OBJECTIVES: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct “high-risk” patients not captured by prior LCA classifications. DESIGN: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar’s test and then tested the correlation between IL-18 and LCA biomarkers using Pearson’s exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup. SETTING: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients. SUBJECTS: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17–0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8–6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2–3.8; p = 0.009). CONCLUSIONS: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts.
Introduction Liberal administration of supplemental oxygen (O 2 ) is ubiquitous across numerous healthcare settings. However, appropriate O 2 titration targets remain controversial and despite numerous large-scale randomised trials, there is an ongoing lack of consensus regarding optimal oxygenation strategies and the absence of high-quality mechanistic data pertaining to the potential proinflammatory effects of hyperoxia. Methods and analysis We hypothesise that (1) short-term exposure to hyperoxia will induce mild pulmonary inflammation and cellular injury and that (2) hyperoxia will accentuate pulmonary inflammation and cellular injury in the setting of inhaled lipopolysaccharide challenge. To test our hypotheses, we will conduct a randomised, double-blind, placebo-controlled study of hyperoxia administered via a high-flow nasal O 2 delivery system (fractional inspired oxygen 1.0, 60 L/min flow rate) compared with synthetic medical air. Blocked randomisation will be undertaken by an independent clinical trials statistician. Healthy non-smoking adult volunteers (<45 years of age), taking no regular medications will be recruited. Bronchoalveolar lavage (BAL) will be performed at 6 hours. The study outcome measures will include BAL markers of inflammation and injury (including but not limited to interleukin (IL)-8, IL-6, tumour necrosis factor alpha), BAL differential cell counts, BAL markers of oxidative stress (superoxide dismutase and glutathione), alveolar epithelial cell injury (SP-D, vWF, RAGE) and markers of systemic inflammation (neutrophils and plasma C-reactive protein). Ethics and dissemination Dissemination of the research findings will be achieved in the following ways: (1) Our findings will be presented at national and international meetings with open-access abstracts online and (2) in accordance with the open-access policies proposed by the leading research funding bodies we aim to publish the findings in high quality peer-reviewed open-access journals. Trial registration number NCT05414370 .
Mycobacterium avium infects human macrophages causing opportunistic infections. A steady increase of these infections over the past four decades and resistance to common anti-mycobacterial drugs, create an urgent need for new treatments; however, drug discovery is held back by a lack of knowledge about how M. avium replicates or persists in host cells. We implemented an image-based assay using a fluorescence dilution (FD) system to measure M. avium replication and persistence. M. avium strain 104 carrying a plasmid encoding GFP and TurboFP635 under constitutive and inducible promoters, respectively, is induced prior to infection of THP1 macrophages and the fluorescent signals are tracked over time in the absence of the inducer. Loss of the TurboFP635 signal while GFP signal is maintained, identifies replicating and retention of both signals non-replicating bacteria. In the absence of inducer, the M. avium 104 FD strain replicated in the macrophages, leading to increasing numbers of GFP-expressing intracellular bacteria and concomitant loss of TurboFP635 signal in >90% of the infected cells after 24 hours. Upon re-induction, these bacteria expressed TurboFP635, suggesting they are metabolically active and alive. We observed the presence of a small non replicating population that persisted over 96 hours pi. We applied our assay to compare the effect of a panel of anti-mycobacterial drugs, revealing different effects on killing, intracellular replication and induction of persisting, non-replicating bacteria, illustrating the power of this system to facilitate the dissection of the biology of persistence and anti-mycobacterial drug discovery in the future.
Introduction: Tuberculosis is on the rise globally. Northern Ireland is facing the enormous task to identify, diagnose and treat tuberculosis. Anti-tuberculosis treatment can be tedious and the side effects can hamper management and outcome.
Objectives: To note the prevalence among local and immigrant patients, ascertain the HIV status and concordance and tolerance of ant-tuberculosis drugs.
Methods: A retrospective clinical notes review, microbiology and biochemistry laboratory record analysis.
Results: In total 92 patients, half were originally from Northern Ireland [Table]; 61% male and 39% female. The mean age was 50 (± 21) years with a bimodal age distribution between immigrants (36±11 years) and local patients (66.5±15.5 years).
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Table 1
The majority (67%) had pulmonary and 20.5% had lymph node involvement. Rest had skin, bone, peritoneum, and psoas abscess disease. Culture positive were 76% and smear positive 45%. The majority (79%) were fully and 4% were partially sensitive to the treatment. One patient was multi-drug resistant. Four percent had HIV. The commonest side effect was minor GI upset (7%). Hepatitis and arthralgia occurred in 5.5%, minor skin reactions in 3%, and renal impairment, peripheral neuropathy, febrile reaction and retrobulbar neuritis in 2% each. Seven percent of patients received directly observed therapy.
Conclusion: Tuberculosis is increasingly prevalent among the local population. Only 4% were HIV positive. Good drug compliance was observed in two third of patients. Treatment was modified in 24%, no treatment was stopped.
Abstract Background: Both latent class analysis (LCA) assignment based upon a panel of plasma biomarkers and interleukin-18 (IL-18) plasma level have been shown to predict prognosis and treatment response in Acute Respiratory Distress Syndrome (ARDS). Interleukin-18 is a measure of inflammasome activation and plays a distinct role in inflammation that is not captured by the biomarkers used in LCA assignments. We hypothesized that elevated IL-18 would provide additive prognostic and therapeutic information to previously published LCA assignments in ARDS, identifying additional “high-risk” patients not captured by LCA who could be eligible for inclusion in future precision medicine-focused trials. Methods: IL-18 and a panel of protein markers used for LCA had been previously measured in plasma from 683/745 patients in the Statins for Acutely Injured Lungs from Sepsis (SAILS) and 511/540 patients in the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trials. We tested the association between high IL-18 ( > 800 pg/mL) and LCA class assignment using McNemar’s test and evaluated the association of each subgrouping as well as treatment with 60-day mortality using Fisher’s exact test. We assessed 60-day mortality in each combination (high/low IL-18, hypo-/hyper-inflammatory LCA class, and treatment/placebo) using Kaplan-Meier survival analysis. We evaluated the correlation between the log 2 transformed IL-18 level and LCA biomarkers using Pearson’s correlation coefficient. Results: 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. Elevated IL-18 identified a high-risk group of individuals previously classified as hypo-inflammatory by LCA in both SAILS (OR 3.3, 95% CI 1.8-6.1, p<0.001) and HARP-2 (OR 2.1, 95% CI 1.2-3.8, p = 0.009). IL-18 was only moderately correlated with LCA biomarkers with r of 0.17-0.47. Conclusions: High Plasma IL-18 level provides additional prognostic information to LCA sub-phenotypes in two large ARDS cohorts.
Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments.
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