Eosinophilic disorders of the gastrointestinal tract are an emerging subset of immune pathologies within the spectrum of allergic inflammation. Eosinophilic Esophagitis (EoE), once considered a rare disease, is increasing in incidence, with a rate of over 1 in 10,000 in the US, for unknown reasons. The clinical management of EoE is challenging, thus there is an urgent need for understanding the etiology and pathophysiology of this eosinophilic disease to develop better therapeutic approaches. In this open label, single arm, unblinded study, we evaluated the effects of an anti-IgE treatment, omalizumab, on local inflammation in the esophagus and clinical correlates in patients with EoE. Omalizumab was administered for 12 weeks to 15 subjects with long standing EoE. There were no serious side effects from the treatment. Esophageal tissue inflammation was assessed both before and after therapy. After 3 months on omalizumab, although tissue Immunoglobulin E (IgE) levels were significantly reduced in all but two of the subjects, we found that full remission of EoE, which is defined as histologic and clinical improvement only in 33% of the patients. The decrease in tryptase-positive cells and eosinophils correlated significantly with the clinical outcome as measured by improvement in endoscopy and symptom scores, respectively. Omalizumab-induced remission of EoE was limited to subjects with low peripheral blood absolute eosinophil counts. These findings demonstrate that in a subset of EoE patients, IgE plays a role in the pathophysiology of the disease and that anti-IgE therapy with omalizumab may result in disease remission. Since this study is open label there is the potential for bias, hence the need for a larger double blind placebo controlled study. The data presented in this pilot study provides a foundation for proper patient selection to maximize clinical efficacy.Trial RegistrationClinicalTrials.gov NCT01040598

Background: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela.Aims: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. Materials & Methods:We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls.Results: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. Discussion: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Conclusion:Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.

Background:The short stability window of several hours from blood collection to measuring basophil activation has limited the use of flow cytometry-based basophil activation assays in clinical settings. We examine if it is possible to extend this

LETTERS TO THE EDITOR4. Squeglia V, Barbarino A, Bova M, et al. High attack frequency in patients with angioedema due to C1-inhibitor deficiency is a major determinant in switching to home therapy: a real-life observational study. Orphanet J Rare Dis. 2016;11(1):133. 5. Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009;161(5):1153-1158. 6. Bygum A. Hereditary angioedema -consequences of a new treatment paradigm in Denmark. Acta Derm Venereol. 2014;94(4): 436-441. 7. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. 8. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks-final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66(12):1604-1611. 9. Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013;8(2):e53773.

At present, there are is no effective vaccine and only one FDA approved early-stage therapy against infection with the SARS-CoV-2 virus to prevent disease progression. The excessive inflammation and tissue damage associated with COVID-19 can lead to immediate (i.e. respiratory failure, sepsis, and ultimately, death) or long-term health problems (i.e. fatigue, dyspnea, cough, joint pain, anosmia) and the risk for these complications are higher in the elderly population, certain ethnic groups, as well as those with various co-morbid conditions. Cellular caspases play a role in the pathophysiology of a number of disorders that overlap with the list of co-morbid conditions seen in severe COVID-19. In this study, we assessed transcriptional states of caspases in immune cells from COVID-19 patients and profiled intra-cellular caspases in immune cells and red blood cells derived from a spectrum of COVID-19 patients hospitalized with acute disease or convalescent. Gene expression levels of select caspases were increased in in vitro SARS-CoV-2 infection models and single cell RNA-Seq data of peripheral blood from COVID-19 patients showed a distinct pattern of caspase expression in T cell, neutrophils, and dendritic cells. Flow cytometric evaluation of CD4 T cells showed up-regulation of caspase-1 in hospitalized COVID-19 patients compared to unexposed controls, with the exception of a subset of patients with asthma and chronic rhinosinusitis (CRS). Convalescent COVID-19 patients with lingering symptoms (long haulers) showed persistent up-regulation of caspase-1 in CD4 T cells that was attenuated ex vivo following co-culture with a select pan-caspase inhibitor. Further, we observed elevated caspase 3 levels in red blood cells from COVID-19 patients compared to controls that were responsive to caspase inhibition. Taken together, our results expose an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate, reduce, or prevent severe COVID-19 outcomes.

No abstract

COVID-19 can present with lymphopenia and extraordinary complex multi-organ pathologies that can trigger long-term sequela. Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subjects presenting with various co-morbid conditions served as controls. Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells and eosinophils compared to controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared to unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed up-regulated caspase-1 activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7 levels in red blood cells from COVID-19 patients compared to controls that was reduced following caspase inhibition. Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.

No abstract