Clinical significance of serum cytokine profiles for differentiating between Kawasaki disease and its mimickers.

OBJECTIVES: To investigate the clinical significance of serum cytokine profiles for differentiating between Kawasaki disease (KD) and its mimickers. METHODS: Patients with KD, including complete KD, KD shock syndrome (KDSS), and KD with macrophage activation syndrome (KD-MAS), and its mimickers, including multisystem inflammatory syndrome in children, toxic shock syndrome, and Yersinia pseudotuberculosis infection, were enrolled. Serum levels of interleukin (IL)-6, soluble tumor necrosis factor receptor type II (sTNF-RII), IL-10, IL-18, and chemokine (C-X-C motif) ligand 9 (CXCL9) were measured using enzyme-linked immunosorbent assay and compared them with clinical manifestations. RESULTS: Serum IL-6, sTNF-RII, and IL-10 levels were significantly elevated in patients with KDSS. Serum IL-18 levels were substantially elevated in patients with KD-MAS. Patients with KD-MAS and KD mimickers had significantly elevated serum CXCL9 levels compared with those with complete KD. Area under the receiver operating characteristic curve analysis showed that serum IL-6 was the most useful for differentiating KDSS from the others, IL-18 and CXCL9 for KD-MAS from complete KD, and CXCL9 for KD mimickers from complete KD and KD-MAS. CONCLUSION: Serum cytokine profiles may be useful for differentiating between KD and its mimickers.

Emergency decompression for patients with ureteral stones and SIRS: a prospective randomized clinical study.

OBJECTIVE: Patients with ureteral calculi and systemic inflammatory response syndrome (SIRS) often require emergency drainage, and percutaneous nephrostomy (PCN) and retrograde ureteral stent insertion (RUSI) are the most commonly used methods. Our study aimed to identify the best choice (PCN or RUSI) for these patients and to examine the risk factors for progression to urosepsis after decompression. METHODS: A prospective, randomized clinical study was performed at our hospital from March 2017 to March 2022. Patients with ureteral stones and SIRS were enrolled and randomized to the PCN or RUSI group. Demographic information, clinical features and examination results were collected. RESULTS: Patients (n = 150) with ureteral stones and SIRS were enrolled into our study, with 78 (52%) patients in the PCN group and 72 (48%) patients in the RUSI group. Demographic information was not significantly different between the groups. The final treatment of calculi was significantly different between the two groups (p < .001). After emergency decompression, urosepsis developed in 28 patients. Patients with urosepsis had a higher procalcitonin (p = .012) and blood culture positivity rate (p < .001) and more pyogenic fluids during primary drainage (p < .001) than patients without urosepsis. CONCLUSION: PCN and RUSI were effective methods of emergency decompression in patients with ureteral stone and SIRS. Patients with pyonephrosis and a higher PCT should be carefully treated to prevent the progression to urosepsis after decompression.Key messageIn this study, we evaluate the best choice (PCN or RUSI) for patients who have ureteral stones and SIRS and to examine the risk factors for progression to urosepsis after decompression. This study found that PCN and RUSI were effective methods of emergency decompression. Pyonephrosis and higher PCT were risk factors for patients to develop to urosepsis after decompression.

NT-proBNP Levels Following IVIG Treatment of Multisystem Inflammatory Syndrome in Children.

BACKGROUND AND OBJECTIVES: N-terminal of probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels are often elevated in multisystem inflammatory syndrome in children (MIS-C) secondary to inflammation, myocardial dysfunction, or increased wall tension. Intravenous immunoglobulin (IVIG), accepted treatment of MIS-C, may transiently increase myocardial tension and contribute to an increase in NT-proBNP. We sought to study the association between pre- and post-IVIG levels of NT-proBNP and CRP and their clinical significance. METHODS: This single-center, retrospective, cohort study included consecutive children, aged ≤21 years, with diagnosis of MIS-C who received IVIG from April 2020 to October 2021. Data collection included clinical characteristics, laboratory tests, management, and outcomes. Study cohort consisted of patients who received IVIG and had NT-proBNP levels available pre- and post-IVIG. RESULTS: Among 35 patients with MIS-C, 30 met inclusion criteria. Twenty-four, 80%, showed elevation in NT-proBNP post-IVIG. The median NT-proBNP level pre-IVIG was 1921 pg/mL (interquartile range 548-3956), significantly lower than the post-IVIG median of 3756 pg/mL (interquartile range 1342-7634)) (P = .0010). The median pre-IVIG CRP level was significantly higher than the post-IVIG level (12 mg/dL vs 8 mg/dL, P = .0006). All but 1 recovered before discharge, and none had signs of worsening cardiac function post-IVIG. In those who recovered, NT-proBNP had normalized by discharge or 1-week follow-up. CONCLUSIONS: Our study shows that NT-proBNP levels often transiently increase immediately after IVIG therapy without signs of worsening myocardial function. These values should be interpreted in the context of CRP levels and clinical recovery.

Expression of Peripheral Blood DCs CD86, CD80, and Th1/Th2 in Sepsis Patients and Their Value on Survival Prediction.

Objective: To explore the expression of peripheral blood dendritic cells (DCs) CD86, CD80, and Th1/Th2 in patients with sepsis and their value on survival prediction. Methods: 118 patients with sepsis from January 2019 to December 2020 were selected, According to the prognosis, the patients were divided into the death group (n = 46) and survival group (n = 72). The general data and pathogen division of the two groups were collected, and the levels of peripheral blood DCs CD86, CD80, and Th1/Th2; APACHE II score; inflammatory factor (procalcitonin (PCT)); and cell growth chemokine (GRO) were compared between the two groups heparin-binding protein (HBP) and myocardial enzyme indexes (creatine kinase (CK), creatine kinase isozyme (CK-MB), and lactate dehydrogenase (LDH)) to explore the relationship between CD86, CD80, Th1/Th2, and various serological indexes and the evaluation value of prognosis. Results: 124 strains of pathogenic bacteria were isolated from 118 patients, including 78 strains of gram-negative bacteria (62.90%), 31 strains of Gram-positive bacteria (25.00%), and 15 strains of fungi (12.10%). The scores of CD86, CD80, Th1, Th2, Th1/Th2, and APACHE II in the dead group were higher than those in the surviving group, and the difference was statistically significant (P < 0.05). PCT, GRO-α, HBP, LDH, CK-MB, and CK levels of patients in death group were higher than those in survival group, and the difference was statistically significant (P < 0.05). The levels of peripheral blood DCs CD86, CD80, and Th1/Th2 were positively correlated with PCT, GRO-α, HBP, LDH, CK-MB, and CK (P < 0.05). ROC curve analysis showed that the AUC of the combined detection of DCs CD86, CD80, and Th1/Th2 in peripheral blood was 0.951, which was higher than 0.882, 0.883, and 0.734 of single index (P < 0.05). Conclusion: All patients with sepsis have immune imbalance, and the peripheral blood CD86, CD80, and Th1/Th2 of the dead patients are higher than those of the survivors. The combined detection of these three indicators has the highest predictive value for the prognosis of patients.

Circulating cardiomyocyte-derived extracellular vesicles reflect cardiac injury during systemic inflammatory response syndrome in mice.

The release of extracellular vesicles (EVs) is increased under cellular stress and cardiomyocyte damaging conditions. However, whether the cardiomyocyte-derived EVs eventually reach the systemic circulation and whether their number in the bloodstream reflects cardiac injury, remains unknown. Wild type C57B/6 and conditional transgenic mice expressing green fluorescent protein (GFP) by cardiomyocytes were studied in lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome (SIRS). EVs were separated both from platelet-free plasma and from the conditioned medium of isolated cardiomyocytes of the left ventricular wall. Size distribution and concentration of the released particles were determined by Nanoparticle Tracking Analysis. The presence of GFP + cardiomyocyte-derived circulating EVs was monitored by flow cytometry and cardiac function was assessed by echocardiography. In LPS-treated mice, systemic inflammation and the consequent cardiomyopathy were verified by elevated plasma levels of TNFα, GDF-15, and cardiac troponin I, and by a decrease in the ejection fraction. Furthermore, we demonstrated elevated levels of circulating small- and medium-sized EVs in the LPS-injected mice. Importantly, we detected GFP+ cardiomyocyte-derived EVs in the circulation of control mice, and the number of these circulating GFP+ vesicles increased significantly upon intraperitoneal LPS administration (P = 0.029). The cardiomyocyte-derived GFP+ EVs were also positive for intravesicular troponin I (cTnI) and muscle-associated glycogen phosphorylase (PYGM). This is the first direct demonstration that cardiomyocyte-derived EVs are present in the circulation and that the increased number of cardiac-derived EVs in the blood reflects cardiac injury in LPS-induced systemic inflammation (SIRS).

Acute kidney injury in paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is not associated with progression to chronic kidney disease.

BACKGROUND: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a rare complication of SARS-CoV-2 associated with single or multiorgan dysfunction. OBJECTIVE: We aimed to evaluate the incidence of acute kidney injury (AKI) and risk factors for kidney dysfunction in PIMS-TS, with reporting of 6-month renal follow-up data. We also evaluated renal involvement between first and second waves of the SARS-CoV-2 pandemic in the UK, the latter attributed to the Alpha variant. DESIGN: A single-centre observational study was conducted through patient chart analysis. SETTING: Data were collected from patients admitted to Great Ormond Street Hospital, London, UK, between April 2020 and March 2021. PATIENTS: 110 patients <18 years of age. MAIN OUTCOME MEASURE: AKI during hospitalisation. AKI classification was based on upper limit of reference interval (ULRI) serum creatinine (sCr) values. RESULTS: AKI occurred in 33 (30%) patients. Hypotension/hypoperfusion was associated with almost all cases. In univariate analysis, the AKI cohort had higher peak levels of triglycerides (OR, 1.27 (95% CI, 1.05 to 1.6) per 1 mmol/L increase) and C reactive protein (OR, 1.06 (95% CI, 1.02 to 1.12) per 10 mg/L increase), with higher requirement for mechanical ventilation (OR, 3.8 (95% CI, 1.46 to 10.4)) and inotropic support (OR, 15.4 (95% CI, 3.02 to 2.81)). In multivariate analysis, triglycerides were independently associated with AKI stages 2-3 (adjusted OR, 1.26 (95% CI, 1.04 to 1.6)). At follow-up, none had macroalbuminuria and all had sCr values

A comparative study of IL-6, CRP and NT-proBNP levels in post-COVID multisystem inflammatory syndrome in children (MISC) and Kawasaki disease patients.

BACKGROUND: Post-COVID multisystem hyperinflammatory syndrome in children (MISC) has clinical and laboratory similarities with Kawasaki disease (KD). Inflammatory markers like C-reactive protein (CRP), interleukin 6 (IL6) as well as N-terminal probrain natriuretic peptide (NT-proBNP) are elevated in both. This study attempts a comparative analysis of the 3 markers in an attempt at early differentiation for planning appropriate management. METHODOLOGY: This analytical study conducted at the Institute of Child Health, Kolkata, India compared the levels of the above 3 markers at admission between 72 patients with KD, 30% of whom had coronary artery lesions (CALs) collected over a period of 18 months (Jan 2017-June 2018), with 71 MISC patients over a period of 6 months (July 2020-December 2020). The non-parametric Mann-Whitney U test was used to test for similarity in distributions of the samples of CRP, NT-proBNP and IL6 in KD and MISC patients using correction factor for similar ranks. The 3 parameters were compared using receiver operating characteristic (ROC) curve analysis. RESULTS: Mean IL6 value in KD was 83.22 pg/mL and in MISC 199.91 pg/mL, which was not found to be statistically significant (P = .322 > .05).However mean NT-proBNP (914.91 pg/mL) with CRP level (96.32 mg/L) in KD was significantly lower (P < .05 for both cases) than that in MISC (9141.16 pg/mL and 145.66 mg/L respectively). ROC analysis showed NT-proBNP has the best sensitivity and specificity in predicting MISC. CONCLUSION: NT-proBNP and CRP are significantly higher among MISC patients; ROC analysis shows levels >935.7 pg/mL and >99.55 mg/L respectively might act as a guide to differentiate between them.

Endothelial injury in COVID-19 and septic patients.

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.

Differentiating multisystem inflammatory syndrome in children: a single-centre retrospective cohort study.

OBJECTIVE: Features of multisystem inflammatory syndrome in children (MIS-C) overlap with other febrile illnesses, hindering prompt and accurate diagnosis. The objectives of this study were to identify clinical and laboratory findings that distinguished MIS-C from febrile illnesses in which MIS-C was considered but ultimately excluded, and to examine the diseases that most often mimicked MIS-C in a tertiary medical centre. STUDY DESIGN: We identified all children hospitalised with fever who were evaluated for MIS-C at our centre and compared clinical signs and symptoms, SARS-CoV-2 status and laboratory studies between those with and without MIS-C. Multivariable logistic LASSO (least absolute shrinkage and selection operator) regression was used to identify the most discriminative presenting features of MIS-C. RESULTS: We identified 50 confirmed MIS-C cases (MIS-C+) and 68 children evaluated for, but ultimately not diagnosed with, MIS-C (MIS-C-). In univariable analysis, conjunctivitis, abdominal pain, fatigue, hypoxaemia, tachypnoea and hypotension at presentation were significantly more common among MIS-C+ patients. MIS-C+ and MIS-C- patients had similar elevations in C-reactive protein (CRP), but were differentiated by thrombocytopenia, lymphopenia, and elevated ferritin, neutrophil/lymphocyte ratio, BNP and troponin. In multivariable analysis, predictors of MIS-C included age, neutrophil/lymphocyte ratio, platelets, conjunctivitis, oral mucosa changes, abdominal pain and hypotension. CONCLUSIONS: Among hospitalised children undergoing evaluation for MIS-C, children with MIS-C were older, more likely to present with conjunctivitis, oral mucosa changes, abdominal pain and hypotension, and had higher neutrophil/lymphocyte ratios and lower platelet counts. These data may be helpful for discrimination of MIS-C from other febrile illnesses, including bacterial lymphadenitis and acute viral infection, with overlapping features.

Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome.

BACKGROUND AND AIMS: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. APPROACH AND RESULTS: A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients. CONCLUSIONS: Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.

Osteopontin as a biomarker for COVID-19 severity and multisystem inflammatory syndrome in children: A pilot study.

This study sought to evaluate the candidacy of plasma osteopontin (OPN) as a biomarker of COVID-19 severity and multisystem inflammatory condition in children (MIS-C) in children. A retrospective analysis of 26 children (0-21 years of age) admitted to Children's Healthcare of Atlanta with a diagnosis of COVID-19 between March 17 and May 26, 2020 was undertaken. The patients were classified into three categories based on COVID-19 severity levels: asymptomatic or minimally symptomatic (control population, admitted for other non-COVID-19 conditions), mild/moderate, and severe COVID-19. A fourth category of children met the Centers for Disease Control and Prevention's case definition for MIS-C. Residual blood samples were analyzed for OPN, a marker of inflammation using commercial ELISA kits (R&D), and results were correlated with clinical data. This study demonstrates that OPN levels are significantly elevated in children hospitalized with moderate and severe COVID-19 and MIS-C compared to OPN levels in mild/asymptomatic children. Further, OPN differentiated among clinical levels of severity in COVID-19, while other inflammatory markers including maximum erythrocyte sedimentation rate, C-reactive protein and ferritin, minimum lymphocyte and platelet counts, soluble interleukin-2R, and interleukin-6 did not. We conclude OPN is a potential biomarker of COVID-19 severity and MIS-C in children that may have future clinical utility. The specificity and positive predictive value of this marker for COVID-19 and MIS-C are areas for future larger prospective research studies.

Coronary Artery Changes in Patients with Multisystem Inflammatory Syndrome in Children: Los Angeles Experience.

We compared cardiac findings in patients with multisystem inflammatory syndrome in children and Kawasaki disease in the first 6 months of the 2020 coronavirus disease pandemic to patients with Kawasaki disease during 2016-2019. We saw a high rate of coronary aneurysms in 2020, with a similar rate of coronary involvement but greater volume and incidence of cardiac dysfunction compared with previous years.

Utility of specific laboratory biomarkers to predict severe sepsis in pediatric patients with SIRS.

OBJECTIVE: To identify the association between readily available laboratory biomarkers and the development of severe sepsis in children presenting to the emergency department (ED) with systemic inflammatory response syndrome (SIRS). METHODS: In this retrospective cohort study, ED patient encounters from June 2018 to June 2019 that triggered an automated sepsis alert based on SIRS criteria were analyzed. Encounters were included if the patient had any of the following laboratory tests sent within 6 h of ED arrival: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactic acid, and procalcitonin. For each of the biomarkers, a receiver operating characteristic (ROC) curve was created for our primary outcome, severe sepsis within 24 h of ED disposition, and our secondary outcome, severe sepsis with a positive bacterial culture. For each ROC curve, we calculated the area under the curve (AUC) with 95% confidence intervals (95% CI) and created cutoff points to achieve 90% sensitivity and 90% sensitivity for the primary and secondary outcomes. RESULTS: During the study period, 4349/61,195 (7.1%) encounters triggered an automated sepsis alert. Of those, 1207/4349 (27.8%) had one of the candidate biomarkers sent within 6 h of ED arrival and were included in the study. A total of 100/1207 (8.3%) met criteria for severe sepsis within 24 h of arrival, and 41/100 severe sepsis cases (41%) were deemed culture-positive. Procalcitonin had the highest AUC for identifying severe sepsis [0.62 (95% CI 0.52-0.73)] while ESR and CRP had the highest AUC for culture-positive sepsis [0.68 (95% CI 0.47-0.89) and 0.67 (95% CI 0.53-0.81), respectively]. At 90% sensitivity for detecting severe sepsis, all of the biomarker threshold values fell within that laboratory test's normal range. At 90% specificity for severe sepsis, threshold values were as follows: procalcitonin 2.72 ng/mL, CRP 16.79 mg/dL, ESR 79.5 mm/h and lactic acid 3.6 mmol/L. CONCLUSION: Our data indicate that CRP, ESR, lactic acid, and procalcitonin elevations were all specific, but not sensitive, in identifying children in the ED with SIRS who go on to develop severe sepsis.

Plasmin drives burn-induced systemic inflammatory response syndrome.

Severe injuries, such as burns, provoke a systemic inflammatory response syndrome (SIRS) that imposes pathology on all organs. Simultaneously, severe injury also elicits activation of the fibrinolytic protease plasmin. While the principal adverse outcome of plasmin activation in severe injury is compromised hemostasis, plasmin also possesses proinflammatory properties. We hypothesized that, following a severe injury, early activation of plasmin drives SIRS. Plasmin activation was measured and related to injury severity, SIRS, coagulopathy, and outcomes prospectively in burn patients who are not at risk of hemorrhage. Patients exhibited early, significant activation of plasmin that correlated with burn severity, cytokines, coagulopathy, and death. Burn with a concomitant, remote muscle injury was employed in mice to determine the role of plasmin in the cytokine storm and inflammatory cascades in injured tissue distant from the burn injury. Genetic and pharmacologic inhibition of plasmin reduced the burn-induced cytokine storm and inflammatory signaling in injured tissue. These findings demonstrate (a) that severe injury-induced plasmin activation is a key pathologic component of the SIRS-driven cytokine storm and SIRS-activated inflammatory cascades in tissues distant from the inciting injury and (b) that targeted inhibition of plasmin activation may be effective for limiting both hemorrhage and tissue-damaging inflammation following injury.

A poor and delayed anti-SARS-CoV2 IgG response is associated to severe COVID-19 in children.

BACKGROUND: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown. METHODS: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods. FINDINGS: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines. INTERPRETATION: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize pediatric severe COVID-19. Because comorbidities are highly prevalent in children with severe COVID-19, further studies are needed to clarify their contribution in the weak antibody response observed in severe disease. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548).

Peripheral Blood Cell Variables Related to Systemic Inflammation in Patients With Unresectable or Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

ABSTRACT: Systemic inflammatory response (SIR) plays a central role in the prognosis of unresectable or metastatic pancreatic ductal adenocarcinoma (mPDAC), and many SIR-related peripheral blood cell (PBC)-derived variables have been proposed as prognostic factors. The study aims to perform a systematic review and, for the more studied PBC-derived variables, a meta-analysis. A systematic review from 2000 to 2020 on 2 databases by predefined criteria was performed for PBC-derived variables in patients with mPDAC receiving chemotherapy in relation with overall survival. Eligible studies were selected by inclusion criteria, and only the PBC variables reported in at least 10 studies were evaluated by meta-analysis. Three hundred and eighty articles were found, and 28 studies were selected. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were reported in 28 and 10 articles, respectively. The subsequent meta-analyses supported the prognostic effect for both, NLR (hazard ratio, 2.10; 95% confidence interval, 1.87-2.37) and PLR (hazard ratio, 1.22; 95% confidence interval, 1.08-1.37). Heterogeneity was significant for NLR (I2 = 62%) and low for PLR (I2 = 24%). Among SIR-related PBC-derived variables, NLR is the most suitable prognostic factor for future clinical trials of patients with mPDAC.

Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.

The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II.

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1ß have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1ß. Following IVIG treatment, activated IL-1ß+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1ß can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Severe Inflammatory Reactions in Mice Expressing a GFI1P2A Mutant Defective in Binding to the Histone Demethylase KDM1A (LSD1).

GFI1 is a DNA-binding transcription factor that regulates hematopoiesis by repressing target genes through its association with complexes containing histone demethylases such as KDM1A (LSD1) and histone deacetylases (HDACs). To study the consequences of the disruption of the complex between GFI1 and histone-modifying enzymes, we have used knock-in mice harboring a P2A mutation in GFI1 coding region that renders it unable to bind LSD1 and associated histone-modifying enzymes such as HDACs. GFI1P2A mice die prematurely and show increased numbers of memory effector and regulatory T cells in the spleen accompanied by a severe systemic inflammation with high serum levels of IL-6, TNF-α, and IL-1ß and overexpression of the gene encoding the cytokine oncostatin M (OSM). We identified lung alveolar macrophages, CD8 T cell from the spleen and thymic eosinophils, and monocytes as the sources of these cytokines in GFI1P2A mice. Chromatin immunoprecipitation showed that GFI1/LSD1 complexes occupy sites at the Osm promoter and an intragenic region of the Tnfα gene and that a GFI1P2A mutant still remains bound at these sites even without LSD1. Methylation and acetylation of histone H3 at these sites were enriched in cells from GFI1P2A mice, the H3K27 acetylation being the most significant. These data suggest that the histone modification facilitated by GFI1 is critical to control inflammatory pathways in different cell types, including monocytes and eosinophils, and that a disruption of GFI1-associated complexes can lead to systemic inflammation with fatal consequences.