Corticosteroid Response Research Articles

Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells.

The mechanisms underlying corticosteroid insensitivity in severe asthma have not been elucidated although some indirect clinical evidence points toward a role of mast cells. Here, we tested the hypothesis that mast cells can drive corticosteroid insensitivity in airway smooth muscle cells, a key player in asthma pathogenesis. Conditioned media from resting or FcεR1-activated human lung mast cells were incubated with serum-deprived ASM cells (1:4 dilution, 24 h) to determine their impact on the anti-inflammatory action of fluticasone on ASM cell chemokine expression induced by TNFα (10 ng/ml). Conditioned media from FcεR1-activated mast cells (but not that from non-activated mast cells or control media) significantly reduced the ability of 100 nM fluticasone to suppress ASM TNFα-dependent CCL5 and CXCL10 production at both mRNA and protein levels. In contrast, fluticasone inhibition of CXCL-8 production by TNFα was still preserved in the presence of activated mast cell conditioned media. Transcriptomic analysis validated by individual qPCR assays revealed that activated mast cell conditioned media dramatically reduced the number of anti-inflammatory genes induced by fluticasone in ASM cells. Our study demonstrates for the first time that conditioned media from FcεR1-activated mast cells blunt the anti-inflammatory action of corticosteroids in ASM cells by altering their transactivation properties. Because infiltration of mast cells within the ASM bundles is a defining feature of asthma, mast cell-derived mediators may contribute to the glucocorticoid insensitivity present in severe asthma.

Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene

Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. Variants with P values less than 10-4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor- and (2) RNA polymerase II-binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. Four variants had significant (q value< 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2≥ 0.8) near glucocorticoid receptor-binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P< .05) with ICS response in 3 independent studies and others with asthma in 1 study. BIRC3 should be prioritized for further functional studies of ICS response.

Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells.

The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy. We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients. We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells. Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN. In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.

Corticosteroid-induced intraocular pressure elevation in the pediatric patients: A protocol for systematic review.

Background:Corticosteroids have been one of the most frequently used therapeutics in ophthalmology over the past decades, known for their potent anti-inflammatory and immunosuppressive actions. Intraocular pressure elevation has proven to be a significant ocular side effect that could accompany steroid use. However, the information on ocular-hypertensive corticosteroid response is scant in children. We aim to systematically describe the corticosteroid-induced intraocular pressure elevation in the pediatric age group.Methods:PubMed, Embase, Web of Science, Cochrane Library, Latin American and Caribbean Health Sciences Literature, and the Chinese Biomedical Literature database will be searched for potential articles from database inception to April 29, 2021. No language restrictions will be applied. Studies involving patients less than 18 years old receiving corticosteroids will be included. We will screen abstracts for relevance, extract data, and assess the risk of bias in duplicate. We will rate the certainty of evidence using the Grading of Recommendations Assessment Development and Evaluation approach. The primary outcome will be the intraocular pressure in pediatric patients group. We will provide a narrative synthesis of the findings.Results:The systematic review will provide high-quality evidence to assess the relationship between dosage, frequency, route of administration, and duration of corticosteroid on intraocular pressure in children.Conclusion:The systematic review will provide evidence to assess the safety of corticosteroid for ocular diseases in pediatric population.PROSPERO registration number:CRD42021252298.

Case Series of Steroid-Resistant Immune Checkpoint Inhibitor Associated Myocarditis: A Comparative Analysis of Corticosteroid and Tofacitinib Treatment.

Background: Immune checkpoint inhibitor (ICI)–associated myocarditis is an uncommon and potentially fatal immune-related adverse event (irAE). Although corticosteroids are recommended as the first-line treatment by current guidelines, patients still have variable responses to it, and the guidelines vary significantly in terms of treatment strategies. Objectives: In this study, we performed a retrospective analysis of ICI-associated myocarditis in our hospital to propose a new comparative analysis to aid individualized treatment. Methods: We reviewed detailed records of 24 patients with confirmed ICI-associated myocarditis in our hospital from July 1, 2019, to April 1, 2021. Although all the cases in our study received recommended initial corticosteroid treatment according to the guidelines, different responses to corticosteroid were observed during the process of subsequent corticosteroid tapering. Basing on troponin cardiac troponin T rebound during corticosteroid tapering, we propose a new classification analysis of ICI-associated myocarditis that included two subgroups: corticosteroid-sensitive (n = 8) and corticosteroid-resistant group (n = 16). Results: Compared with corticosteroid-sensitive patients, larger doses of corticosteroid, longer period of treatment, and higher mortality rate were found in corticosteroid-resistant patients. Corticosteroid-resistant patients were characterized by more prominent ptosis, muscle weakness, elevated cardiac biomarkers, creatine kinase, and hepatic enzymes levels than that in the corticosteroid-sensitive patients. Tofacitinib (5 mg twice a day) was used in 11 corticosteroid-resistant patients, with seven patients recovered from ICI-associated myocarditis, showing a promising therapeutic effect. Conclusion: Our group analysis of corticosteroid responsiveness in patients with ICI-associated myocarditis may help clinicians to apply individualized treatment in this high-risk cohort. In addition, tofacitinib could provide clinical benefits when used early in the corticosteroid-resistant patients and may provide a new option for the treatment of ICI-associated myocarditis.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma

Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. National Institutes of Health, National Heart, Lung, and Blood Institute.

Machine-Learning Model for Resistance/Relapse Prediction in Immune Thrombocytopenia Using Gut Microbiota and Function Signatures

IntroductionGrowing evidence has implicated gut microbiota in the pathogenesis of immune thrombocytopenia (ITP). In a previous research study, we found dysbiosis in the phylogenetic composition and function of gut microbiome in ITP and that corticosteroid treatment may have a strong effect on gut microbiota [Sci China Life Sci, 2020]. Corticosteroids have been widely used in the initial treatment of newly diagnosed ITP patients, but most adult patients relapse upon cessation of steroid treatment. Patients on agents in subsequent therapy may improve at any time, but which patients improve and when is unpredictable. The gut microbiome has been increasingly used in the assessment and prediction of immunomodulatory therapy in autoimmune diseases and cellular immunotherapy in cancers. Here, we provide evidence that gut microbiota and function signatures can be used to predict immune thrombocytopenia patients at high risk of relapse/resistance after corticosteroid treatment and to identify patients that are more likely to benefit from TPO-RAs in subsequent therapy.MethodsSeventy-five fecal samples from 60 patients with newly diagnosed ITP (60 specimens before corticosteroid therapy and 15 specimens after corticosteroid therapy) and 41 samples from persistent/chronic ITP before and after treatment with TPO-RAs, including eltrombopag and avatrombopag were collected for deep shotgun metagenomic sequencing. To identify the microbial biomarkers related to relapse/resistance after corticosteroid treatment, we constructed a random forest classifier using machine learning to determine the risk of relapse/resistance of a training cohort of 30 patients from baseline samples and validated the classifier for 30 patients. Patients with persistent/chronic ITP were divided into responders and nonresponders according to their response to TPO-RA treatment in subsequent therapy. After identifying the microbial species and functional biomarkers related to the response to TPO-RA therapy, a random forest classifier was constructed using a training set of 20 patients and validated using a validation set of 21 patients.ResultsWe used a metagenomic sequencing technique to investigate the differences among gut microbiota associated with relapse within 3 months of corticosteroid treatment. We observed that the diversity and composition of the microbial community in ITP patients after corticosteroid therapy (Post-C) changed significantly from the baseline (Pre-C), whereas the gut microbiota of the remission group was similar to that of the HC group, which implies that a shift in the gut microbiome could represent a return to homeostasis. To identify the microbial biomarkers related to early relapse after corticosteroid treatment, the Pre-C samples were divided into a remission group and a resistant/relapse group according to the response to corticosteroid therapy within 3 months. Nine significant associations with the microbial species and function were identified between the remission and resistant/relapse groups. A risk index built from this panel of microbes and functional pathways was used to differentiate remission from resistant/relapsed patients based on the baseline characteristics. The receiver operating characteristic (ROC) curve demonstrated that the risk index was a strong predictor of treatment response, with an area under the curve (AUC) of 0.87.Furthermore, to predict the response to TPO-RAs in subsequent therapy, the baseline gut microbiomes of responders and nonresponders before TPO-RA treatment were compared. Patients who responded to treatment exhibited an increase in Ruminococcaceae, Clostridiaceae and Bacteroides compared to nonresponders, with elevated abundance of the phosphotransferase system, tyrosine metabolism and secondary bile acid biosynthesis pathways according to KEGG analysis. Our prediction model based on the gut microbiome for TPO-RA response was robust across the cohorts and showed 89.5% and 79.2% prediction accuracy for persistent/chronic ITP patients in the training and validation sets, respectively.ConclusionsThe gut microbiome and function signatures based on machine learning analysis are novel potential biomarkers for predicting resistance/relapse after corticosteroid treatment and response to TPO-RAs, which may have important manifestations in the clinical. DisclosuresNo relevant conflicts of interest to declare.

Pharmaco-Metabolomics of Inhaled Corticosteroid Response in Individuals with Asthma.

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value < 6.2 × 10−4). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value < 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability.

Pathophysiological and Clinical Aspects of Chronic Rhinosinusitis: Current Concepts.

Adult chronic rhinosinusitis (CRS) is a chronic inflammation of the mucosa of the nose and paranasal sinuses. According to the latest EPOS guidelines CRS should be regarded as primary or secondary with distinction between diffuse and localized disease. Further pathophysiologic research identified different inflammatory patterns leading to the term “endotyping of CRS.” The primary focus of endotyping is to define a dominant inflammatory type allowing for better orientation of therapy. The current approach proposes the differentiation between type 2 (eosinophilic) and non-type 2 inflammatory responses. In this review pathophysiological concepts of CRS will be discussed, focusing on the different inflammatory endotypes of T cells with special attention to the eosinophilic type 2 inflammatory response. The contribution of innate and adaptive immune system responses is presented. The possibility of endotyping based on sinonasal secretions sampling is brought to attention because it is indicative of corticosteroid responsiveness and available to most ENT surgeons. Furthermore, the clinical aspects of the three distinct phenotypes are analyzed in view of their characteristics, the related endoscopic findings, typical radiological imaging, histopathology findings, their relation toward allergy and obvious therapeutical implications. This overview will enable clinicians to relate pathophysiological patterns with clinical observations by explaining the different inflammatory mechanisms, hence providing a better understanding of therapy.

LIMITED INTRAVENOUS ACCESS: ROLE OF IM VASOPRESSIN IN VASODILATORY SHOCK

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Introduction:Vasopressin is an antidiuretic hormone analog that has become an important drug in the treatment of vasodilatory shock through its vasoconstrictive and water retention properties to maintain blood pressure. We present two cases of vasodilatory shock where intravenous access was limited and intramuscular (IM) vasopressin was used for management. CASE PRESENTATION: Patient 1: An 85 year old female with a medical history of hypertension and colon cancer presented with septic shock. She received dopamine via midline on the upper left arm to maintain blood pressure, with the patient's healthcare proxy refusing a central line. Multiple attempts to obtain venous access for a blood transfusion were unsuccessful. The dopamine drip could not be held due to severe hypotension. The decision was made to administer IM vasopressin (10 Units) to maintain blood pressure while stopping dopamine during the blood transfusion. The transfusion was completed over two hours and the blood pressure improved from 76/39 - 123/63. Patient 2: A 63 year old male with a medical history of smoking and peripheral vascular disease was admitted for tachycardia and hypoxia. He had necrotizing pneumonia and was in septic shock. He continued to be volume unresponsive despite intravenous fluid resuscitation. He was placed on a dopamine drip to maintain blood pressure and became tachycardic and remained in shock. Bedside ultrasound showed signs of volume overload. Twenty units of intramuscular vasopressin was given and blood pressure improved within 15 minutes and was maintained between 120/76-105/69 for 1.5 hours. DISCUSSION: Very frequently we encounter difficulties obtaining intravenous access while resuscitating a patient. Such situations pose an immense challenge in managing shock. Vasopressin is unique in its ability to be utilized intramuscularly.[1] Utilizing medications intramuscularly for urgent situations has a significant impact on management when there is limited, or lack of, intravenous access for hemodynamically unstable patients. The onset of action for vasopressin is approximately two hours, however our patient showed response within 15 minutes, demonstrating its potential.[1] After the initial onset of shock, endogenous stores of antidiuretic hormone are consumed and the vasodilatory mechanisms of shock may propagate.[3] Vasopressin itself may reverse some of the vasodilatory changes induced in shock, and in combination with other pressors may prove to be of greater benefit than that of pressors alone.[2] CONCLUSIONS: In the setting of shock with limited intravenous access, intramuscular vasopressin may be an effective option for initial stabilization until IV access is obtained. REFERENCE #1: Brostoff J, James VH, Landon J. Plasma corticosteroid and growth hormone response to lysine-vasopressin in man. J Clin Endocrinol Metab. 1968;28(4):511-518. REFERENCE #2: Forrest P. Vasopressin and shock. Anaesth Intensive Care. 2001;29(5):463-472. REFERENCE #3: Russell JA. Bench-to-bedside review: Vasopressin in the management of septic shock. Crit Care. 2011;15(4):226. DISCLOSURES: No relevant relationships by George Apergis, source=Web Response No relevant relationships by Dushyant Damania, source=Web Response No relevant relationships by Aaron Douen, source=Web Response No relevant relationships by Jean Mallipudi, source=Web Response No relevant relationships by George Mbolu, source=Web Response No relevant relationships by Ryan Panetti, source=Web Response

Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia.

Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.

Inhaled corticosteroid response in smoker versus non-smoker asthmatic patients: a cross-sectional study

BackgroundAsthmatic smokers are a distinct phenotype of asthma. There is a lack of specific information about the treatment of asthma in smokers. The purpose of this study was to compare the effects of inhaled corticosteroid (ICS) on asthmatic smokers and non-smokers.ResultsThe present observational, cross-sectional study was conducted at the Chest Department in Assiut University Hospital, during the period from August 2018 to January 2020. Hundred and seventeen asthmatic patients (42 smokers, 30 ex-smokers, and 45 non-smokers) were assessed using an asthma control questionnaire (ACQ), spirometry, sputum cytology, and serum periostin and eotaxin-2 to compare between a patient on inhaled corticosteroid for at least 3 months and patients who do not receive any form of corticosteroid. Asthmatic smokers had poor response to ICS and had insignificant improvement as regard all parameters. However, asthmatic ex-smokers had a partial response to ICS. They had higher post-bronchodilator FEV1 in comparison to those who did not receive ICS. Asthmatic non-smokers on ICS showed the best response as they were well controlled as regard ACQ. Moreover, they had higher post-bronchodilator FEV1/FVC, post-bronchodilator FEV1, and post-bronchodilator FEF25-75, and lower sputum eosinophils and neutrophils.ConclusionSmoking adversely affects the course and response to ICS therapy in asthma.Trial registrationInterrelation between bronchial asthma and smoking: ClinicalTrials.gov ID: NCT03207620. Registered 27 June 2017.

Efficacy of mepolizumab in usual clinical practice and characteristics of responders

BackgroundSevere eosinophilic asthma is a high-burden disease. Mepolizumab has been effective in several randomized clinical trials. However, such success might not be applicable to patients treated in usual clinical practice. The objectives of this article are to evaluate the efficacy of mepolizumab in severe uncontrolled eosinophilic asthma under usual clinical practice, and to determine characteristics associated with the response to this treatment. MethodsWe have conducted a retrospective, multicentre study, including all adult patients with severe uncontrolled eosinophilic asthma in Galicia, Spain, on whom mepolizumab treatment was started before June 2020, at least 6 months before the time of inclusion, and had received at least one dose of the drug. Patient characteristics, clinical data, respiratory function and comorbidities were collected at baseline and at the 6-month-follow-up. Responders and super-responders were defined according to clinical response and requirement of systemic corticosteroids. Results122 patients (mean age 58 years old) were included. In the follow-up treatment 6 months later, 75.4% of the patients were well-controlled, displaying a significant reduction in blood eosinophil counts (p < 0.001), hospital admissions and disease exacerbations (p < 0.001), and had their systemic glucocorticosteroid dose significantly reduced (p < 0.001). The inhaled corticosteroid dose was also lowered (p < 0.01) after 6 months of treatment. Around two-thirds had a clinically significant increase in FEV1, 95% of the patients were considered responders and 43% super-responders. ConclusionIn routine clinical practice, mepolizumab is effective in patients with severe eosinophilic asthma and it has a good safety profile.

Effect of Steroid Therapy on Growth hormone in Children with Nephrotic Syndrome

Background: Nephrotic syndrome is the most frequent kidney-related condition in the United States today, providing a severe health risk. The cornerstone of therapy is still corticosteroids. Protein deficiency was a major cause of linear growth retardation in nephrotic individuals before steroids were administered. The goal of our research was to see how corticosteroids affected growth hormone in children with nephrotic syndrome. Methodologies: From February to December 2020, a cross-sectional research was conducted on children with nephrotic syndrome who visited the Benha University Nephrology clinic. After receiving written agreement from the patients' parents, the research included 36 patients with nephritic syndrome of both sexes, divided into two groups: corticosteroid response group and corticosteroid plus other immunosuppressive medications group. The following conditions were applied to all of the instances in the study: Growth hormone level in blood was measured after a thorough history, full clinical examination, and laboratory testing. Results: The majority of our NS patients (66.7%) were on corticosteroid medication, while 33.3 percent were on corticosteroid plus immunosuppressive medication, according to our research. Complete remission was 1 (2.8%), steroid dependent was 20 (55.5%), rare recurrence was 3 (8.4%), and corticosteroid resistant was 12 in our research (33.3). According to the findings of the present research, small stature accounted for 15 percent of the cases analysed (41.7 percent ). The G.H distribution in the examined cases was found to vary between 0.04 and 2.80ng/ml, with a mean of 0.76 0.86. The distribution of elicited growth hormone in the examined patients varied from 1.17 to 14.60 (ng/ml), with a mean of 5.28 2.81. According to this research, the distribution of activated growth hormone categories among the analysed patients was as follows: borderline (10.78%), normal (6.17%), and subnormal (20%). (55.6 percent ). There was a statistically significant negative connection between cumulative steroid dosage and mortality in the present trial (growth hormone and provocated Growth hormone). Conclusion: The majority of children with nephrotic syndrome exhibited a height disadvantage. Children with nephrotic syndrome may have growth retardation as a result of chronic steroid therapy. In most instances of NS, growth hormone levels are below normal. Corticosteroid cumulative doses have a negative impact on linear growth.

Identification of ROBO2 as a Potential Locus Associated with Inhaled Corticosteroid Response in Childhood Asthma.

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.

Immune-Mediated Sensorineural Hearing Loss in the Pediatric Population.

A case series with chart review of pediatric patients with immune-mediated sensorineural hearing loss, including sudden sensorineural hearing loss and autoimmune-mediated hearing loss, was performed. Ninety-eight patients with sensorineural hearing loss were reviewed, and 41 patients met the inclusion criteria, which included corticosteroid therapy for a decline in sensorineural hearing. The primary outcome was the corticosteroid response rate: 61% of patients responded. The secondary outcome was a sustained response following multiple courses of corticosteroids for additional hearing loss, which correlated with timely corticosteroid treatment: 57% showed sustained response with multiple treatments, but as anticipated, patients were more likely to respond when treated promptly. Sustained responses fell over time with multiple treatments. These data demonstrate pediatric immune-mediated sensorineural hearing loss is corticosteroid responsive in at a rate similar to their adult counterparts and should be considered for similar treatment approaches.

Increasing utility of FeNO as a biomarker of type-2 inflammation in severe asthma

Since the discovery that nitric oxide (NO) can be measured in the exhaled breath and that the fractional exhaled NO (FeNO) is increased in asthma, FeNO has been recognised as a biomarker of type 2 inflammation in the airways, reflecting the effect of type 2-associated cytokines, interleukin (IL)-4 and IL-13, that play an important role in bronchial hyperresponsiveness, mucus secretion and goblet cell hyperplasia, and T-helper type 2 polarisation, and also in allergic and eosinophilic inflammation. Since 2011, FeNO, which remains a convenient measurement for patients as young as 5 years, has been recommended for use in the diagnosis of eosinophilic airway inflammation as a supportive adjunct towards the diagnosis of asthma and in assessing corticosteroid responsiveness. 1 Dweik RA Sorkness RL Wenzel S et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med. 2010; 181: 1033-1041 Crossref PubMed Scopus (220) Google Scholar Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysisIn uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations. Full-Text PDF The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational studyExacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. Full-Text PDF

A case of steroid responsive nivolumab-induced cholangitis

Immune checkpoint inhibitors (ICIs) such as nivolumab are widely used agents in the treatment of a range of advanced malignancies given their demonstrated ability to achieve sustained clinical response and long-term survival in a significant subset of treated patients.1 ICIs enhance the endogenous anti-tumour immune response and hence are associated with a distinct set of immunologically-mediated toxicities referred to as immune related adverse events (irAEs). ICI-related cholangitis is a rare irAE which currently lacks established diagnostic criteria or treatment guidelines.2 Here we present a case of a 75-year-old female with non-small cell lung cancer treated with palliative nivolumab who subsequently developed nivolumab-induced small duct cholangitis which demonstrated an excellent response to corticosteroid therapy. We believe this is the first such reported Australian case. Given previous reports of poor corticosteroid response, more clinicopathological data is needed to characterise the potentially heterogeneous nature of ICI-cholangitis.3 Though a rare phenomenon, given the increasingly common use of these agents, it is an important reaction pattern of which pathologists and clinicians should be aware. 1.Yoneda K, Imanishi N, Ichiki Y, et al. Immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). J UOEH 2018; 40: 173–89.2.Onoyama T, Takeda Y, Yamashita T, et al. Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review. World J Gastroenterol 2020; 26: 353–65.3.Talbot S, MacLaren V, Lafferty H. Sclerosing cholangitis in a patient treated with nivolumab. BMJ Case Rep 2021; 14: e241700.

Corticosteroid Resistance in Smokers-A Substudy Analysis of the CORTICO-COP Randomised Controlled Trial.

The CORTICO-COP trial showed that eosinophil-guided corticosteroid-sparing treatment for acute exacerbation of chronic obstructive pulmonary disease was non-inferior to standard of care and decreased the accumulated dose of systemic corticosteroids that patients were exposed to by approximately 60%. Smoking status has been shown to affect corticosteroid responsiveness. This post hoc analysis investigated whether eosinophil-guided treatment is non-inferior to conventional treatment in current smokers. The main analysis of current smokers showed no significant difference in the primary endpoint, days alive, and out of hospital within 14 days between the control group (mean, 9.8 days; 95% confidence interval (CI), 8.7–10.8) and the eosinophil-guided group (mean, 8.7 days; 95% CI, 7.5–9.9; p = 0.34). Secondary analyses of the number of exacerbations or deaths, the number of intensive care unit admissions or deaths, lung function improvement, and change in health-related quality of life also showed no significant differences between the two groups. The results of a sensitivity analysis of ex-smokers are consistent with the main analysis. Our results suggest that eosinophil-guided treatment is non-inferior to standard of care in current smokers and ex-smokers. Because data on the impact of smoking status on eosinophil-guided treatments are sparse, more randomised trials are needed to confirm our results.

Early Dynamics of MELD Scores Predict Corticosteroid Responsiveness to Severe Acute-Onset Autoimmune Hepatitis

Timely diagnosis and management of severe acute-onset autoimmune hepatitis (SA-AIH), a potential cause of acute liver failure (ALF), are challenging. An initial trial of corticosteroids (CS) followed by an assessment of clinical responses over 1-2 weeks is advocated by the latest international practice guidelines^1,2 and expert reviews.^3,4 Consideration of a second-line drug while evaluating for liver transplantation (LT) is also recommended.² Established predictors of "CS responsiveness" to guide decision-making are nonexistent. Herein, we determined the diagnostic abilities of early dynamics to define CS responsiveness in SA-AIH using the model for end-stage liver disease (MELD) scores.