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1.  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 
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.
PMCID: PMC4161279  PMID: 23587334
Chronic rhinosinusitis; endotypes; phenotypes; cytokines; biological agents; treatment; diagnosis; IgE; nasal polyps; pathophysiology
2.  Research needs in allergy: an EAACI position paper, in collaboration with EFA 
Papadopoulos, Nikolaos G | Agache, Ioana | Bavbek, Sevim | Bilo, Beatrice M | Braido, Fulvio | Cardona, Victoria | Custovic, Adnan | deMonchy, Jan | Demoly, Pascal | Eigenmann, Philippe | Gayraud, Jacques | Grattan, Clive | Heffler, Enrico | Hellings, Peter W | Jutel, Marek | Knol, Edward | Lötvall, Jan | Muraro, Antonella | Poulsen, Lars K | Roberts, Graham | Schmid-Grendelmeier, Peter | Skevaki, Chrysanthi | Triggiani, Massimo | vanRee, Ronald | Werfel, Thomas | Flood, Breda | Palkonen, Susanna | Savli, Roberta | Allegri, Pia | Annesi-Maesano, Isabella | Annunziato, Francesco | Antolin-Amerigo, Dario | Apfelbacher, Christian | Blanca, Miguel | Bogacka, Ewa | Bonadonna, Patrizia | Bonini, Matteo | Boyman, Onur | Brockow, Knut | Burney, Peter | Buters, Jeroen | Butiene, Indre | Calderon, Moises | Cardell, Lars Olaf | Caubet, Jean-Christoph | Celenk, Sevcan | Cichocka-Jarosz, Ewa | Cingi, Cemal | Couto, Mariana | deJong, Nicolette | Del Giacco, Stefano | Douladiris, Nikolaos | Fassio, Filippo | Fauquert, Jean-Luc | Fernandez, Javier | Rivas, Montserrat Fernandez | Ferrer, Marta | Flohr, Carsten | Gardner, James | Genuneit, Jon | Gevaert, Philippe | Groblewska, Anna | Hamelmann, Eckard | Hoffmann, Hans Jürgen | Hoffmann-Sommergruber, Karin | Hovhannisyan, Lilit | Hox, Valérie | Jahnsen, Frode L | Kalayci, Ömer | Kalpaklioglu, Ayse Füsun | Kleine-Tebbe, Jörg | Konstantinou, George | Kurowski, Marcin | Lau, Susanne | Lauener, Roger | Lauerma, Antti | Logan, Kirsty | Magnan, Antoine | Makowska, Joanna | Makrinioti, Heidi | Mangina, Paraskevi | Manole, Felicia | Mari, Adriano | Mazon, Angel | Mills, Clare | Mingomataj, ErvinÇ | Niggemann, Bodo | Nilsson, Gunnar | Ollert, Markus | O'Mahony, Liam | O'Neil, Serena | Pala, Gianni | Papi, Alberto | Passalacqua, Gianni | Perkin, Michael | Pfaar, Oliver | Pitsios, Constantinos | Quirce, Santiago | Raap, Ulrike | Raulf-Heimsoth, Monika | Rhyner, Claudio | Robson-Ansley, Paula | Alves, Rodrigo Rodrigues | Roje, Zeljka | Rondon, Carmen | Rudzeviciene, Odilija | Ruëff, Franziska | Rukhadze, Maia | Rumi, Gabriele | Sackesen, Cansin | Santos, Alexandra F | Santucci, Annalisa | Scharf, Christian | Schmidt-Weber, Carsten | Schnyder, Benno | Schwarze, Jürgen | Senna, Gianenrico | Sergejeva, Svetlana | Seys, Sven | Siracusa, Andrea | Skypala, Isabel | Sokolowska, Milena | Spertini, Francois | Spiewak, Radoslaw | Sprikkelman, Aline | Sturm, Gunter | Swoboda, Ines | Terreehorst, Ingrid | Toskala, Elina | Traidl-Hoffmann, Claudia | Venter, Carina | Vlieg-Boerstra, Berber | Whitacker, Paul | Worm, Margitta | Xepapadaki, Paraskevi | Akdis, Cezmi A
In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.
The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.
Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
PMCID: PMC3539924  PMID: 23121771
Allergy; Allergic diseases; Policy; Research needs; Research funding; Europe
3.  Rhinoplasty from a rhinologist's perspective: Need for recognition of associated sinonasal conditions 
Facial plastic surgeons may primarily focus on esthetic improvement of the nasal shape in patients seeking rhinoplasty (RP). However, medical conditions inside the nasal cavity should not be neglected because they may lead to unresolved sinonasal problems and, hence, dissatisfaction after esthetic RP. This observational study investigated the prevalence of sinonasal symptoms and endonasal pathology in patients requesting esthetic RP.
Patients seeking RP (n = 269) were given a questionnaire evaluating nasal obstruction and sinonasal symptoms using visual analog scales and the 22-item Sino-Nasal Outcome Test. In addition, patients underwent nasal endoscopy to evaluate anatomic and/or mucosal disease and skin-prick testing in case of clinical suspicion of allergy. Two control groups consisted of patients with an otological or general ear/nose/throat problem (n = 65) and patients who planned for endoscopic sinus surgery (ESS; n = 90).
The general appraisal of nasal breathing on a scale from 0–10 in patients seeking RP was as low as 4.3 ± 3.1. Structural pathology was found in 62% of RP patients, with septal deviation being the most frequent problem encountered (54%), followed by internal nasal valve dysfunction (14%). Mucosal disease was present in 28% of RP patients. The mean SNOT-22 score of RP patients (31.8 ± 23.3) was significantly higher than the control group (11.6 ± 7.9; p < 0.001), but lower than the ESS patients (48.5 ± 22.0; p < 0.001).
The prevalence of endonasal structural or mucosal pathology in patients seeking RP is high and should not be overlooked at the time of planning surgery.
PMCID: PMC3903105  PMID: 23232202
ESS; esthetic; facial; functional; mucosal disease; nasal breathing; nasal valve; revision; rhinoplasty; sinonasal
4.  Explorative study on patient’s perceived knowledge level, expectations, preferences and fear of side effects for treatment for allergic rhinitis 
In spite of the high prevalence of allergic rhinitis (AR) and the evidence-based guidelines for treatment, little is known about the patients’ perceived knowledge level, expectations, preferences for treatment, and fear for side effects of treatment for AR. This study aimed at gaining insight into these patient-related factors.
This explorative cross-sectional survey study included a convenience sample of 170 patients with rhinitis and clinical suspicion of allergy at the department of Otorhinolaryngology and Allergology. Patients’ perceived knowledge level, expectations, patient preferences, and fear of side effects of allergy treatment were collected via a self-report questionnaire developed for the purpose of this study.
22% of all patients (38/170) reported to have knowledge about anti-allergic treatment. 40% (55/170) of rhinitis patients expected to be cured by the prescribed treatment, whereas 43% (73/170) of patients expected suppression of allergic symptoms. Nasal spray was the preferred route of anti-allergic drug administration in 30% (52/170) of patients, followed by oral treatment (24%; 42/170), combination therapy (16%; 30/170), and injection therapy (15%; 27/170). More patients would choose a combination treatment with step-down approach (31%; 53/170) than mono-therapy with a step-up approach (20%; 34/170). Fear for side effects was reported mainly for nasal corticosteroids (48%; 81/170) and less for oral antihistamines (33%; 36/170), leucotriene antagonists (21%, 36/170) and immunotherapy (19%, 33/170).
Patients consulting for rhinitis have high expectations of anti-allergic treatment, prefer a nasal spray above oral treatment, prefer combined treatment rather than monotherapy, and fear adverse events of anti-allergic treatment.
PMCID: PMC3447732  PMID: 22643067
Allergy; Rhinitis; Treatment; Patient reported outcomes; Preferences; Side-effects
5.  Sensitization rate and clinical profile of Congolese patients with rhinitis 
Allergy & Rhinology  2012;3(1):e16-e24.
In the African continent, the sensitization pattern and clinical profile are unknown in patients with rhinitis/rhinosinusitis attending the outpatient ear, nose, and throat (ENT) clinics. We therefore aimed to analyze the clinical characteristics of rhinitis/rhinosinusitis patients in Democratic Republic of Congo (DRC), classify allergic rhinitis (AR) according to the Allergic Rhinitis and Its Impact on Asthma criteria, and evaluate the sensitization profile and its associated factors. From January to May 2009, 423 patients with rhinitis symptoms attending the Outpatient ENT clinic of the University Hospital and Saint Joseph Hospital of Kinshasa were evaluated for allergy symptoms, severity, and duration of symptoms and underwent skin-prick tests (SPTs) for a panel of 15 allergens. Of 423 patients 35.2% had positive SPT results, with 40.9% showing polysensitization. Dermatophagoides pteronyssinus (DPT) (68.5%) and cockroach (36.2%) were the most common allergens among sensitized patients. Patients with rhinitis/rhinosinusitis mainly presented in decreasing order with sneezing, facial pain/pressure, nasal obstruction, postnasal discharge, nose itching, clear nasal discharge, and eye itching. Persistent and moderate/severe AR represented 61.4 and 69.3%, respectively. Sensitization was independently associated with younger age, rhinoconjunctivitis, and reaction to nonspecific trigger factors. In conclusion, 35.2% of patients attending the ENT Outpatient Clinic in DRC for rhinitis problems had a positive SPT to at least one allergen, with mainly DPT and cockroach allergens being involved; and a substantial portion showed persistent and moderate/severe AR. Therefore, allergy should not be neglected as an etiologic factor in rhinologic disease in the African continent.
PMCID: PMC3404473  PMID: 22852125
Congo; rhinitis; rhinosinusitis; skin-prick testing; symptoms
6.  Exacerbation of cigarette smoke-induced pulmonary inflammation by Staphylococcus aureus Enterotoxin B in mice 
Respiratory Research  2011;12(1):69.
Cigarette smoke (CS) is a major risk factor for the development of COPD. CS exposure is associated with an increased risk of bacterial colonization and respiratory tract infection, because of suppressed antibacterial activities of the immune system and delayed clearance of microbial agents from the lungs. Colonization with Staphylococcus aureus results in release of virulent enterotoxins, with superantigen activity which causes T cell activation.
To study the effect of Staphylococcus aureus enterotoxin B (SEB) on CS-induced inflammation, in a mouse model of COPD.
C57/Bl6 mice were exposed to CS or air for 4 weeks (5 cigarettes/exposure, 4x/day, 5 days/week). Endonasal SEB (10 μg/ml) or saline was concomitantly applied starting from week 3, on alternate days. 24 h after the last CS and SEB exposure, mice were sacrificed and bronchoalveolar lavage (BAL) fluid and lung tissue were collected.
Combined exposure to CS and SEB resulted in a raised number of lymphocytes and neutrophils in BAL, as well as increased numbers of CD8+ T lymphocytes and granulocytes in lung tissue, compared to sole CS or SEB exposure. Moreover, concomitant CS/SEB exposure induced both IL-13 mRNA expression in lungs and goblet cell hyperplasia in the airway wall. In addition, combined CS/SEB exposure stimulated the formation of dense, organized aggregates of B- and T- lymphocytes in lungs, as well as significant higher CXCL-13 (protein, mRNA) and CCL19 (mRNA) levels in lungs.
Combined CS and SEB exposure aggravates CS-induced inflammation in mice, suggesting that Staphylococcus aureus could influence the pathogenesis of COPD.
PMCID: PMC3125222  PMID: 21615971
7.  IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? 
Respiratory Research  2006;7(1):135.
The role of Th2 cells (producing interleukin (IL-)4, IL-5 and IL-13) in allergic asthma is well-defined. A distinct proinflammatory T cell lineage has recently been identified, called Th17 cells, producing IL-17A, a cytokine that induces CXCL8 (IL-8) and recruits neutrophils. Neutrophilic infiltration in the airways is prominent in severe asthma exacerbations and may contribute to airway gland hypersecretion, bronchial hyper-reactivity and airway wall remodelling in asthma.
to study the production of IL-17 in asthmatic airways at the mRNA level, and to correlate this with IL-8 mRNA, neutrophilic inflammation and asthma severity.
We obtained airway cells by sputum induction from healthy individuals (n = 15) and from asthmatic patients (n = 39). Neutrophils were counted on cytospins and IL-17A and IL-8 mRNA expression was quantified by real-time RT-PCR (n = 11 controls and 33 asthmatics).
Sputum IL-17A and IL-8 mRNA levels are significantly elevated in asthma patients compared to healthy controls. IL-17 mRNA levels are significantly correlated with CD3γ mRNA levels in asthmatic patients and mRNA levels of IL-17A and IL-8 correlated with each other and with sputum neutrophil counts. High sputum IL-8 and IL-17A mRNA levels were also found in moderate-to-severe (persistent) asthmatics on inhaled steroid treatment.
The data suggest that Th17 cell infiltration in asthmatic airways links T cell activity with neutrophilic inflammation in asthma.
PMCID: PMC1636037  PMID: 17083726
8.  The Lectin-like Domain of Thrombomodulin Confers Protection from Neutrophil-mediated Tissue Damage by Suppressing Adhesion Molecule Expression via Nuclear Factor κB and Mitogen-activated Protein Kinase Pathways 
Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH2-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TMLeD/LeD), we show that the lectin-like domain of TM interferes with polymorphonuclear leukocyte (PMN) adhesion to ECs by intercellular adhesion molecule 1–dependent and –independent pathways through the suppression of extracellular signal–regulated kinase (ERK)1/2 activation. TMLeD/LeD mice have reduced survival after endotoxin exposure, accumulate more PMNs in their lungs, and develop larger infarcts after myocardial ischemia/reperfusion. The recombinant lectin-like domain of TM suppresses PMN adhesion to ECs, diminishes cytokine-induced increase in nuclear factor κB and activation of ERK1/2, and rescues ECs from serum starvation, findings that may explain why plasma levels of soluble TM are inversely correlated with cardiovascular disease. These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis.
PMCID: PMC2193995  PMID: 12208873
inflammation; coagulation; endotoxin; sepsis; protein C

Results 1-8 (8)