Search

Objective The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine endorse checklist use to improve obstetric care. However, there is limited research into development, implementation, and sustained use of perinatal emergency checklists to inform individual institutions. This study aimed to investigate the development and implementation of perinatal emergency checklists in diverse hospital settings in the United States. Study Design A qualitative study was conducted individually with clinicians from three health care systems. The participants developed and implemented institution-tailored perinatal emergency checklists. Interview transcriptions were coded using the Consolidated Framework for Implementation Research. Results The study sites included two health care systems and one individual hospital. Delivery volumes ranged from 3,500 to 48,000 deliveries a year. Interviews were conducted with all 10 participants approached. Checklists for 19 perinatal emergencies were developed at the three health care systems. Ten of the checklist topics were the same at all three institutions. Participants described the checklists as improving patient care during crises. The tools were viewed as opportunities to promote a shared mental model across clinical roles, to reduce redundancy and coordinate obstetric crisis management. Checklist were developed in small groups. Implementation was facilitated by those who developed the checklists. Participants agreed that simulation was essential for checklist refinement and effective use by response teams. Barriers to implementation included limited clinician availability. There was also an opportunity to strengthen integration of checklists workflow early in perinatal emergencies. Participants articulated that culture change took time, active practice, persistence, reinforcement, and process measurement. Conclusion This study outlines processes to develop, implement, and sustain perinatal emergency checklists at three institutions. Participants agreed that multiple, parallel implementation tactics created the culture shift for integration. The overview and specific Consolidated Framework for Implementation Research components may be used to inform adaptation and sustainability for others considering implementing perinatal emergency checklists. Key Points

Basophils have been implicated in promoting the early development of TH 2 cell responses in some murine models of TH 2 cytokine-associated inflammation. However, the specific role of basophils in allergic asthma remains an active area of research. Recent studies in animal models and human subjects suggest that IgE may regulate the homeostasis of human basophil populations. Here, we examine basophil populations in children with severe asthma before and during therapy with the IgE-directed monoclonal antibody omalizumab. Omalizumab therapy was associated with a significant reduction in circulating basophil numbers, a finding that was concurrent with improved clinical outcomes. The observation that circulating basophils are reduced following omalizumab therapy supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.

SummaryExtramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern-recognition receptor (PRR)-expressing HSCs, EMH, and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells, and granulocytes and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway might operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.

Background Food protein–induced enterocolitis (FPIES) is a rare non-IgE mediated disease. Most studies have been limited in nature, with the largest cohort being 66 patients. The most common foods that have been reported are milk and soy. Objective A retrospective chart review of patients seen in the Allergy Section at The Children's Hospital of Philadelphia with International Classification of Diseases Ninth Revision code of 558.3 (Allergic Gastroenteritis and Colitis) between 2007 and 2012 was conducted to identify patients with suspected FPIES. Diagnosis of FPIES was confirmed based on meeting clinical criteria of delayed reaction with pronounced vomiting and/or diarrhea. Data regarding patient characteristics and features of their reactions were collected for analysis and comparison with existing studies. Results A total of 462 cases were identified in our chart review. Patients had a similar demographic profile to the normal allergy patients seen in our clinic. The most common foods identified were milk (67%), soy (41%), rice (19%), oat (16%), and egg (11%). Patients had onset of FPIES to milk and soy around 7 months of age compared with 12 months of age for solid foods. FPIES reactions were identified to meats, tree nuts, peanuts, fruits, and vegetables; 70% of the patients reacted to one or two foods. Skin prick testing and atopy patch testing were not helpful in identifying the foods. Conclusion FPIES reactions were seen more frequently than previously described. However, the presentation and clinical features were similar to previous reports. Milk- and soy-triggered FPIES were common, and 43.5% of patients who had a milk trigger reacted to soy. There is no laboratory test to identify foods that cause FPIES, and clinician-supervised oral food challenge is the only definitive test available.

Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in which dietary antigens (in particular, milk) play a major role. EoE is most likely a mixed IgE and non-IgE food-mediated reaction in which overexpression of Th2 cytokines, particularly IL-13, play a major role; however, the cells responsible for IL-13 overexpression remain elusive. Th2-cytokines are secreted following the ligation of invariant natural killer T cell receptors to sphingolipids (SLs). Sphingolipids (SLs) are presented via the CD1d molecule on the INKTs surface. Cow's milk-derived SL has been shown to activate iNKTs from children with IgE-mediated food allergies to milk (FA-MA) to produce Th2 cytokines. The role of iNKTs and milk-SL in EoE pathogenesis is currently unknown.The aim of this study was to investigate the role of iNKTs and milk-SL in EoE.Peripheral blood mononuclear cells (PBMCs) from 10 children with active EoE (EoE-A), 10 children with controlled EoE (EoE-C) and 16 healthy controls (non-EoE) were measured ex vivo and then incubated with α-galactosylceramide (αGal) and milk-SL. INKTs from peripheral blood (PB) and oesophageal biopsies were studied.EoE-A children had significantly fewer peripheral blood iNKTs with a greater Th2-response to αGal and milk-SM compared with iNKTs of EoE-C and non-EoE children. Additionally, EoE-A children had increased iNKT levels in oesophageal biopsies compared with EoE-C children.Milk-SLs are able to activate peripheral blood iNKTs in EoE-A children to produce Th2 cytokines. Additionally, iNKT levels are higher at the site of active oesophageal eosinophilic inflammation.This study suggests that sphingolipids (SLs) contained in milk may drive the development of EoE by promoting an iNKT-cell-mediated Th2-type cytokine response that facilitates eosinophil-mediated allergic inflammation.

Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern recognition receptor (PRR)-expressing HSCs, EMH and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages and granulocytes; and that these cells selectively contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease. These data demonstrate that TSLP-induced EMH contributes to the development of Th2 cytokine-mediated inflammation and indicate that EMH is a conserved mechanism of innate immunity.

Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal eosinophilia, inflammation, and dysfunction. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify new pathways that could be targeted to treat EoE. Recently, EoE was associated with a gain-of-function polymorphism in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation and peripheral basophilia. However, how TSLP and basophils might contribute to the development of eosinophil responses during EoE remains unknown. Here, we employed a new murine model of EoE-like disease to investigate the role of TSLP and basophils in promoting esophageal eosinophil responses. Development of esophageal eosinophil responses was dependent on TSLP-elicited basophils, and antibody-mediated neutralization of TSLP or depletion of basophils ameliorated established esophageal eosinophilia. In addition, we examined how sort-purified human basophils influence eosinophil responses in vitro. Finally, elevated TSLP levels and exaggerated basophil responses observed in esophageal biopsies from EoE patients correlated with eosinophil responses. Together, these data indicate that TSLP-elicited basophil responses may play a key role in mediating eosinophil responses in EoE, suggesting that the TSLP-basophil axis could represent a new and promising therapeutic target to treat this disease.

Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies established a link between pattern recognition receptor-expressing HSCs, EMH and innate immune responses to bacterial or viral pathogens. However, the factors that regulate EMH and whether EMH is a conserved mechanism of innate immunity to diverse stimuli remain poorly defined. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of Lineage − , CD34 + , c-Kit + granulocyte-monocyte progenitor (GMP)-like cells in the periphery. TSLP-elicited progenitors possess the capacity to differentiate into macrophages, mast cells and basophils. Critically, adoptive transfer of TSLP-elicited GMP-like cells was sufficient to promote Th2 cytokine-dependent immunity to an intestinal helminth parasite, demonstrating a role for TSLP-elicited GMP-like cells in promoting inflammation. Further, circulating progenitor cells were also increased in allergic patients with a gain-of-function polymorphism in TSLP , suggesting that the TSLP-EMH pathway may be operational in human disease. These data demonstrate a previously unrecognized role for TSLP in promoting EMH that contributes to the development of Th2-cytokine-mediated inflammation and identify the TSLP-EMH pathway as a possible therapeutic target to treat allergic inflammation.

Eosinophilic esophagitis (EoE) is a food allergy-associated disease characterized by esophageal eosinophilia and associated inflammation. EoE has become increasingly common in industrialized countries. However, current management strategies, such as treatment with swallowed steroids and dietary restrictions, are nonspecific or negatively impact the quality of life of EoE patients. In addition, use of more specific therapies that target immunoglobulin E (IgE) and interleukin (IL)-5 have been largely unsuccessful in ameliorating EoE. Thus, there is an urgent need to identify novel, specific immunological pathways that underlie the pathogenesis of EoE that could be targeted to treat this disease. Recently, a genome-wide association study identified that EoE is associated with a gain-of-function polymorphism in the gene that encodes thymic stromal lymphopoietin (TSLP). TSLP is an IL-7 family member cytokine that promotes allergic inflammation by eliciting T helper type 2 cytokine responses, IgE production, and the expansion of a distinct population of basophils. However, whether TSLP directly promotes allergic inflammation in the esophagus and the mechanisms by which TSLP might contribute to the pathogenesis of EoE remain unknown. Here, we describe a new murine model of experimental EoE-like disease that was used to investigate the role of TSLP in allergic inflammation of the esophagus. Murine experimental EoE-like disease developed independently of IgE but was dependent on TSLP-elicited basophils. Critically, therapeutic antibody-mediated neutralization of TSLP or depletion of basophil populations ameliorated established EoE-like disease in mice. Finally, elevated TSLP levels and exaggerated basophil responses were observed in esophageal biopsies from EoE patients, and a gain-of-function polymorphism in TSLP correlated with increased basophil responses in patients with EoE. Together, these data indicate that TSLP-elicited basophil responses may play a key role in mediating the pathogenesis of EoE, suggesting that targeting the TSLP-basophil axis could represent a new and promising therapeutic target in the treatment of EoE.