Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung.

Foxp3+ regulatory T (Treg) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether Treg cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2+ Treg cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2+ Treg cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in Treg cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for Treg cell-mediated suppression of γδ T cells. This response resulted in fewer eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing allergen-induced inflammation. Thus, we define a fundamental role for ST2+ Treg cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.

Dupilumab improves health-related quality of life in patients with chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) negatively affects health-related quality of life (HRQoL). In a previously reported randomized clinical trial (NCT01920893), addition of dupilumab to mometasone furoate in patients with CRSwNP refractory to intranasal corticosteroids (INCS) significantly improved endoscopic, radiographic, and clinical endpoints and patient-reported outcomes. The objective of this analysis was to examine the impact of dupilumab treatment on HRQoL and productivity using secondary outcome data from this trial. METHODS: Following a 4-week mometasone furoate nasal spray run-in, patients were randomized to commence subcutaneous dupilumab (600 mg loading dose, then 300 mg once weekly for 15 weeks [n = 30], or matched placebo [n = 30]). Outcomes included scores on the CRS disease severity visual analog scale (VAS), 22-item Sino-Nasal Outcome Test (SNOT-22), 5-dimension EuroQoL (EQ-5D) general health status VAS, and 36-item Short-Form Health Survey (SF-36) for HRQoL and nasal polyp-related healthcare resource use questionnaires. RESULTS: Following 16 weeks of treatment, the proportion of patients with moderate-to-severe CRSwNP (VAS > 3-10) decreased from 86.2% to 21.4% with dupilumab and 88.0% to 84.2% with placebo. Dupilumab (vs placebo) resulted in significantly greater improvement in HRQoL, based on SNOT-22, SF-36, and EQ-5D VAS scores. The dupilumab group had a significantly lower adjusted annualized mean number of sick leave days (0.09, vs 4.18 with placebo, P = .015) and significantly greater improvement (vs placebo) in the SNOT-22 item "reduced productivity." CONCLUSIONS: In adults with CRSwNP refractory to treatment with INCS alone, the addition of dupilumab reduced disease severity, significantly improved HRQoL, and improved productivity.

Novel CARD9 mutation in a patient with chronic invasive dermatophyte infection (tinea profunda).

Caspase Recruitment Domain Family Member 9 (CARD9) is an adaptor molecule that drives antifungal activity of macrophages and neutrophils in the skin. Autosomal recessive loss-of-function mutations in CARD9 confer increased susceptibility to invasive disease with select fungi in non-immunosuppressed patients. We report on a patient with X-linked ichthyosis complicated by chronic cutaneous invasive dermatophyte infection. We identified a previously reported c.271T>C (p.Y91H) mutation and a novel intronic c.1269+18G>A mutation in CARD9 underlying recurrent deep dermatophytosis in this patient despite various antifungals for over three decades. Our case highlights susceptibility to invasive dermatophytosis related to autosomal recessive CARD9 deficiency and illustrates the range of CARD9 mutations to be pursued in immunocompetent patients with unexplained deep dermatophyte infections. Further studies are needed to define the best therapeutic regimen.

Dupilumab reduces opacification across all sinuses and related symptoms in patients with CRSwNP.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with substantial sinus opacification. In a phase 2a study (NCT01920893), dupilumab, a fully human anti-IL-4Rα monoclonal antibody, improved outcomes in CRSwNP refractory to intranasal corticosteroids. We evaluated dupilumab’s effect on sinus opacification in relation to effects on nasal polyp burden, symptoms, and health-related quality of life (HRQoL) in patients with CRSwNP. METHODOLOGY: 16-week randomized, double-blind, placebo-controlled, parallel-group study in 60 adults with CRSwNP. Patients received weekly subcutaneous dupilumab 300-mg or placebo and daily mometasone furoate nasal spray. Sinus opacification was assessed using standard and Zinreich-modified Lundâ€"Mackay (zLMK) scoring. Correlation was assessed between zLMK score and CRSwNP endpoints, including nasal polyp score (NPS), SNOT-22, daily symptom scores, and UPSIT smell-test score. RESULTS: Baseline characteristics were similar across treatment groups. Mean plus/minus SD baseline LMK scores of 18.7 plus/minus 5.5 (placebo) and 18.6 plus/minus 5.0 (dupilumab) indicated severe disease with extensive opacification involving all sinuses. Baseline LMK and LMK scores correlated with NPS severity and loss of sense of smell (daily symptoms; SNOT-22 smell/taste; loss of sense of smell [UPSIT]). At Week 16, dupilumab-treated patients had significantly improved sinus opacification measured by LMK in all individual sinuses vs placebo. Dupilumab also showed similar efficacy with zLMK, with only small differences from LMK, and correlated with SNOT22 smell/taste. The most common adverse events were nasopharyngitis, injection-site reactions, and headache. CONCLUSIONS: In patients with CRSwNP, baseline LMK showed extensive sinus opacification and correlated with symptoms, HRQoL, and hyposmia. Dupilumab treatment reduces opacification across all sinuses and related symptoms in patients with CRSwNP.

Quantitative assessment of airway remodelling and response to allergen in asthma.

BACKGROUND AND OBJECTIVE: In vivo evaluation of the microstructural differences between asthmatic and non-asthmatic airways and their functional consequences is relevant to understanding and, potentially, treating asthma. In this study, we use endobronchial optical coherence tomography to investigate how allergic airways with asthma differ from allergic non-asthmatic airways in baseline microstructure and in response to allergen challenge. METHODS: A total of 45 subjects completed the study, including 20 allergic, mildly asthmatic individuals, 22 non-asthmatic allergic controls and 3 healthy controls. A 3-cm airway segment in the right middle and right upper lobe were imaged in each subject immediately before and 24 h following segmental allergen challenge to the right middle lobe. Relationships between optical airway measurements (epithelial and mucosal thicknesses, mucosal buckling and mucus) and airway obstruction (FEV1 /FVC (forced expiratory volume in 1 s/forced vital capacity) and FEV1 % (FEV1 as a percentage of predictive value)) were investigated. RESULTS: Significant increases at baseline and in response to allergen were observed for all four of our imaging metrics in the asthmatic airways compared to the non-asthmatic airways. Epithelial thickness and mucosal buckling exhibited a significant relationship to FEV1 /FVC in the asthmatic group. CONCLUSION: Simultaneous assessments of airway microstructure, buckling and mucus revealed both structural and functional differences between the mildly asthmatic and control groups, with airway buckling seeming to be the most relevant factor. The results of this study demonstrate that a comprehensive, microstructural approach to assessing the airways may be important in future asthma studies as well as in the monitoring and treatment of asthma.

Drivers of chronic rhinosinusitis: Inflammation versus infection.

Studies of the underlying cause or causes of chronic rhinosinusitis (CRS) over the past 20 or more years have expanded from a focus on systemic immune and allergic mechanisms to an intense search for the underlying drivers of mucosal inflammation. These drivers involve mucosal inflammatory pathways that become activated by allergens, microbial stimuli, or poorly understood exogenous or endogenous stimuli. The holy grail in the study of CRS is to identify specific drivers of mucosal inflammation and translate these into more effective treatment for CRS. Certain deficiencies in local innate immunity have been described in patients with CRS that predispose to increased sinus mucosal bacterial colonization/infection, including deficient local production of antimicrobial lactoferrin and deficient functioning of the bitter taste receptor TAS2R38. Conversely, certain innate factors, namely IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), are elaborated by sinus epithelial cells in response to microbial stimulation or airway injury and promote local TH2 inflammation. The precise physiologic role of these factors in innate or adaptive immunity is unclear, although IL-33 might function as an alarmin triggered by damage-associated molecular patterns. The cytokines IL-25 and TSLP, similarly promote proinflammatory tissue responses. Another feature of epithelial dysregulation in patients with CRS is overproduction of eosinophil-promoting C-C chemokines by sinus epithelium, perhaps driven in part through innate stimuli, as well as TH2 cytokines, such as IL-13. Strategies to reduce the microbial stimulation of maladaptive TH2 inflammation or to suppress the local elaboration of TH2-promoting epithelial factors, such as IL-33, have potential therapeutic benefit in patients with CRS, although the extent to which this is realized in patient care remains limited at present. This rostrum will summarize my views on the major microbial drivers of mucosal inflammation and dysregulation of innate TH2-promoting factors in patients with CRS based on recent experimental data.

Host-microbial interactions in patients with chronic rhinosinusitis.

There has been considerable investigation of host-microbial interactions in patients with chronic rhinosinusitis (CRS) in hopes of elucidating mechanisms of disease and better treatment. Most attention has been paid to bacterial infection and potential underlying defects in innate immunity. Bacterial biofilm is present in most patients with CRS undergoing surgical intervention, and its presence is associated with more severe disease and worse surgical outcomes. A role for viral or fungal infection in patients with CRS is less clear. There is no evidence for a primary defect in mucociliary clearance in most patients with CRS. Decreased levels of certain antimicrobial proteins, most notably lactoferrin, have been found in sinus secretions, whereas levels of other antimicrobial proteins have been found to be normal. No primary defects in Toll-like receptors have been found in patients with CRS, although a 50% reduced expression of Toll-like receptor 9 was reported in patients with recalcitrant nasal polyps. A polymorphism in a bitter taste receptor was recently associated with refractory CRS and persistent Pseudomonas aeruginosa infection. A downregulation of innate immunity by maladaptive TH2 tissue inflammation has also been described in patients with recalcitrant nasal polyps, suggesting a link to persistent infection. To date, an effective means of restoring host-microbial balance and mitigating disease in patients with CRS remains elusive.

The nasal and sinus microbiome in health and disease.

There has been great interest in unraveling the complex inter-relationships between microbes and humans as they relate to human health and disease. This review will focus on recent advances in the appreciation and understanding of these relationships in terms of the upper respiratory tract, specifically the nose and paranasal sinuses.

Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation.

BACKGROUND: Induction of endogenous regulatory T (Treg) cells represents an exciting new potential modality for treating allergic diseases, such as asthma. Treg cells have been implicated in the regulation of asthma, but the anatomic location in which they exert their regulatory function and the mechanisms controlling the migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg cell biology will be important for harnessing their power in the clinic. OBJECTIVE: We sought to determine the anatomic location at which Treg cells exert their regulatory function in the sensitization and effector phases of allergic asthma and to determine the chemokine receptors that control the migration of Treg cells to these sites in vivo in both mice and human subjects. METHODS: The clinical efficacy and anatomic location of adoptively transferred chemokine receptor-deficient CD4(+)CD25(+) forkhead box protein 3-positive Treg cells was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Treg cells recruited into the human airway after bronchoscopic segmental allergen challenge of asthmatic patients. RESULTS: We show that CCR7, but not CCR4, is required on Treg cells to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Treg cells to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, human subjects with allergic asthma had an increase in CCR4-expressing functional Treg cells in the lungs after segmental allergen challenge. CONCLUSION: The location of Treg cell function differs during allergic sensitization and allergen-induced recall responses in the lung, and this differential localization is critically dependent on differential chemokine function.

Consensus statement on the pathology of IgG4-related disease.

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.

Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial.

BACKGROUND: Inhaled corticosteroids (ICS) and long-acting ß(2)-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy. OBJECTIVE: To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy. DESIGN: Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314575). SETTING: 193 investigational sites in the United States and 4 sites in Canada. PATIENTS: 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers. INTERVENTION: Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks. MEASUREMENTS: The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events. RESULTS: During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (-0.27 puff/d [CI, -0.49 to -0.04 puff/d]), and decreased mean asthma symptom score (-0.26 [CI, -0.42 to -0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively. LIMITATIONS: The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup. CONCLUSION: In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy. PRIMARY FUNDING SOURCE: Genentech and Novartis Pharmaceuticals.

Chronic rhinosinusitis: epidemiology and medical management.

Chronic rhinosinusitis (CRS) affects 12.5% of the US population. On epidemiologic grounds, some association has been found between CRS prevalence and air pollution, active cigarette smoking, secondhand smoke exposure, perennial allergic rhinitis, and gastroesophageal reflux. The majority of pediatric and adult patients with CRS are immune competent. Data on genetic associations with CRS are still sparse. Current consensus definitions subclassify CRS into CRS without nasal polyposis (CRSsNP), CRS with nasal polyposis (CRSwNP), and allergic fungal rhinosinusitis (AFRS). Evaluation and medical management of CRS has been the subject of several recent consensus reports. The highest level of evidence for treatment for CRSsNP exists for saline lavage, intranasal steroids, and long-term macrolide antibiotics. The highest level of evidence for treatment of CRSwNP exists for intranasal steroids, systemic glucocorticoids, and topical steroid irrigations. Aspirin desensitization is beneficial for patients with aspirin-intolerant CRSwNP. Sinus surgery followed by use of systemic steroids is recommended for AFRS. Other modalities of treatment, such as antibiotics for patients with purulent infection and antifungal drugs for patients with AFRS, are potentially useful despite a lack of evidence from controlled treatment trials. The various modalities of medical treatment are reviewed in the context of recent consensus documents and the author's personal experience.

Rhinitis and sinusitis.

Rhinitis and sinusitis are among the most common medical conditions and are frequently associated. In Western societies an estimated 10% to 25% of the population have allergic rhinitis, with 30 to 60 million persons being affected annually in the United States. It is estimated that sinusitis affects 31 million patients annually in the United States. Both rhinitis and sinusitis can significantly decrease quality of life, aggravate comorbid conditions, and require significant direct medical expenditures. Both conditions also create even greater indirect costs to society by causing lost work and school days and reduced workplace productivity and school learning. Management of allergic rhinitis involves avoidance, many pharmacologic options, and, in appropriately selected patients, allergen immunotherapy. Various types of nonallergic rhinitis are treated with avoidance measures and a more limited repertoire of medications. For purposes of this review, sinusitis and rhinosinusitis are synonymous terms. An acute upper respiratory illness of less than approximately 7 days' duration is most commonly caused by viral illness (viral rhinosinusitis), whereas acute bacterial sinusitis becomes more likely beyond 7 to 10 days. Although the mainstay of management of acute bacterial sinusitis is antibiotics, treatment of chronic sinusitis is less straightforward because only some chronic sinusitis cases have an infectious basis. Chronic rhinosinusitis (CRS) has been subdivided into 3 types, namely CRS without nasal polyps, CRS with nasal polyps, and allergic fungal rhinosinusitis. Depending on the type of CRS present, a variety of medical and surgical approaches might be required.

International consensus statement on allergy and rhinology: rhinosinusitis 2021.

I. EXECUTIVE SUMMARY: BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. METHODS: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. RESULTS: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. CONCLUSION: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.

Phenotypes of Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is a complex heterogeneous disease with different phenotypes and endotypes. Recent advances in our understanding of the pathogenetic mechanisms of CRS endotypes have led to the introduction of effective biologic agents for CRS management. Traditionally, CRS phenotypes have been divided into with or without nasal polyps depending on the presence of polyps. Although this classification does not reflect the various endotypes that are recently emerging, it is simple and easily recognized by clinicians. Other phenotypes of CRS are fungal rhinosinusitis (including invasive and noninvasive subtypes), infectious rhinosinusitis, aspirin-exacerbated respiratory disease, cystic fibrosis, pediatric CRS, and CRS associated with systemic diseases. This article reviews the diagnostic approaches and up-to-date treatment strategies for each CRS phenotype with the hope that a better understanding of endotypes will result in a more scientific understanding of phenotypes and precise, personalized treatments.

Nasal and sinus endoscopy for medical management of resistant rhinosinusitis, including postsurgical patients.

Nasal endoscopy has been practiced by allergists since the early 1980s; however, allergists in general have not embraced endoscopic evaluation of patients with sinus disease, either before or after surgery. Allergists are in a unique position to render medical (as opposed to surgical) care of patients with sinusitis. There has been a growing realization that endoscopy is a valuable procedure for the evaluation and medical treatment of patients with difficult sinusitis. This has resulted in the need for a resource to allow allergists to understand the nature of endoscopic findings in patients with sinusitis, either preoperatively or postoperatively. This article introduces the findings at endoscopy that are common in patients with sinusitis, including those that may be seen after surgery. The findings include perforation of the septum, retained secretions, small surgical ostium caused by postoperative ostial stenosis, previous Caldwell Luc procedure, recirculation of mucus, hyperplastic nasal disease, synechiae, recurrent disease in previously unaffected sinuses, empty nose syndrome, frontal sinus disease, dental disease, and other, more complicated entities.

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5 expression in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is characterized by persistent mucosal inflammation and frequent exacerbations. OBJECTIVE: To determine whether innate epithelial responses to cigarette smoke or bacterial or viral pathogens may be abnormal in CRS leading to an inappropriate inflammatory response. METHODS: Primary nasal epithelial cells (PNECs) were grown from middle turbinate biopsies of 9 healthy controls and 11 patients with CRS. After reaching 80% to 90% confluence, PNECs were exposed to medium or cigarette smoke extract (CSE) 5% (vol/vol) for 1 hour, washed, then stimulated with staphylococcal lipoteichoic acid, LPS, or double-stranded RNA (dsRNA). After 24 hours, gene expression was quantified by QRT-PCR. RESULTS: At baseline, PNECs revealed elevated TNF-alpha and growth-related oncogene-alpha (a C-X-C chemokine)/CXCL1 (GRO-alpha) (4-fold increase, P = .02; and 16-fold increase, P = .004, respectively) in subjects with CRS compared with controls with normal levels of IL-1beta, IL-6, IL-8/CXCL8, human beta-defensin-2, monocyte chemoattractant protein 2/CCL8, monocyte chemoattractant protein 3/CCL7, and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5. Immunostaining of nasal biopsies, however, revealed comparable epithelial staining for TNF-alpha, GRO-alpha, and RANTES. There were no differences in mRNA induction by CSE, TNF-alpha, lipoteichoic acid, LPS, or dsRNA alone. The combination of CSE+dsRNA induced exaggerated RANTES (12,115-fold vs 1500-fold; P = .03) and human beta-defensin-2 (1120-fold vs 12.5-fold; P = .05) in subjects with CRS. No other genes were differentially induced. Furthermore, CSE+dsRNA induced normal levels of IFN-beta, IFN-lambda1, and IFN-lambda2/3 mRNA in subjects with CRS. CONCLUSION: Cigarette smoke extract plus dsRNA induces exaggerated epithelial RANTES expression in patients with CRS. We propose that an analogous response to cigarette smoke plus viral infection may contribute to acute exacerbations and eosinophilic mucosal inflammation in CRS.