Evidence Of Systemic Inflammation Research Articles

Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma

Peripheral blood transcriptomes from 383 newly-diagnosed melanoma patients were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor infiltrating lymphocytes (TILs)) and evidence of systemic inflammation (high-sensitivity C-reactive protein (hsCRP) and fibrinogen levels). Higher fibrinogen levels were associated with thicker primaries. In single gene analysis hsCRP levels were significantly associated with higher blood CD274 expression, (coding for PD-L1), but each was independently prognostic, with hsCRP associated with increased mortality, and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signalling pathways in the blood of people with thicker tumors and notable upregulation of STAT1 in people with brisk TILs. Transcriptomic data provided evidence for increased NFB signalling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274 suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer TILs, at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma suggesting that systemic inflammation contributes to that reduced immune function.

Fetal and neonatal alloimmune thrombocytopenia: No evidence of systemic inflammation as a modulator of disease severity. Couldplacental inflammation be key?

In fetal/neonatal alloimmune thrombocytopenia (FNAIT), maternal alloantibodies against paternal human platelet antigens (HPA) cross the placenta and lead to platelet destruction. The extent of thrombocytopenia varies among neonates, and inflammation may constitute an important trigger. A set of stable inflammatory markers was measured in serum samples from neonates with low platelet counts, of which n = 50 were diagnosed with FNAIT due to anti-HPA-1a antibodies and n = 50 were thrombocytopenic without detectable maternal HPA antibodies. Concentrations of C-reactive protein, soluble CD14, procalcitonin, and sFlt-1 did not differ between the two cohorts. There was no correlation between C-reactive protein or soluble CD14 and the platelet count, but a negative correlation between procalcitonin concentrations and the neonatal platelet count in both cohorts. sFlt-1 concentration and the platelet count were correlated in FNAIT cases exclusively. None of the inflammatory markers was statistically different between cases with and without intracranial haemorrhage. We were unable to identify systemic inflammation as a relevant factor for thrombocytopenia in FNAIT. The antiangiogenic enzyme sFlt-1, released by the placenta, did correlate with the platelet count in FNAIT cases. Our findings may give rise to the hypothesis that placental inflammation rather than systemic inflammation modulates disease severity in FNAIT.

86 Biomarkers of Inflammation in Neonatal Calves Supplemented with Condensed Solubles from Milk Permeate

Abstract Neonatal and weaning periods are the most challenging phases for enteric infections in dairy calves. While different approaches are used to minimize calf health issues, the neonatal diet remains the core approach to enhance pre- and post-weaning animal health and performance. Previous studies have shown that bioactive compounds, including oligosaccharides present in the diet of neonatal dairy calves, enhanced their growth performance post-weaning. However, the effects of oligosaccharides supplementation during the neonatal period and the impact on the health status of the calf remain to be elucidated. Thus, we aimed to evaluate blood biomarkers of inflammation in calves supplemented with condensed solubles from milk permeate (CS) during the neonatal period (from birth to 21 d) of dairy calves. Twenty-four newborn Holstein calves (n = 12/group) housed in individual hutches were used in a randomized complete block design study. Calves were blocked by birth date and sex. At 2-days old, calves were randomly assigned into two groups (n = 6 females and 6 males per group): control with no supplement; or treatment with 50 g/d of CS. Both treatment and control groups were fed pasteurized waste milk during the preweaning period. Calves were fed 2.83 L of pasteurized waste milk 2×/d during week 1 to 5, 1×/d in week 6, and weaned at week 7. At each milk feeding during week 1 to 5, 25 g of CS was added to the pasteurized waste milk for each calf on the CS treatment. Healthy scores were recorded daily. Calf growth measurements and blood samples were collected weekly. Data were analyzed using MIXED procedures of SAS 9.4 with repeated measures. Significant differences were declared at P < 0.05. Overall, body weight, fecal and respiratory scores were similar between groups during the preweaning period. During the first 3 weeks of age, a group×sex×time interaction was observed for the enzyme myeloperoxidase (MPO) expressed by neutrophils. Female calves on the CS treatment had decreased MPO concentrations in the blood relative to the female controls at week 3. Other biomarkers of inflammation (i.e., haptoglobin) or consequent liver response (i.e., albumin, paraoxonase) did not differ between groups. Based on these parameters, there was no evidence of systemic inflammation during the first 21 days of age. However, circulating MPO is an indicative of phagocytosis by neutrophils resulting in a local or systemic inflammatory responses. The decreased MPO in CS female calves can be associated with a lesser microbial infiltration in the gut. The latter suggests that oligosaccharides from the diet stimulate the growth of commensal microbiota on the host, which serve as decoy receptors to pathogenic microorganisms (i.e., blocking microbial infiltration). Overall, these findings suggest that bioactive molecules as feed supplements such as CS can help the local immune response in neonatal dairy calves.

Abstract CT180: Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007

Abstract Background. PRTX007 is an orally administered prodrug of PRX034, a toll-like receptor 7 (TLR7) agonist that elicits an unprecedented pattern of systemic immune induction in non-human primates and in humans. Notably, there is no evidence of NF-Kβ-mediated systemic inflammation at drug levels that stimulate IFN-responsive pathways and corresponding downstream cellular processes, including activation of CD8+ T cells and NK cells. We have previously reported interim results from a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study of PRTX007. PRTX007 demonstrated a favorable safety profile with no serious adverse events (SAEs) and a lack of the adverse events (AEs) historically associated with TLR7 agonists. Robust systemic immune induction was achieved, without counter-regulation or evidence of systemic inflammation, in participants receiving PRTX007 in the 300 - 500 mg MAD cohorts. This report describes new results from the 750 mg MAD cohort, the highest MAD dose level in this now-completed study. Methods. Phase 1, single-center, prospective, randomized, double-blind, placebo-controlled study of 9 SAD and 4 MAD cohorts of PRTX007 administered QOD orally to healthy adult participants. Primary objectives were safety and tolerability. Secondary objectives were evaluation of pharmacokinetics (PK) and pharmacodynamics. In total, 104 of the 130 participants in this study received study drug. Results. AEs were limited to non-dose-related mild headache, minor dose-related increases in ALT (<2X ULN) that rapidly resolved, and mild-moderate fever that were transiently observed in 1 of 8 participants. The PKs of PRTX007 and PRX034 are well-behaved with exposure increasing proportionally to PRTX007 dose without accumulation upon repeated dosing (mean PRX034 AUC (hr*ng/ml) on D1: 13,432; D13: 13,796). Coordinated expression of interferon-stimulated genes and genes known to be related to TLR7 agonism were observed in immune cells in blood in all participants. Increases in IL-1RA, MCP-1 and IP10 in plasma were also observed. IL-6, TNFα and IL- 1β remained essentially unchanged from pretreatment levels. The proportion of CD8+ T cells and NK cells, with significant expression of the proliferation marker Ki67 and activation marker CD38, increased markedly from pretreatment to end of dosing in all participants. Ki67+ expressing CD8+ T cells increased from 1.1% to 9.8% and Ki67+ expressing NK cells increased from 3.6% to 10.3% during the two-week period of drug administration. CD38+ CD8+ T cells increased from 11.8% to 21.9% and CD38+ NK cells increased from 59.4% to 80.0% during the corresponding period. Conclusion. PRTX007 demonstrated a favorable safety profile in all SAD and MAD cohorts. In the 750 mg MAD cohort, activation of the innate and adaptive immune response including important effector cell populations were observed without systemic increases in proinflammatory factors. Citation Format: Charlotte R. Lemech, Christopher Argent, Curtis L. Scribner, Andrew Sharabi, Richard Daniels, James R. Appleman. Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT180.

Proteomic characterization of atopic dermatitis blood from infancy to adulthood

Patients with atopic dermatitis (AD) have systemic biomarker dysregulation that differs by age group; however, the proteomic characteristics of these age-based changes are unknown. To profile blood proteins of patients with AD across different age groups versus age-appropriate controls. Using the Olinkhigh-throughput proteomic platform, we profiled 375 serum proteins of 20 infants (age, 0-5years), 39 children (age, 6-11years), 21 adolescents (age, 12-17years), and 20 adults (age, ≥18years) with moderate-to-severe AD and 83 age-appropriate controls. Each group presented a distinct systemic proteomic signature. Th2-related proteins were increased in infant AD and further intensified with age through adolescence and adulthood (interleukin 4/CCL13/CCL17). In contrast, Th1 axis down-regulation was detected in infants with AD and gradually reversed to increased Th1 products (interferon γ/CXCL9/CXCL10/CCL2) in patients with AD from childhood to adulthood. Despite their short disease duration, infants already had evidence of systemic inflammation, with significant upregulation of innate immunity (interleukin 17C/ interleukin-1RN), T-cell activation/migration (CCL19), Th2 (CCL13/CCL17), and Th17 (PI3) proteins. Adults with AD present unique upregulation of cardiovascular proteins related to coagulation and diabetes. Cross-sectional observational study with a single time point. Systemic immune signatures of AD are age-specific beyond the shared Th2 immune activation. These data advocate for precision medicine approaches based on age-specific AD profiles.

The tendency of anemia of inflammation in periodontal diseases.

Anemia of inflammation (AI) is associated with inflammatory diseases, and inflammation-induced iron metabolism disorder is the major pathogenic factor. Earlier studies have reported a tendency of AI in periodontitis patients, but the explicit relationship and possible pathological mechanisms remain unclear. Here, the analyses of both periodontitis patients and a mouse model of ligature-induced experimental periodontitis showed that periodontitis was associated with lower levels of hemoglobin and hematocrit with evidence of systemic inflammation (increased white blood cell levels) and evidence of iron restriction (low serum iron along with a high serum hepcidin and ferritin levels), in accordance with the current diagnosis criteria for AI. Moreover, periodontal therapy improved the anemia status and iron metabolism disorders. Furthermore, the increased level of hepcidin and significant correlation between hepcidin and key indicators of iron metabolism emphasized the pivotal role of hepcidin in the pathogenesis of periodontitis-related AI. Administration of the signal transducer and activator of transcription 3 (STAT3) inhibitors Stattic suggested that the IL-6-STAT3-hepcidin signaling pathway participated in this regulatory process. Together, these findings demonstrated that periodontitis should be considered an inflammatory disease that contributes to the development of AI; furthermore, IL-6-STAT3-hepcidin signaling pathway plays a key regulatory role in the pathogenesis of periodontitis-related AI. Our study will provide new insights into the systemic effects of periodontitis, while meaningfully expanding the spectrum of inflammatory diseases that contribute to AI.

Design and rationale for the SIB trial: a randomized parallel comparison of semaglutide versus placebo on intestinal barrier function in type 2 diabetes mellitus

Objective: To describe the rationale and design of the SIB trial, an interventional clinical trial testing the hypothesis that subcutaneous (s.c.) once-weekly semaglutide can improve intestinal permeability and reduce systemic inflammation in participants with type 2 diabetes (T2D) and obesity. Methods: SIB (NCT04979130) is an investigator-initiated, single-center randomized, double-blinded, placebo-controlled clinical study being conducted at the University of Colorado Anschutz Medical Campus. The primary objective of this novel trial is to test the hypothesis that subcutaneous (s.c.) once-weekly semaglutide could improve intestinal permeability and reduce systemic inflammation in participants with T2D and obesity. Eligible participants had a diagnosis of type 2 diabetes, elevated body mass index, and evidence of systemic inflammation. Participants were randomized 1:1 to s.c. semaglutide or placebo. Participants were assessed for intestinal permeability and markers of inflammation at baseline, mid-study, and at the end of the study. Efficacy assessments were based on the analysis of the following: lactulose:mannitol ratio test, serum lipopolysaccharide-binding protein (LBP), fecal calprotectin, inflammatory biomarkers (IL-6, TNF, IL-1, IL-8, hs-CRP), and HbA1c. All participants who enrolled in the trial provided written informed consent after having received written and oral information on the trial. The risks of semaglutide use were minimized by administration according to FDA-labeled use and close monitoring for adverse events. Discussion: SIB is the first study to examine the effects of GLP-1 receptor agonists on intestinal permeability in humans and will provide important data on their impact on systemic inflammation and intestinal permeability in the setting of T2D and obesity.

Molecular and Cellular Markers in Chlorhexidine-Induced Peritoneal Fibrosis in Mice.

Understanding the tissue changes and molecular mechanisms of preclinical models is essential for creating an optimal experimental design for credible translation into clinics. In our study, a chlorhexidine (CHX)-induced mouse model of peritoneal fibrosis was used to analyze histological and molecular/cellular alterations induced by 1 and 3 weeks of intraperitoneal CHX application. CHX treatment for 1 week already caused injury, degradation, and loss of mesothelial cells, resulting in local inflammation, with the most severe structural changes occurring in the peritoneum around the ventral parts of the abdominal wall. The local inflammatory response in the abdominal wall showed no prominent differences between 1 and 3 weeks. We observed an increase in polymorphonuclear cells in the blood but no evidence of systemic inflammation as measured by serum levels of serum amyloid A and interleukin-6. CHX-induced fibrosis in the abdominal wall was more pronounced after 3 weeks, but the gene expression of fibrotic markers did not change over time. Complement system molecules were strongly expressed in the abdominal wall of CHX-treated mice. To conclude, both histological and molecular changes were already present in week 1, allowing examination at the onset of fibrosis. This is crucial information for refining further experiments and limiting the amount of unnecessary animal suffering.

The effect of trehalose administration on miRNA-10a expression in patients with history of myocardial infarction (MI) and systemic inflammation

Abstract Background MicroRNAs (miRNAs) are small non-coding RNAs involved in the regulation of endothelial function, inflammatory cells, and cholesterol homeostasis, may cause the onset of vascular inflammation which plays an important role in the development of cardiovascular disease. Trehalose is a nonreducing disaccharide which anti-inflammatory properties have been indicated in different experimental models. Purpose This study aimed to evaluate the effectiveness of intravenous (IV) trehalose administration on the circulating level of miRNA-10a as a biomarker of coronary inflammation in patients with history of myocardial infarction (MI) and elevated C-reactive protein (CRP). Methods This was a randomized, double-blind trial comprised 15 men (aged 18–80) with history of MI and evidence of systemic inflammation. The patients were randomly allocated to 2:1 ratio and respectively underwent the injection of either IV trehalose (15 g/week) or placebo for 12 weeks. At baseline and at the end of study, the serum level of miRNA-10a was measured by SYBR Green qPCR, quantified by the comparative method, and normalized to U6 expression. Relative expression software tool (REST) was used to analyze the miRNA-10a fold change (FC) expression level. Results At the baseline, patients in trehalose group showed slightly lower level of miRNA-10a relative to the placebo group (FC: 0.272, P=0.052), while it was not statistically significant. Within-group analysis showed that miRNA-10a had a significantly lower level in placebo group at the end of the study in comparison with the baseline (FC; 0.19, P=0.029). Albeit, miRNA-10a level increased after trehalose administration in relation to the baseline, while it was not statistically significant (FC: 1.963, P=0.114), Moreover, these changes in miRNA-10a levels were statistically significant in trehalose group related to the placebo group (P=0.047). Conclusions Together these findings demonstrate that trehalose administration could effectively increase the circulating level of miRNA-10a and may contribute to the regulation of coronary inflammation in patients with a history of MI and elevated CRP levels. This anti-inflammatory effect of trehalose can be confirmed in the large-scale studies or by evaluating other miRNAs related to the vascular inflammatory processes. Funding Acknowledgement Type of funding sources: None.

To Start Comprehensive Health Care System with Combination of Traditional, Herbal, Allopathy, Complementary Medicine and Integrative Medicines in Primary Health Care.

We are reporting an unusual case of a 26-year-old immunocompetent patient of miliary tuberculosis of cerebellum with meningitis and lung involvement, presenting with ataxia without any evidence of systemic inflammation. Since, prognosis depends on correct diagnosis and timely treatment, recognition and prompt diagnosis are important for overall outcome.

Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

Isolated Miliary Tuberculosis of Brain in an Immuno-Competent Patient, Presenting as Cerebellar Ataxia

We are reporting an unusual case of a 26-year-old immunocompetent patient of miliary tuberculosis of cerebellum with meningitis and lung involvement, presenting with ataxia without any evidence of systemic inflammation. Since, prognosis depends on correct diagnosis and timely treatment, recognition and prompt diagnosis are important for overall outcome.

The effect of trehalose administration on vascular inflammation in patients with coronary artery disease

BackgroundIn recent years, several trials investigated the role of anti-inflammatory agents in reducing cardiovascular events. Trehalose is a natural disaccharide able to reduce inflammation by enhancing macrophage autophagic activity. This action has been demonstrated to attenuate atherosclerotic plaque development in various pro-atherogenic animal models. However, at present, no data about the efficacy of this compound in human subjects have been published. MethodsWe performed a randomized, double-blind trial involving 15 patients with history of myocardial infarction and evidence of systemic inflammation (defined as C-reactive protein > 2 mg/L). The patients were randomly assigned, in 2:1 ratio, to receive either intravenous trehalose (15 g once weekly) or placebo for 12 weeks. The primary efficacy end-point was the change in arterial wall inflammation, assessed by quantifying 18F-FDG PET/CT uptake in carotid arteries and ascending aorta. ResultsThe MDS TBR change of the index vessel at 3-month follow-up was not significant in treatment and placebo groups. Furthermore, we could not demonstrate any significant difference between the trehalose group and control group in changes of cIMT from baseline to 3 months in the overall population. No significant changes in echocardiographic measurement were noted after trehalose treatment. Except for the change in urea level in placebo group (31.00 ± 6.59 vs. 25.60 ± 6.402 P = 0.038) no other changes were detected after treatment. Also, there was a significant difference between changes in alanine aminotransferase (ALT) trehalose and placebo groups. ConclusionThis was the first study that specifically assessed the effects of intravenous trehalose on atherogenesis in human subjects. Trehalose treatment was characterized by an optimal safety profile, but no significant reduction in arterial wall inflammation could be observed. This might be a consequence of the small sample size of this trial. Larger studies are needed to better assess the efficacy of this compound in this clinical context.

Does the modified Glasgow Prognostic Score aid in the management of patients undergoing surgery for a soft-tissue sarcoma? : an international multicentre study.

The modified Glasgow Prognostic Score (mGPS) uses preoperative CRP and albumin to calculate a score from 0 to 2 (2 being associated with poor outcomes). mGPS is validated in multiple carcinomas. To date, its use in soft-tissue sarcoma (STS) is limited, with only small cohorts reporting that increased mGPS scores correlates with decreased survival in STS patients. This retrospective multicentre cohort study identified 493 STS patients using clinical databases from six collaborating hospitals in three countries. Centres performed a retrospective data collection for patient demographics, preoperative blood results (CRP and albumin levels and neutrophil, leucocyte, and platelets counts), and oncological outcomes (disease-free survival, local, or metastatic recurrence) with a minimum of two years' follow-up. We found that increased mGPS, tumour size, grade, neutrophil/lymphocyte ratio, and disease recurrence were associated with reduced survival. Importantly, mGPS was the best at stratifying prognosis and could be used in conjunction with tumour grade to sub-stratify patient survival. This study demonstrated that prognosis of localized STS strongly correlates with mGPS, as an increasing score is associated with a poorer outcome. We note that 203 patients (41%) with an STS have evidence of systemic inflammation. We recommend the mGPS and other biochemical blood indicators be introduced into the routine diagnostic assessment in STS patients to stratify patient prognosis. Its use will support clinical decision-making, especially when morbid treatment options such as amputation are being considered. Cite this article: Bone Joint J2022;104-B(1):168-176.

Clinical Trials in Pericardial Disease: New Paradigm Shift.

Aim of the review is to discuss the results of major clinical trials and how they can have impact on clinical practice. Pericardial diseases have been the Cinderella of cardiovascular diseases for many years, but improvements in the knowledge of etiology and the pathophysiology especially of recurrent pericarditis have led to first clinical trials that have demonstrated the efficacy and safety of colchicine on top of standard anti-inflammatory therapies and of anti-IL-1 agents (anakinra and rilonacept) in corticosteroid-dependent and colchicine-resistant pericarditis. Current pooled data suggest that anti-IL-1 agents should be a first option for corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation by means of elevated C-reactive protein. This could translate into an upgraded recommendation for these agents in future guidelines. Treatment of pericardial diseases is improving moving towards a more personalized therapy according to the presentation and etiology, and new or old drugs could be important to expand the therapeutic spectrum.

S2058 Three Rare Cases of Neuroendocrine Carcinoma of the Esophagus in a Rural Community

Introduction: The frequency of cannabis use has increased in the USA in the last few years. The prevalence of cannabis induced hyperemesis has also increased during this time. We present a case of presumed esophageal perforation in a patient with cannabis hyperemesis syndrome. Case Description/Methods: A 26 year old female with daily inhaled cannabis use presents with nausea, vomiting and epigastric pain for 3 weeks. She denies chest pain or fever. She has been told in the past that she has Cannabis Hyperemesis Syndrome. Typically, her bouts last for one week and her symptoms improve with hot showers. On initial physical exam she was in moderate distress and tachycardic with tenderness over the epigastrium. Her WBC count was elevated at 18.53. She was also COVID-19 positive. CT of the abdomen performed in the ED noted free air surrounding the distal esophagus consistent with pneumomediastinum concerning for esophageal rupture. She was managed conservatively with close monitoring for a presumed esophageal perforation with spontaneous closure. She was made NPO and started on IV antibiotics. Over the next 48 hours, she developed crepitus in her neck and chest wall. Repeat imaging confirmed progression of pneumomediastinum. 48 hours later, she underwent a water-soluble esophagram negative for perforation and her diet was advanced. She was counseled on cannabis cessation and provided community resources for rehabilitation and discharged. Discussion: Cannabis Hyperemesis Syndrome is a functional disorder marked by episodes of nausea and vomiting provoked by cannabis use. It is considered to be a variant of cyclical vomiting syndrome. These episodes of retching and vomiting can lead to complications including Mallory-Weiss tears and in rare cases esophageal rupture. The treatment for cannabis hyperemesis syndrome includes volume resuscitation, anti-emetics and cannabis cessation. Esophageal perforations often present a diagnostic challenge due to the variability in presentation. This patient was fortunate to present early. She remained clinically stable without evidence of systemic inflammation or pleural or peritoneal collections and therefore was able to be managed conservatively. With increasing legalization and popularity of cannabis use, it is important to recognize the potentially devastating complications of chronic marijuana use resulting in cannabinoid hyperemesis syndrome. Although esophageal perforation is rare, it has the potential for great morbidity.

Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.

Limited utility of the HScore in detecting secondary haemophagocytic lymphohistiocytosis in COVID‐19

Limited utility of the HScore in detecting secondary haemophagocytic lymphohistiocytosis in COVID‐19

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

SummaryBackgroundIn this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation.MethodsThis randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).FindingsBetween April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001).InterpretationIn hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Presentation of SARS-CoV-2 in a Pediatric Heart Transplant Recipient with Multiple Underlying Comorbidities

A six-year-old heart transplant recipient with additional significant co-morbidities, including severe hypoxic-ischemic injury, gastrostomy, tracheostomy, and mechanical ventilation dependency, encountered SARS-CoV-2 infection. The patient received tacrolimus and mycophenolate to prevent graft rejection, presented initially with SARS-CoV-2 positive and presumed pseudomonas aeruginosa pneumonia. Twenty-three days later, the patient presented with fever recurrence with evidence for systemic inflammation, which resolved rapidly with high-dose methylprednisolone. Interestingly, while IgM to SARS-CoV-2 was present, IgG was not detected even three months after his first positive test for SARS-CoV-2. The author discusses potential immune mechanisms that might have affected the course of multi-system inflammatory syndrome children (MIS-C) in this patient.