS was significantly different among the non-elevated, responder, and non-responder groups (p < 0.01), with 1-year survival rates of 69%, 61%, and 31%, respectively. Early CRP kinetics could discriminate the OS of patients without objective response. Non-responder was an independent predictor for OS (HR 3.65, p < 0.01), as well as liver metastasis and ECOG PS ≥ 2. Early CRP kinetics is associated with survival of advanced urothelial cancer patients treated with pembrolizumab and could be a potential biomarker for clinical benefit from immune checkpoint inhibitors.

Characterization of Immune Checkpoint Inhibitor-Related Cardiotoxicity in Lung Cancer Patients From a Rural Setting

BackgroundImmune checkpoint inhibitor (ICI)-related cardiotoxicity (iRC) is uncommon but can be fatal. There have been few reports of iRC from a rural cancer population and few data for iRC and inflammatory biomarkers. ObjectivesThe purpose of this study was to characterize major adverse cardiac events (MACE) in ICI-treated lung cancer patients based in a rural setting and to assess the utility of C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) in the diagnosis of iRC. MethodsPatients with lung cancer treated with ICIs at Vidant Medical Center/East Carolina University (VMC/ECU) between 2015 and 2018 were retrospectively identified. MACE included myocarditis, non-ST-segment elevated myocardial infarction (NSTEMI), supraventricular tachycardia (SVT), and pericardial disorders. Medical history, laboratory values, pre-ICI electrocardiography (ECG), and echocardiography results were compared in patients with and without MACE. ResultsAmong 196 ICI-treated patients, 23 patients (11%) developed MACE at a median of 46 days from the first ICI infusion (interquartile range [IQR]: 17 to 83 days). Patients who developed MACE experienced myocarditis (n = 9), NSTEMI (n = 3), SVT (n = 7), and pericardial disorders (n = 4). Ejection fraction was not significantly different at the time of MACE compared to that at baseline (p = 0.495). Compared to baseline values, NLR (10.9 ± 8.3 vs. 20.7 ± 4.2, respectively; p = 0.032) and CRP (42.1 ± 10.1 mg/l vs. 109.9 ± 15.6 mg/l, respectively; p = 0.010) were significantly elevated at the time of MACE. ConclusionsNLR and CRP were significantly elevated at the time of MACE compared to baseline values in ICI-treated patients. Larger datasets are needed to validate these findings and identify predictors of MACE that can be used in the diagnosis and management of ICI-related iRC.

699O Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers

In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1 IgG1 antibody) 1L maintenance + BSC significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC without disease progression with 1L induction chemotherapy in all randomized pts and pts with PD-L1+ tumors. We report exploratory biomarker analyses. Tumor biopsies were collected prior to randomization. Tumor analyses included PD-L1 (Ventana SP263 assay) and CD8 immunohistochemistry, whole-exome sequencing (including FCGR2A and FCGR3A genotypes), whole-transcriptome sequencing, and T-cell receptor (TCR) sequencing. Analyses of peripheral blood included baseline C-reactive protein (CRP) level and neutrophil:lymphocyte ratio (NLR) as well as TCR sequencing before and on treatment. Associations between OS or progression-free survival and biomarkers were evaluated using the Cox proportional hazards model. Hazard ratios and nominal p values were reported, and no multiplicity adjustments were made (5% level for statistical significance). Increased OS benefit with avelumab 1L maintenance + BSC vs BSC alone was positively associated with CD8+ T cells in the invasive margin or tumor center, high tumor mutation burden, and tumor gene expression signatures of innate and adaptive immune response. Increased OS benefit was also positively associated with the number of FCGR2A/FCGR3A alleles encoding high-affinity Fcγ receptors for IgG1. OS benefit with avelumab was negatively associated with tumor epithelial cell gene signatures, mutations affecting fibroblast growth factor receptor signaling, CRP, and NLR. In pts with elevated immune gene expression signatures, lower TGFb expression was associated with greater OS benefit with avelumab. Further analyses will be presented, including outcomes by exploratory PD-L1 cutoffs in tumor vs immune cells. OS benefits of avelumab 1L maintenance in pts with advanced UC are positively associated with biomarkers of immune activity and negatively associated with biomarkers of tumor homeostasis and chronic inflammation.

Association of High Serum Interleukin‐6 Levels With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis

ObjectiveThe development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin‐6 (IL‐6) levels; however, the utility of IL‐6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL‐6 levels are predictive of sarilumab treatment responses in 2 phase III studies.MethodsSerum IL‐6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient‐reported outcomes were compared between and within groups according to IL‐6 tertile using linear and logistic regression.ResultsIn MONARCH, patients with high baseline IL‐6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL‐6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL‐6 levels. In MOBILITY, compared to patients with low IL‐6 levels (n = 397), patients with high IL‐6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks’ treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL‐6 and C‐reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL‐6 tertiles.Conclusion IL‐6 may be a prognostic marker of disease progression and severity, and patients with high IL‐6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.