Evaluating the potential of IL-27 as a novel therapeutic agent in HIV-1 infection

Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection.     

Combination of sepsis biomarkers may indicate an invasive fungal infection in haematological patients

Background: Invasive fungal infections are a major threat to a large cohort of immunocompromised patients, including patients with chemotherapy-associated neutropenia. Early differential diagnosis with bacterial infections is often complicated, which leads to a delay in empirical antifungal therapy and increases risk for adverse outcome. Accessibility and performance of specific fungal antigen and PCR-tests are still limited, while sepsis biomarkers are more broadly used in most settings currently.

Methods: Haematological patients hospitalized to receive chemotherapy with proven or probable invasive fungal infection or microbiologically proven bacterial bloodstream infection were included in the study. C-reactive protein was assessed daily during the profound neutropenia period, while procalcitonin or presepsin were measured during the first 48?hours after the onset of febrile episode.

Results: There were totally 64 patients included in the study, 53 with bacterial bloodstream infections and 11 with invasive fungal infections. Combination of CRP >120 with PCT <1.25 or presepsin <170 was shown to be a possible combined biomarker for invasive fungal infections in immunocompromised patients, with areas under the ROC-curves: 0.962 (95% CI 0.868 to 0.995) for PCT-based combination and 0.907 (95% CI 0.692 to 0.990) for presepsin-based combination.     

DNA methylation pattern of CALCA in preterm neonates with bacterial sepsis as a putative epigenetic biomarker

Diagnosis of bacterial sepsis in preterm neonates can be difficult when using serum markers that rely on physiological changes because these changes may not necessarily be the result of bacterial infections alone. This retrospective investigation explores the potential use of the DNA methylation pattern of CpG sites in the promoter region of the calcitonin-related polypeptide α (CALCA) gene as an epigenetic biomarker for bacterial sepsis in preterm newborns. Four novel changes in the DNA methylation of eight CpG sites were detected in this gene and are present only in neonates with bacterial sepsis: (1) partial methylation at -769 CpG in gram-negative or gram-positive early onset sepsis (EOS) and late onset sepsis (LOS) episodes; (2) demethylation of 8 CpGs in gram-negative EOS followed by LOS (ELS) and in gram-negative EOS; (3) demethylation of 7 CpGs in gram-positive ELS and gram-positive EOS; (4) -771 C:G > T:A; 5′ de novo -778 CpG mutation on both alleles in EOS. These changes were not detected in birth weight and gestational age matched controls or in newborns with isolated infections. Our results indicate that the DNA methylation pattern of the promoter region of the CALCA gene varies in different types of bacterial preterm sepsis, thus suggesting a potential use as an epigenetic biomarker. A prospective confirmation of these results is essential.     

Risk of infection following a visit to the emergency department: a cohort study

Background:

The risk of infection following a visit to the emergency department is unknown. We explored this risk among elderly residents of long-term care facilities.

Methods:

We compared the rates of new respiratory and gastrointestinal infections among elderly residents aged 65 years and older of 22 long-term care facilities. We used standardized surveillance definitions. For each resident who visited the emergency department during the study period, we randomly selected two residents who did not visit the emergency department and matched them by facility unit, age and sex. We calculated the rates and proportions of new infections, and we used conditional logistic regression to adjust for potential confounding variables.

Results:

In total, we included 1269 residents of long-term care facilities, including 424 who visited the emergency department during the study. The baseline characteristics of residents who did or did not visit the emergency department were similar, except for underlying health status (visited the emergency department: mean Charlson Comorbidity Index 6.1, standard deviation [SD] 2.5; did not visit the emergency department: mean Charlson Comorbidity index 5.5, SD 2.7; p < 0.001) and the proportion who had visitors (visited the emergency department: 46.9%; did not visit the emergency department: 39.2%; p = 0.01). Overall, 21 (5.0%) residents who visited the emergency department and 17 (2.0%) who did not visit the emergency department acquired new infections. The incidence of new infections was 8.3/1000 patient-days among those who visited the emergency department and 3.4/1000 patient-days among those who did not visit the emergency department. The adjusted odds ratio for the risk of infection following a visit to the emergency department was 3.9 (95% confidence interval 1.4–10.8).

Interpretation:

A visit to the emergency department was associated with more than a threefold increased risk of acute infection among elderly people. Additional precautions should be considered for residents following a visit to the emergency department.Infections associated with health care are an important health risk. A recent survey by the World Health Organization reported that 8.7% of patients in hospital developed such infections.^1,2 The third leading cause of death in the United States is health care–associated deaths, with over 100 000 people dying from infections associated with health care each year.³ In Canada, a point-prevalence survey found that 11.6% of adults in hospital experience a health care–associated infection.⁴Little attention has been paid to infections acquired in other health care settings. Visiting an emergency department has been identified as a risk for disease during outbreaks of measles^5,6 and SARS,^7,8 but little is known about the potential risk of endemic infection from exposure in this setting. A visit to the emergency department differs from a stay in hospital: exposure and duration of contact with other patients is shorter, but the number and density of patients with acute illness with whom there could be contact is higher.Elderly residents of long-term care facilities are likely to be at the greatest risk of morbidity and mortality from communicable diseases acquired in the emergency department. When residents are transferred to the emergency department for assessment, they are likely to have longer stays and to be cared for in multibed observation areas and corridors.⁹ If they acquire an infection while in the emergency department, these residents may be the source of an outbreak upon return to their facility; this can lead to increases in workload and costs. A Canadian study estimated the cost of an influenza outbreak to be over $6000 per 30-day period, with an estimated incidence of death of 0.75/100 residents during the same period.¹⁰ In this study, we explored the risk of acute respiratory and gastrointestinal infection associated with a visit to the emergency department among elderly residents of long-term care facilities.     

Estimating the probability of stroke in Korean hypertensive patients visiting tertiary hospitals using a risk profile from the framingham study

Background  

Hypertension is the most important single modifiable risk factor for stroke. We investigated the distribution of stroke risk factors and 10-year probability of stroke in Korean hypertensive patients.     

Methicillin-resistant Staphylococcus aureus nasal colonization among adult patients visiting emergency department in a medical center in Taiwan

Background

Within the past 10 years, methicillin-resistant Staphylococcus aureus (MRSA) has not only been a hospital pathogen but also a community pathogen. To understand the carriage rate of methicillin-resistant Staphylococcus aureus (MRSA) among the adult patients visiting emergency department (ED), we conducted this study.

Methodology/Principal Findings

From May 21 to August 12, 2009, a total of 502 adult patients visiting emergency department (ED) of a tertiary care hospital in northern Taiwan were recruited in this study and surveyed for nasal carriage of MRSA. A questionnaire regarding the risk factors for MRSA acquisition was also obtained.The overall prevalence of MRSA nasal carriage among the patients was 3.8%. The carriage rate was significantly higher in patients with risk factors for MRSA acquisition (5.94%) than those without risk factors (2.12%). Patients with urinary complaints, diabetes mellitus, chronic kidney disease and current percutaneous tube usage were significantly associated with MRSA colonization. By multiple logistic regression analysis, only current usage of catheters or tubes was the independent predictor for MRSA nasal colonization. Of the 19 MRSA, most isolates belonged to one of two linages, characterized as sequence type (ST) 239 (32%) and ST 59 (58%). The latter linage, accounting for 83% of 6 isolates from patients without risk factors, is a community-associated (CA) clone in Taiwan, while the former linage is among healthcare-associated clones.

Conclusion/Significance

A substantial proportion of patients visiting ED, particularly with current usage of percutaneous catheter or tubes, in northern Taiwan carried MRSA, mostly community strains, in nares.     

Evaluation of a kit for rapid detection of group A streptococci in a pediatric emergency department.

We evaluated a kit for the rapid detection of group A streptococci from throat swabs (Culturette Brand 10-Minute Group A Strep ID, Marion Scientific, Division of Marion Laboratories, Inc., Kansas City, Missouri) in the laboratory and in a busy pediatric emergency department. The sensitivity of the kit in the laboratory was 80% for all specimens and 94% for specimens with more than 10 colony-forming units of group A streptococci; the specificity was 99%. After initial training, emergency department pediatricians and nurses achieved sensitivities of 72% and 69% respectively. The specificity achieved by the pediatricians was 76% initially but 96% after further training. Untrained residents achieved a sensitivity of 58%. We conclude that this kit is potentially useful in the hands of adequately trained personnel, but without training the accuracy of the results is unacceptable. We recommend that the kit be used by designated staff trained and monitored by laboratory personnel.     

Mortality among patients with frequent emergency department use for alcohol-related reasons in Ontario: a population-based cohort study

BACKGROUND:Little is known about the risk of death among people who visit emergency departments frequently for alcohol-related reasons, including whether mortality risk increases with increasing frequency of visits. Our primary objective was to describe the sociodemographic and clinical characteristics of this high-risk population and examine their 1-year overall mortality, premature mortality and cause of death as a function of emergency department visit frequency in Ontario, Canada.METHODS:We conducted a population-based retrospective cohort study using linked health administrative data (Jan. 1, 2010, to Dec. 31, 2016) in Ontario for people aged 16–105 years who made at least 2 emergency department visits for mental or behavioural disorders due to alcohol within 1 year. We subdivided the cohort based on visit frequency (2, 3 or 4, or ≥ 5). The primary outcome was 1-year mortality, adjusted for age, sex, income, rural residence and presence of comorbidities. We examined premature mortality using years of potential life lost (YPLL).RESULTS:Of the 25 813 people included in the cohort, 17 020 (65.9%) had 2 emergency department visits within 1 year, 5704 (22.1%) had 3 or 4 visits, and 3089 (12.0%) had 5 or more visits. Males, people aged 45–64 years, and those living in urban centres and lower-income neighbourhoods were more likely to have 3 or 4 visits, or 5 or more visits. The all-cause 1-year mortality rate was 5.4% overall, ranging from 4.7% among patients with 2 visits to 8.8% among those with 5 or more visits. Death due to external causes (e.g., suicide, accidents) was most common. The adjusted mortality rate was 38% higher for patients with 5 or more visits than for those with 2 visits (adjusted hazard ratio 1.38, 95% confidence interval 1.19–1.59). Among 25 298 people aged 16–74 years, this represented 30 607 YPLL.INTERPRETATION:We observed a high mortality rate among relatively young, mostly urban, lower-income people with frequent emergency department visits for alcohol-related reasons. These visits are opportunities for intervention in a high-risk population to reduce a substantial mortality burden.

Alcohol is a leading driver of morbidity and mortality worldwide.¹ An estimated 3 million deaths in 2016 — 5% of all global deaths — were attributable to alcohol consumption.² The 2016 Global Burden of Disease Study showed that alcohol was the single greatest risk factor for ill health worldwide among people aged 15–49 years.³ In Canada, hospital admissions for alcohol-attributable conditions out-number those for myocardial infarction.⁴ Alcohol-related harms cost Canadians about $14.6 billion annually, with $3.3 billion in health care costs.⁵In addition to the societal impact of mental and behavioural disorders due to alcohol (henceforth referred to as alcohol-related) — mainly acute intoxication and withdrawal — these disorders are common reasons for emergency department visits.^6,7 Data from the United States and Canada, furthermore, suggest that alcohol-related emergency department visits have increased in recent years.^8,9 For example, a study in Ontario showed that, between 2003 and 2016, the age-standardized rates of alcohol-attributable emergency department visits increased by 86.5% in women and 53.2% in men.⁸ People who visit emergency departments frequently for alcohol-related reasons have high levels of comorbidity and social disadvantage,^10,11 and represent a readily identifiable patient population for whom interventions to address unmet social and health care needs could be developed.^12–14 A systematic review suggested that screening and brief intervention for alcohol-related problems in the emergency department is a promising approach for reducing problematic alcohol consumption.¹³Despite this, little is known about the risk of death, a key outcome for health system performance, among people who use emergency departments frequently for alcohol-related reasons, including whether mortality risk increases with increasing frequency of visits. To address this gap, our primary objective was to describe the sociodemographic and clinical characteristics of this high-risk population and examine their 1-year overall mortality, premature mortality and cause of death as a function of emergency department visit frequency in Ontario, the most populous Canadian province.¹⁵     

Estimating the probability of identity among genotypes in natural populations: cautions and guidelines

Individual identification using DNA fingerprinting methods is emerging as a critical tool in conservation genetics and molecular ecology. Statistical methods that estimate the probability of sampling identical genotypes using theoretical equations generally assume random associations between alleles within and among loci. These calculations are probably inaccurate for many animal and plant populations due to population substructure. We evaluated the accuracy of a probability of identity (P(ID)) estimation by comparing the observed and expected P(ID), using large nuclear DNA microsatellite data sets from three endangered species: the grey wolf (Canis lupus), the brown bear (Ursus arctos), and the Australian northern hairy-nosed wombat (Lasiorinyus krefftii). The theoretical estimates of P(ID) were consistently lower than the observed P(ID), and can differ by as much as three orders of magnitude. To help researchers and managers avoid potential problems associated with this bias, we introduce an equation for P(ID) between sibs. This equation provides an estimator that can be used as a conservative upper bound for the probability of observing identical multilocus genotypes between two individuals sampled from a population. We suggest computing the actual observed P(ID) when possible and give general guidelines for the number of codominant and dominant marker loci required to achieve a reasonably low P(ID) (e.g. 0.01-0.0001).     

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study

Objectives: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings.

Methods: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers.

Results: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock.

Conclusion: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.     

Serum levels of interleukin (IL)-27 in patients with ischemic heart disease

Objective

Cytokines, the key mediators of immune responses, play an important role in the pathogenesis of cardiovascular diseases. The aim of this study was to evaluate the serum levels of IL-27 in patients with ischemic heart disease (IHD) and also to clarify its association with traditional risk factors of the disease.

Methods

A total of 120 patients with IHD as having acute myocardial infarction (AMI; n = 60) or unstable angina (UA; n = 60) and 60 sex- and age-matched healthy subjects as a control group were enrolled in this cross-sectional, case-controlled study. Serum samples were collected from all participants (for AMI patients at 3–5 days after events and for UA at admission time) and tested for the levels of IL-27 by use of ELISA method.

Results

The mean serum levels of IL-27 in AMI group (38.00 ± 14.38 Pg/ml) and UA group (35.77 ± 18.93 Pg/ml) were significantly higher than those observed in the control group (24.91 ± 14.96 Pg/ml; P < 0.0001 and 0.001, respectively). The mean serum levels of IL-27 in IHD patients with or without a certain traditional risk factor including hypertension, dyslipidemia, diabetes smoking were significantly higher as compared to those in the control group.

Conclusions

These results showed that the higher serum levels of IL-27 were associated with IHD. The presence or absence of certain traditional risk factors of IHD did not influence the serum levels of cytokine.     

Towards a rational development of anti-endotoxin agents: novel approaches to sequestration of bacterial endotoxins with small molecules.

Endotoxins, or lipopolysaccharides (LPS), present on the surface of Gram-negative bacteria, play a key role in the pathogenesis of septic shock, a common clinical problem and a leading cause of mortality in critically ill patients, for which no specific therapeutic modalities are available at the present time. The toxic moiety of LPS is a glycolipid called 'lipid A', which is composed of a bisphosphorylated diglucosamine backbone bearing up to seven acyl chains in ester and amide linkages. Lipid A is structurally highly conserved in Gram-negative bacteria, and is therefore an attractive target for developing anti-endotoxin molecules designed to sequester, and thereby neutralize, the deleterious effects of endotoxins. The anionic and amphipathic nature of lipid A enables the interaction of a wide variety of cationic amphiphiles with the toxin. This review describes the systematic evaluation of several structural classes of cationic amphiphiles, both peptides and non-peptidic small molecules, in the broader context of recent efforts aimed at developing novel anti-endotoxin strategies. The derivation of a pharmacophore for LPS recognition has led to the identification of novel, nontoxic, structurally simple small molecules, the lipopolyamines. The lipopolyamines bind and neutralize LPS in in vitro experiments as well as in animal models of endotoxicity, and thus present novel and exciting leads for rational, structure-based development of LPS-sequestering agents of potential clinical value.     

Opposing roles of IL-10 in acute bacterial infection

Interleukin-10 (IL-10) is recognized as an anti-inflammatory cytokine that downmodulates inflammatory immune responses at multiple levels. In innate cells, production of this cytokine is usually triggered after pathogen recognition receptor (PRR) engagement by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patters (DAMPs), as well as by other soluble factors. Importantly, IL-10 is frequently secreted during acute bacterial infections and has been described to play a key role in infection resolution, although its effects can significantly vary depending on the infecting bacterium. While the production of IL-10 might favor host survival in some cases, it may also result harmful for the host in other circumstances, as it can prevent appropriate bacterial clearance. In this review we discuss the role of IL-10 in bacterial clearance and propose that this cytokine is required to recover from infection caused by extracellular or highly pro-inflammatory bacteria. Altogether, we propose that IL-10 drives excessive suppression of the immune response upon infection with intracellular bacteria or in non-inflammatory bacterial infections, which ultimately favors bacterial persistence and dissemination within the host. Thus, the nature of the bacterium causing infection is an important factor that needs to be taken into account when considering new immunotherapies that consist on the modulation of inflammation, such as IL-10. Indeed, induction of this cytokine may significantly improve the host’s immune response to certain bacteria when antibiotics are not completely effective.     

Characterization of a subclone (D10S) of the D10.G4.1 helper t-cell line which proliferates to attomolar concentrations of interleukin-1 in the absence of mitogens

Most studies have shown that interleukin-1 (IL-1) acts as a helper or co-stimulator in T-lymphocyte activation and proliferation by mitogens or antigens. We describe here a stable subclone (D10S) of the murine D10.G4.1 helper T-cell which proliferates to subfemtomolar (attomolar) concentrations of IL-1 beta or alpha in the absence of mitogens. D10S cells have been maintained in culture for over two years without splenic cell feeder layers nor antigen stimulation. Detection of proliferation can be made by either uptake of tritiated thymidine at 72 h or in 48 h by a colorimetric assay which measures mitochondrial dehydrogenases; the latter assay is rapid and inexpensive. D10S cells are distinct from the parent clone D10.G4., which requires mitogens for IL-1 activity. IL-1-induced proliferation is independent of the elaboration of IL-2, IL-4, or IL-6, although these cells proliferate to these lymphokines at considerably higher concentrations when compared to IL-1. The D10S cells proliferate in direct correlation to the duration of IL-1 presence in the culture. We found no evidence that IL-1 induced more IL-1 in these cells. The subclone is highly specific for IL-1: proliferation was not observed to endotoxin, human or murine interferon-gamma (IFN gamma), tumor necrosis factor (TNF), lymphotoxin, or granulocyte-macrophage colony stimulating factor (GM-CSF). There was no suppressive effect of transforming growth factor (TGF beta). Only at high concentrations (100 ng/ml) did IL-6 induce proliferation. We conclude that this stable, feeder layer-free cell line is highly sensitive to IL-1 which acts as a direct stimulant for these cells; they are also useful for bioassays as well as the study of IL-1 receptors as described in the accompanying paper.     

Characteristics of chest pain in COVID-19 patients in the emergency department

IntroductionPatients with coronavirus disease 2019 (COVID-19) can present with chest pain. However, the characteristics of this chest pain are unknown. We performed a single-centre observational study to review and summarise chest pain characteristics in COVID-19 patients at first presentation to the emergency department (ED).MethodsWe collected data on characteristics of ‘chest pain’ reported by COVID-19 patients who attended the ED of Bernhoven Hospital, the Netherlands from 4 through 30 March 2020.ResultsWe included 497 COVID-19 patients, of whom 83 (17%) reported chest pain upon presentation to the ED. Chest pain characteristics were: present since disease onset (88%), retrosternal location (43%), experienced as compressing/pressure pain (61%), no radiation (61%) and linked to heavy coughing (39%). Patients who reported chest pain were younger than those without chest pain (61 vs 73 years; p < 0.001). Patients with syncope were older (75 vs 72 years; p = 0.017), had a shorter duration of symptoms (5 vs 7 days; p < 0.001) and reported fewer respiratory complaints (68% vs 90%; p < 0.001) than those without syncope. Patients with new-onset atrial arrhythmias presented with a shorter duration of symptoms (5 vs 7 days; p = 0.013), experienced fewer respiratory complaints (72% vs 89%; p = 0.012) and more frequently had a history of cardiovascular disease (79% vs 50%; p = 0.003) than patients who presented without arrythmias.ConclusionChest pain and other cardiac symptoms were frequently observed in COVID-19 patients. Treating physicians should be aware that chest pain, arrhythmias and syncope can be presenting symptoms of COVID-19.Supplementary InformationThe online version of this article (10.1007/s12471-022-01730-7) contains supplementary material, which is available to authorized users.