Pediatric sepsis inflammatory blood biomarkers that correlate with clinical variables and severity of illness scores.

BACKGROUND: Sepsis is a dysregulated systemic inflammatory response triggered by infection, resulting in organ dysfunction. A major challenge in clinical pediatrics is to identify sepsis early and then quickly intervene to reduce morbidity and mortality. As blood biomarkers hold promise as early sepsis diagnostic tools, we aimed to measure a large number of blood inflammatory biomarkers from pediatric sepsis patients to determine their predictive ability, as well as their correlations with clinical variables and illness severity scores. METHODS: Pediatric patients that met sepsis criteria were enrolled, and clinical data and blood samples were collected. Fifty-eight inflammatory plasma biomarker concentrations were determined using immunoassays. The data were analyzed with both conventional statistics and machine learning. RESULTS: Twenty sepsis patients were enrolled (median age 13 years), with infectious pathogens identified in 75%. Vasopressors were administered to 85% of patients, while 55% received invasive ventilation and 20% were ventilated non-invasively. A total of 24 inflammatory biomarkers were significantly different between sepsis patients and age/sex-matched healthy controls. Nine biomarkers (IL-6, IL-8, MCP-1, M-CSF, IL-1RA, hyaluronan, HSP70, MMP3, and MMP10) yielded AUC parameters > 0.9 (95% CIs: 0.837-1.000; p < 0.001). Boruta feature reduction yielded 6 critical biomarkers with their relative importance: IL-8 (12.2%), MCP-1 (11.6%), HSP70 (11.6%), hyaluronan (11.5%), M-CSF (11.5%), and IL-6 (11.5%); combinations of 2 biomarkers yielded AUC values of 1.00 (95% CI: 1.00-1.00; p < 0.001). Specific biomarkers strongly correlated with illness severity scoring, as well as other clinical variables. IL-3 specifically distinguished bacterial versus viral infection (p < 0.005). CONCLUSIONS: Specific inflammatory biomarkers were identified as markers of pediatric sepsis and strongly correlated to both clinical variables and sepsis severity.

Evaluation of Local Pediatric Out-of-Hospital Cardiac Arrest and Emergency Services Response.

Background: Survival after pediatric out-of-hospital cardiac arrest is poor. Paramedic services provide critical interventions that impact survival outcomes. We aimed to describe local pediatric out-of-hospital cardiac arrest (POHCA) events and evaluate the impact of the paramedic service response to POHCA. Methods: The Canadian Resuscitation Outcomes Consortium and corresponding ambulance call records were used to evaluate deviations from best practice by paramedics for patients aged 1 day to <18 years who had an atraumatic out-of-hospital cardiac arrest between 2012 and 2020 in Middlesex-London County. Deviations were any departure from protocol as defined by Middlesex-London Paramedic Services. Results: Fifty-one patients were included in this study. All POHCA events had at least one deviation, with a total of 188 deviations for the study cohort. Return of spontaneous circulation (ROSC) was achieved in 35.3% of patients and 5.8% survived to hospital discharge. All survivors developed a new, severe neurological impairment. Medication deviations were most common (n = 40, 21.3%) followed by process timing (n = 38, 20.2%), vascular access (n = 27, 14.4%), and airway (n = 27, 14.4%). A delay in vascular access was the most common deviation (n = 25, 49.0%). The median (IQR) time to epinephrine administration was 8.6 (5.90-10.95) min from paramedic arrival. Cardiac arrests occurring in public settings had more deviations than private settings (p = 0.04). ROSC was higher in events with a deviation in any circulation category (p = 0.03). Conclusion: Patient and arrest characteristics were similar to other POHCA studies. This cohort exhibited high rates of ROSC and bystander cardiopulmonary resuscitation but low survival to hospital discharge. The study was underpowered for its primary outcome of survival. The total deviations scored was low relative to the total number of tasks in a resuscitation. Epinephrine was frequently administered outside of the recommended timeframe, highlighting an important quality improvement opportunity.

Validation of ICD-10 codes for the identification of paediatric out-of-hospital cardiac arrest patients.

AIM: There is a need for large-scale epidemiological studies of paediatric out-of-hospital cardiac arrest (POHCA). To enable this, we developed and validated international classification of disease (ICD-10) search algorithms for the identification of POHCA patients from health administrative data. METHODS: We validated the algorithms with a registry of POHCA (CanRoc) as the reference standard. The reference standard included all atraumatic POHCA in Middlesex-London region for January 2012-June 2020. All algorithms included 1 day to <18-year-old patients transported to emergency department (ED) by ambulance and excluded trauma. We tested three algorithms, which were applied to the National Ambulatory Care Reporting System and Discharge Abstract Database. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR) and negative likelihood ration (NLR) were calculated for each algorithm. RESULTS: During the study period, 17,688 children presented to the ED by ambulance. The reference standard included 51 POHCA patients. The algorithm using only ICD-10 code for cardiac arrest had a sensitivity of 65.5% and PPV of 90%. The algorithm with the highest sensitivity of 87.3% added sudden infant death syndrome, drowning or asphyxiation with CPR in addition to the cardiac arrest codes for inpatient and ED records. This algorithm had a specificity of 99.9%, PPV of 81.4% and NPV of âˆ¼100.0%. CONCLUSION: It is important that algorithms used for cohort identification are validated prior to use. The ICD-10 code for cardiac arrest alone misses many POHCA cases but the use of additional codes can improve the sensitivity while maintaining specificity.

TLR7 Ligation Inhibits TLR8 Responsiveness in IL-27-Primed Human THP-1 Monocytes and Macrophages.

Regulation of proinflammatory cytokine expression is critical in the face of single-stranded RNA (ssRNA) virus infections. Many viruses, including coronavirus and influenza virus, wreak havoc on the control of cytokine expression, leading to the formation of detrimental cytokine storms. Understanding the regulation and interplay between inflammatory cytokines is critical to the identification of targets involved in controlling the induction of cytokine expression. In this study, we focused on how the antiviral cytokine interleukin-27 (IL-27) regulates signal transduction downstream of Toll-like receptor 7 (TLR7) and TLR8 ligation, which recognize endosomal single-stranded RNA. Given that IL-27 alters bacterial-sensing TLR expression on myeloid cells and can inhibit replication of single-stranded RNA viruses, we investigated whether IL-27 affects expression and function of TLR7 and TLR8. Analysis of IL-27-treated THP-1 monocytic cells and THP-1-derived macrophages revealed changes in mRNA and protein expression of TLR7 and TLR8. Although treatment with IL-27 enhanced TLR7 expression, only TLR8-mediated cytokine secretion was amplified. Furthermore, we demonstrated that imiquimod, a TLR7 agonist, inhibited cytokine and chemokine production induced by a TLR8 agonist, TL8-506. Delineating the immunomodulatory role of IL-27 on TLR7 and TLR8 responses provides insight into how myeloid cell TLR-mediated responses are regulated during virus infection.

IL-27, IL-30, and IL-35: A Cytokine Triumvirate in Cancer.

The role of the immune system in anti-tumor immunity cannot be overstated, as it holds the potential to promote tumor eradication or prevent tumor cell escape. Cytokines are critical to influencing the immune responses and interactions with non-immune cells. Recently, the IL-12 and IL-6 family of cytokines have accumulated newly defined members each with specific immune functions related to various cancers and tumorigenesis. There is a need to better understand how cytokines like IL-27, IL-30, and IL-35 interact with one another, and how a developing tumor can exploit these interactions to enhance immune suppression. Current cytokine-based immunotherapies are associated with cytotoxic side effects which limits the success of treatment. In addition to this toxicity, understanding the complex interactions between immune and cancer cells may be one of the greatest challenges to developing a successful immunotherapy. In this review, we bring forth IL-27, IL-30, and IL-35, "sister cytokines," along with more recent additions to the IL-12 family, which serve distinct purposes despite sharing structural similarities. We highlight how these cytokines function in the tumor microenvironment by examining their direct effects on cancer cells as well their indirect actions via regulatory functions of immune cells that act to either instigate or inhibit tumor progression. Understanding the context dependent immunomodulatory outcomes of these sister cytokines, as well as their regulation within the tumor microenvironment, may shed light onto novel cancer therapeutic treatments or targets.

The Toll for Trafficking: Toll-Like Receptor 7 Delivery to the Endosome.

Toll-like receptor (TLR)-7 is an endosomal innate immune sensor capable of detecting single-stranded ribonucleic acid. TLR7-mediated induction of type I interferon and other inflammatory cytokine production is important in antiviral immune responses. Furthermore, altered TLR7 expression levels are implicated in various autoimmune disorders, indicating a key role for this receptor in modulating inflammation. This review is focused on the regulation of TLR7 expression and localization compared to that of the other endosomal TLRs: TLR3, 8, and 9. Endosomal TLR localization is a tightly controlled and intricate process with some shared components among various TLRs. However, TLR-specific mechanisms must also be in place in order to regulate the induction of pathogen- and cell-specific responses. It is known that TLR7 is shuttled from the endoplasmic reticulum to the endosome via vesicles from the Golgi. Several chaperone proteins are required for this process, most notably uncoordinated 93 homolog B1 (Caenorhabditis elegans), recently identified to also be involved in the localization of the other endosomal TLRs. Acidification of the endosome and proteolytic cleavage of TLR7 are essential for TLR7 signaling in response to ligand binding. Cleavage of TLR7 has been demonstrated to be accomplished by furin peptidases in addition to cathepsins and asparagine endopeptidases. Moreover, triggering receptor expressed on myeloid cells like 4, a protein associated with antigen presentation and apoptosis in immune cells, has been implicated in the amplification of TLR7 signaling. Understanding these and other molecular mechanisms controlling TLR7 expression and trafficking will give insight into the specific control of TLR7 activity compared to the other endosomal TLRs.