Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.
01 Jun 2013-The Journal of Allergy and Clinical Immunology (Elsevier)-Vol. 131, Iss: 6, pp 1479-1490
TL;DR: Better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.
Abstract: Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or "endotypes," which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti-IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.
Citations
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University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Lund University5, Auckland City Hospital6, University of Antwerp7, University of New South Wales8, Katholieke Universiteit Leuven9, Guy's and St Thomas' NHS Foundation Trust10, Queen's University11, University of Zagreb12, Northwestern University13, Medical University of Łódź14, University of Aberdeen15, Medical University of South Carolina16, University of North Carolina at Chapel Hill17, University of Southampton18, University of São Paulo19, National University of Singapore20, Flinders University21
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
2,853 citations
University of Utah1, University of Colorado Boulder2, Stanford University3, Oregon Health & Science University4, University of Chicago5, Rush University Medical Center6, University of Barcelona7, Harvard University8, Vanderbilt University9, University of Arizona10, University of Texas Health Science Center at Houston11, University of Pennsylvania12, Emory University13, Université de Montréal14, Samsung Medical Center15, University of Auckland16, University of Pittsburgh17, University of Amsterdam18, University of Ioannina19, University of California, San Francisco20, Eastern Virginia Medical School21, University of New South Wales22, Katholieke Universiteit Leuven23, Guy's and St Thomas' NHS Foundation Trust24, University of Lorraine25, University of British Columbia26, Northwestern University27, Georgia Regents University28, Johns Hopkins University29, New York University30, Korea University31, University of Texas at Austin32, Uniformed Services University of the Health Sciences33, Jikei University School of Medicine34, University of Washington35, University of Siena36, Medical College of Wisconsin37, University of Adelaide38, West Virginia University39, Innsbruck Medical University40, Pusan National University41, University of Calgary42, Medical University of South Carolina43, University of North Carolina at Chapel Hill44, Cleveland Clinic45, Loyola University Chicago46, Cornell University47, Temple University48, University of São Paulo49, National University of Singapore50, San Antonio Military Medical Center51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: This dissertation aims to provide a history of Chinese medical practice in the United States from 1989 to 2002, a period chosen in order to explore its roots as well as specific cases up to and including the year in which descriptions of “modern China” began to circulate.
Abstract: Background The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS. Conclusion As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.
645 citations
TL;DR: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometAsone alone reduced endoscopic nasal polyp burden after 16 weeks.
Abstract: Importance Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell–mediated diseases. Objective To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis. Design, Setting, and Participants A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up. Interventions Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks. Main Outcomes and Measures Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety. Results Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was −0.3 (95% CI, −1.0 to 0.4) with placebo and −1.9 (95% CI, −2.5 to −1.2) with dupilumab (LS mean difference, −1.6 [95% CI, −2.4 to −0.7]; P P P P Conclusions and Relevance Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications. Trial Registration clinicaltrials.gov Identifier:NCT01920893
605 citations
TL;DR: Recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons are reviewed and their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases are discussed.
Abstract: There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.
560 citations
Cites background from "Endotypes and phenotypes of chronic..."
...…sarcoidosis, graftversus-host disease Drugs: Human recombinant IL-7 (CYT107) Clinical trials: Cancer treatment, improving recovery after allogeneic stem cell transplantation, HIV therapy, sepsis, lymphopenia, cancer (Continued) J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn AKDIS ET AL 13 TABLE II....
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...In addition to neutrophils, IL-8 also attracts NK cells, T cells, basophils, and GM-CSF– or IL-3–primed eosinophils.156 Increased IL-8 concentrations were found in inflammatory sites in patients with diseases such as psoriasis, rheumatoid arthritis, respiratory syncytial virus infection, asthma, and chronic obstructive pulmonary diseases.157 J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn AKDIS ET AL 21 IL-16 IL-16 was discovered as a T cell–specific chemoattractant.158 Pro–IL-16, its 80-kDa precursor protein, is cleaved by caspase3, resulting in a 60-kDa N-terminal fragment and a 14- to 17- kDa C-terminal fragment.159 The N-terminal fragment regulates the cell cycle, whereas the C-terminal fragment forms homotetramers (56 kDa) that mediate cytokine functions....
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...J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn AKDIS ET AL 27 168....
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...IL-13R shares IL-4Ra with 4 J ALLERGY CLIN IMMUNOL nnn 2016 4 AKDIS ET AL = J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn AKDIS ET AL 5 IL-18–deficient mice are more susceptible to bacterial infections than normal mice and have uncontrolled disease progression that is accompanied by reduced TH1 cell responses (see Table E2)....
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...109 J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn AKDIS ET AL 19 IL-28A, IL-28B, and IL-29 (IFN-l) IL-28A, IL-28B, and IL-29 (alternatively termed IFN-l2, IFN- l3 and IFN-l1, respectively) have homology with type I interferons, although the intron-exon structure of their genes more closely resembles that of the IL-10 family.110 A new gene upstream of IL-28B was discovered in 2013, and it was designated IFNL4....
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TL;DR: Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into three major kinds of cell-mediated effector immunity, which are classified as type 1, type 2, and type 3 as discussed by the authors.
Abstract: The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet + IFN-γ–producing group 1 ILCs (ILC1 and natural killer cells), CD8 + cytotoxic T cells (T C 1), and CD4 + T H 1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3 + ILC2s, T C 2 cells, and T H 2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid–related orphan receptor γt + ILC3s, T C 17 cells, and T H 17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases.
502 citations
References
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University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Lund University5, Auckland City Hospital6, University of Antwerp7, University of New South Wales8, Katholieke Universiteit Leuven9, Guy's and St Thomas' NHS Foundation Trust10, Queen's University11, University of Zagreb12, Northwestern University13, Medical University of Łódź14, University of Aberdeen15, Medical University of South Carolina16, University of North Carolina at Chapel Hill17, University of Southampton18, University of São Paulo19, National University of Singapore20, Flinders University21
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012 and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
2,853 citations
University of Amsterdam1, Ghent University2, University of Chicago3, University of Pennsylvania4, Auckland City Hospital5, University of Antwerp6, University of New South Wales7, Katholieke Universiteit Leuven8, St Thomas' Hospital9, University of Nottingham10, University of Zagreb11, Northwestern University12, Medical University of Łódź13, University of Aberdeen14, Innsbruck Medical University15, Medical University of South Carolina16, University of Southampton17, Children's Hospital of Philadelphia18, University of São Paulo19, National University of Singapore20, University of Adelaide21, Flinders University22
TL;DR: The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 as discussed by the authors is the update of similar evidence-based position papers published in 2005 and 2007, it contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinositis, control of disease, and better definitions for rhinosinitis in children.
Abstract: The European Position Paper on Rhinosinusitis and Nasal Polyps 2012 is the update of similar evidence based position papers published in 2005 and 2007. The document contains chapters on definitions and classification, we now also proposed definitions for difficult to treat rhinosinusitis, control of disease and better definitions for rhinosinusitis in children. More emphasis is placed on the diagnosis and treatment of acute rhinosinusitis. Throughout the document the terms chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are used to further point out differences in pathophysiology and treatment of these two entities. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. Last but not least all available evidence for management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is analyzed and presented and management schemes based on the evidence are proposed. This executive summary for otorhinolaryngologists focuses on the most important changes and issues for otorhinolaryngologists. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.
1,608 citations
01 Jan 2007
TL;DR: Autor ukratko opisuje najnovije europske smjernice za lijecenje akutnog i kronicnog rinosinuitisa i nosne polipoze na engleskom jeziku na web stranici www.rhinologyjournal.com.
Abstract: Autor ukratko opisuje najnovije europske smjernice za lijecenje akutnog i kronicnog rinosinuitisa i nosne polipoze. Autor rada jedan je od clanova međunarodnog tima strucnjaka za ovu problematiku koji su sudjelovali u izradi ove smjernice. Ovaj rad predstavlja sažetak EPOS dokumenta koji je u cijelosti pristupacan na engleskom jeziku na web stranici www.rhinologyjournal.com.
1,592 citations
"Endotypes and phenotypes of chronic..." refers background or methods in this paper
...Internationally, there is consensus concerning the clinical diagnosis of rhinosinusitis.(1,75,76) Rhinosinusitis represents a symptomatic inflammation of the paranasal sinuses involving the sinonasal tract....
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...control of disease in patients with CRS was introduced based on subjective and objective parameters of sinonasal inflammation.(1,86) Certain subtypes of CRS, such as cystic fibrosis, primary ciliary dyskinesia, antrochoanal polyps, and fungal disease (allergic and invasive), are not specifically mentioned in the evidencebased guidelines for medical treatment because their medical treatment might not differ substantially from other phenotypes of rhinosinusitis and because surgery is the usual treatment for unilateral disease, such as antrochoanal polyps....
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...Therefore modified treatment strategies for children have been incorporated into the recent update of EPOS.(1,76,87) The general therapeutic approach to CRS consists of medical treatment and surgery in cases of medical failures with persistent symptoms....
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...Acute rhinosinusitis (ARS) is clinically defined as symptoms lasting less than 12 weeks with complete resolution.(1) Chronic rhinosinusitis (CRS), which is the focus of this document, is defined as symptoms on most days lasting at least 12 weeks without complete resolution....
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...Furthermore, children might differ from adults in their pathophysiology because their immune system is not fullymature, and hypertrophy of the structures that constitute the Waldeyer ring might modify the disease phenotype.79 Therefore modified treatment strategies for children have been incorporated into the recent update of EPOS.1,76,87 The general therapeutic approach to CRS consists of medical treatment and surgery in cases of medical failures with persistent symptoms....
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TL;DR: The results show the bronchial tree to contain a characteristic microbiota, and suggest that this microbiota is disturbed in asthmatic airways.
Abstract: Background: A rich microbial environment in infancy protects against asthma [1], [2] and infections precipitate asthma exacerbations [3]. We compared the airway microbiota at three levels in adult patients with asthma, the related condition of COPD, and controls. We also studied bronchial lavage from asthmatic children and controls.
Principal Findings: We identified 5,054 16S rRNA bacterial sequences from 43 subjects, detecting >70% of species present. The bronchial tree was not sterile, and contained a mean of 2,000 bacterial genomes per cm2 surface sampled. Pathogenic Proteobacteria, particularly Haemophilus spp., were much more frequent in bronchi of adult asthmatics or patients with COPD than controls. We found similar highly significant increases in Proteobacteria in asthmatic children. Conversely, Bacteroidetes, particularly Prevotella spp., were more frequent in controls than adult or child asthmatics or COPD patients.
Significance: The results show the bronchial tree to contain a characteristic microbiota, and suggest that this microbiota is disturbed in asthmatic airways.
1,483 citations
"Endotypes and phenotypes of chronic..." refers background in this paper
...Interestingly, certain phyla of bacteria, such as proteobacteria, are more common in the lower airways of patients with asthma or chronic obstructive pulmonary disease based on deep sequencing of 16S RNA on biopsy samples.(12) Consistent with the unclear role of bacterial infection in many cases of CRS, CRS can be relatively unresponsive to most antibiotics....
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TL;DR: Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
Abstract: Background The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. Methods We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced. Results We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without ...
1,098 citations
"Endotypes and phenotypes of chronic..." refers background in this paper
...STAT3 has been strongly linked to immunity because patients with defects in STAT3 manifest the hyper-IgE syndrome (Job disease), which is characterized by frequent infection with bacteria (especially S aureus) and fungi.(36) Studies demonstrate that epithelial host defense molecule release is mediated frequently by activation of STAT3, and a local decrease in STAT3 phosphorylation in tissues from patients with CRS might be mechanistically linked to a blunted innate immune response....
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