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Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.

Background: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. Objective: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patients’ quality of life by addressing unmet needs. Methods: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. Results: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. Conclusions: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders., The authors thank Tania Bray, Jan Hempstead, Heather Mayne, Joanne Mulder-Brambleby, and Irene Wilson for their supporting contributions, and all patients and families affected by MCDs, who shared their needs and concerns for development of this project. Authors involved in study conception and design were P. Valent, S.V. Jennings, C.C. Finnerty, J.S. Hobart, M. Martín-Martínez, K.A. Sinclair, V.M. Slee, J. Agopian, C. Akin, I. Álvarez-Twose, P. Bonadonna, A.A. Bowman, K. Brockow, H. Bumbea, C. de Haro, J.S. Fok, K. Hartmann, N. Hegmann, O. Hermine, M. Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D. Mayne, D. Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea Vaia, M. Niedoszytko, H. Oude Elberink, A. Orfao, D.H. Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink, F. Wimazal, T. Yigit, and C. Zubrinich. Authors involved in acquisition and review of data were S.V. Jennings, C.C. Finnerty, J.S. Hobart, M. Martín-Martínez, K.A. Sinclair, V.M. Slee, J. Agopian, C. Akin, I. Álvarez-Twose, P. Bonadonna, A.A. Bowman, K. Brockow, H. Bumbea, C. de Haro, J.S. Fok, K. Hartmann, N. Hegmann, O. Hermine, M. Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D. Mayne, D. Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea Vaia, M. Niedoszytko, H. Oude Elberink, A. Orfao, D.H. Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink, F. Wimazal, T. Yigit, C. Zubrinich, and P. Valent. The Core Group (analysis and interpretation of data and drafting of the manuscript) include S.V. Jennings, C.C. Finnerty, J.S. Hobart, M. Martín-Martínez, K.A. Sinclair, and V.M. Slee. Critical revision was performed by S.V. Jennings, C.C. Finnerty, J.S. Hobart, M. Martín-Martínez, K.A. Sinclair, V.M. Slee, J. Agopian, C. Akin, I. Álvarez-Twose, P. Bonadonna, A.A. Bowman, K. Brockow, H. Bumbea, C. de Haro, J.S. Fok, K. Hartmann, N. Hegmann, O. Hermine, M. Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D. Mayne, D. Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea Vaia, M. Niedoszytko, H. Oude Elberink, A. Orfao, D.H. Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink, F Wimazal, T. Yigit, C. Zubrinich, and P. Valent.

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM–adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia., T.G. was supported by grants from the Konsul TH C Bergh Foundation and the Stockholm County Council Research Funds (ALF), Sweden. M.C.C., J.J.L, and D.D.M. were supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not represent the official views of the NIH. P.V. was supported by the Austrian Science Fund (FWF; projects P32470-B and F4704-B20).

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by ≥20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (≥10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL. ispartof: BLOOD ADVANCES vol:7 issue:9 pages:1713-1724 ispartof: location:United States status: published

Data de publicació electrònica: 17-04-2023

In 2002, the European Competence Network on Mastocytosis (ECNM) was launched as a multidisciplinary collaborative initiative to increase the awareness and to improve diagnosis and management of patients with mast cell (MC) disorders. The ECNM consists of a net of specialized centers, expert physicians, and scientists who dedicate their work to MC diseases. One essential aim of the ECNM is to timely distribute all available information about the disease to patients, doctors, and scientists. In the past 20 years, the ECNM has expanded substantially and contributed successfully to the development of new diagnostic concepts, and to the classification, prognostication, and treatments of patients with mastocytosis and MC activation disorders. The ECNM also organized annual meetings and several working conferences, thereby supporting the development of the World Health Organization classification between 2002 and 2022. In addition, the ECNM established a robust and rapidly expanding patient registry and supported the development of new prognostic scoring systems and new treatment approaches. In all projects, ECNM representatives collaborated closely with their U.S. colleagues, various patient organizations, and other scientific networks. Finally, ECNM members have started several collaborations with industrial partners, leading to the preclinical development and clinical testing of KIT-targeting drugs in systemic mastocytosis, and some of these drugs received licensing approval in recent years. All these networking activities and collaborations have strengthened the ECNM and supported our efforts to increase awareness of MC disorders and to improve diagnosis, prognostication, and therapy in patients.

Background: Subcutaneous immunotherapy (SCIT) is widely used in the treatment of allergic rhinitis (AR). This study aimed to determine the expression of 48 miRNAs in patients with AR undergoing grass pollen SCIT and investigate relations with clinical outcomes. Methodology: Expression of selected miRNAs was determined using RT-PCR in the full blood of 16 patients with AR and seven healthy controls. Results: miR-136, miR-208 and miR-190 were upregulated in the AR group. After 6 months of SCIT, significant downregulation of some proinflammatory miRNAs and upregulation of several miRNAs regulating Th1/Th2 balance were found. No differences were found between good and poor responders. Conclusion: miRNAs may play a regulatory role in SCIT, leading to tolerance induction.

BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression. (c) 2022 American Academy of Allergy, Asthma & Immunology

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Introduction Allergen-specific immunotherapy (AIT) is the core treatment in allergic rhinitis and asthma. Although widely used, some patients do not benefit from treatment and there is no efficacy objective marker. Aim To define the profile of gene transcripts during the build-up phase of AIT and their comparison to the control group and then search for a viable efficacy marker in relation to patient symptoms. Material and methods AIT was administered in 22 patients allergic to grass pollen. Analysis of 15 selected transcript expression was performed in whole blood samples taken before AIT (sample A) and after reaching the maintenance dose (sample B). The control group included 25 healthy volunteers (sample C). The primary endpoint was Relative Quantification. The gene expression analysis was followed by clinical evaluation with the use of Allergy Control Score (ACS). Results Comparison between samples A and B of gene expression showed a significant increase in IFNG expression (p = 0.03). In relation to the control group, pretreatment samples from patients showed higher levels of AFAP1L1 (p = 0.006), COMMD8 (p = 0.001), PIK3CD (p = 0.027) and TWIST2 (p = 0.0003) in univariate analysis. A generalized linear regression model was built according to the Bayesian Information Criterion based on the IFNG, FCER1A and PCDHB10 expression pattern for prediction of the AIT outcome. The model showed a correlation in predicted and observed changes in ACS. Conclusions There is a significant change in the expression of IFNG during the build-up phase of AIT. The authors propose an in vitro model of AIT efficacy prediction for further validation.

In clinical and epidemiological studies, cut-offs of Patient-Reported Outcome Measures (PROMs) can be used to classify patients into groups of statistical and clinical relevance. However, visual analog scale (VAS) cut-offs in MASK-air® have not been tested.To calculate cut-offs for VAS global, nasal, ocular, and asthma symptoms.In a cross-sectional study design of all MASK-air® participants, we compared (i) approaches based on the percentiles (tertiles or quartiles) of VAS distributions, and (ii) data-driven approaches based on clusters of data from two comparators (VAS work and VAS sleep). We then performed sensitivity analyses for individual countries and for VAS levels corresponding to full allergy control. Finally, we tested the different approaches using MASK-air® real-world cross-sectional and longitudinal data to assess the most relevant cut-offs.We assessed 395,223 days from 23,201 MASK-air® users with self-reported allergic rhinitis. The percentile-oriented approach resulted in lower cut-off values than the data-driven approach. We obtained consistent results in the data-driven approach. Following the latter, the proposed cut-off differentiating "controlled" and "partly-controlled" patients was similar to the cut-off value which had been arbitrarily used (20/100). However, a lower cut-off was obtained to differentiate between "partly-controlled" and "uncontrolled" patients (35 versus the arbitrarily-used value of 50/100).Using a data-driven approach, we were able to define cut-off values for MASK-air® VASs on allergy and asthma symptoms. This may allow for a better classification of rhinitis and asthma patients according to different levels of control, supporting improved disease management.

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-Tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs HαT− cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.

Przedstawiono rekomendacje Polskiego Towarzystwa Alergologicznego dotyczące kwalifikacji osób z alergią i anafilaksją do szczepienia przeciw COVID-19, zarówno dla lekarzy kwalifikujących do szczepień przeciw COVID-19 niebędących alergologami, jak i dla alergologów konsultujących pacjentów z wywiadem przebytej anafilaksji lub ciężkiego (niekontrolowanego) przebiegu chorób alergicznych i astmy szczepionych przeciw COVID-19. Recommendations of the Polish Society of Allergology regarding the qualification of person with allergies and anaphylaxis for vaccination against COVID-19 were presented, both for doctors qualifying for vaccination against COVID-19 who are not allergologists and for allergologists consulting patients with a history of anaphylaxis or severe (uncontrolled) allergic diseases and asthma vaccinated against COVID-19.

Introduction Mastocytosis is a rare disease characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems and is classified as being either cutaneous mastocytosis (CM) or systemic mastocytosis (SM). In the pioneer studies of Slominski's group, a fully functional hypothalamic-pituitary-adrenal axis equivalent has been discovered in various tissues, including skin. Aim In the present study we investigated potential involvement of hypothalamus-pituitary-adrenal (HPA) cutaneous equivalent in ongoing mastocytosis. Material and methods The expression of HPA elements: CRH, UCN1, UCN2, UCN3, CRHR1, POMC, MC1R, MC2R and NR3C1 was assessed for their mRNA level in skin biopsies of adult patients with mastocytosis and healthy donors (n = 16 and 19, respectively), while CRH, UCN1, CRHR1, ACTH and MC1R were selected for immunostaining assay (n = 13 and 7, respectively). The expression of CRH receptor 1 (CRHR1) isomers was investigated by RT-PCR. The ELISA was used for detection of cortisol, CRH, UCN and ACTH in the serum. Results The decrease in the expression of HPA element of skin equivalent was observed on both mRNA and protein levels, however quantification of immunohistochemical data was impeded due to melanin in epidermis. Furthermore, we observed infiltration of dermis with HPA elements overexpressing mononuclear cells, which is in the agreement with an in vitro study showing a high expression of HPA elements by mast cells. Conclusions Taken together, it was confirmed that the expression elements of HPA was modulated in mastocytosis, thus the potential involvement of general and local stress responses in its pathogenesis should be postulated and further investigated.

Introduction Appropriate and targeted psychological care, as well as psychoeducation covering the disease causes, symptoms, and their management are crucial elements of the therapeutic process in patients with mastocytosis. This care is based on the identification of problematic areas that are of the greatest importance for patients. The quality of life questionnaires available in Poland are designed for the general population; therefore, they do not encompass the specificity of difficulties experienced by people suffering from mastocytosis. Aim To develop a questionnaire measuring the quality of life in patients with mastocytosis, and including the issues and symptoms typical for this group. Material and methods The study involved 85 patients (57 women and 28 men) suffering from mastocytosis. Results The analyses revealed that the Quality of Life in Mastocytosis Scale (QLMS) is a reliable and valid tool for measuring the quality of life, and it takes into account the specific difficulties experienced by patients with mastocytosis. Apart from the measurement of the global quality of life, QLMS offers a deeper assessment of the quality of patient’s lives, including the difficulties in professional life, everyday life, leisure time, or those associated with protective behaviours. Conclusions The presented questionnaire completes a gap in quality–of-life studies by allowing to plan psychoeducation and offering a tool for a precise diagnosis of the quality of life in patients with mastocytosis.

Funding Information: IA reports personal fees from Roxall, Menarini, UCB, Faes Farma, Sanofi, Bial, Amgen, Abbott, Bayer, Organon. SBA reports grants from TEVA, personal fees from TEVA, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, Mylan. JB reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi‐Aventis, Takeda, Teva, Uriach, other from KYomed‐Innov, personal fees from Purina, other from MASK‐air. VC reports personal fees from Thermofisher. PCM reports personal fees from Abbvie, AZ, Bial, GSK, Mylan, Medinfar, Novartis, Sanofi. LC reports personal fees from Malesci, Menarini, Astra Zeneca, Novartis. AC reports grants and personal fees from Astrazeneca, GSK, Sanofi, personal fees from Boehringer‐Ingelheim, Chiesi, Glenmark, Novartis, personal fees from Mylan, Abdi‐Ibrahim. PD reports personal fees and non‐financial support from Stallergenes Greer, ALK‐Abello, Astra Zeneca, CHIESI, MYLAN/Meda Pharma, Novartis, GlaxoSmithKline, Sanofi, IQVIA personal fees from MENARINI. JAFonseca reports participation in SME that has mHealth technologies for patients with asthma. JCI reports personal fees from Abbott Ecuador, Bago Bolivia, Faes Farma, Laboratorios Casasco, Sanofi. LK reports grants and personal fees from Allergopharma, LETI Pharma,MEDA/Mylan, Sanofi, personal fees from HAL Allergie, Allergy Therapeut., Cassella med, grants from ALK Abelló, Stallergenes, Quintiles, ASIT biotech, Lofarma, AstraZeneca, GSK, Inmunotk, and Membership: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO‐BV, GPA, EAACI. VK reports other from Norameda, BerlinCHemie Menarini. PK reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, Boehringer Ingelheim, Chiesi, GSK, Novartis, Polpharma. DLL reports personal fees from Allakos, Amstrong, Astrazeneca, Chiesi, DBV Technologies, Grunenthal, GSK, Mylan/Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Alakos, Gossamer, Carnot, grants from Sanofi, Astrazeneca, Novartis, Circassia, UCB, GSK, Purina institute, Abvvie, Lilly, Pfizer. BL reports grants and personal fees from Meda, personal fees from Glenamrk. RL reports grants and personal fees from GSK, AZ, Chiesi, personal fees from Novartis, Sanofi. MM reports personal fees from Novartis, Gsk, Menarini, Az, Chiesi, Sanofi, Pfizer. RM reports personal fees from Angelini Pharma ALK, Allergopharma, Allergy Therapeutics, Friulchem, Hexal, Servier, Klosterfrau, Bayer, FAES, GSK, MSD, Johnson&Johnson, Meda, Stada, UCB, Nuvo, Menarini, Mundipharma, Pohl‐Boskamp, Laboratoire de la Mer, Sidroga, Lek, PRO‐AdWise, grants and personal fees from Bencard, Stallergenes, Ursapharm, HAL BV, grants from Leti, Optima, BitopAG, Hulka, Inmunotek, Cassella‐med GmbH & Co. KG, ASIT biotech, grants, personal fees and non‐financial support from Lofarma, non‐financial support from Roxall, Atmos, Bionorica, Otonomy, Ferrero, personal fees and non‐financial support from Novartis. OP reports grants and personal fees from ALK‐Abelló, Allergopharma, Stallergenes Greer HAL Allergy Holding B.V./HAL Allergie GmbH, Bencard Allergie GmbH/Allergy Therapeutics, Lofarma, ASIT Biotech Tools S.A., Laboratorios LETI/LETI Pharma, Anergis S.A., GlaxoSmithKline, personal fees from MEDA Pharma/MYLAN, Mobile Chamber Experts (a GA2LEN Partner), Indoor Biotechnologies, Astellas Pharma Global, EUFOREA, ROXALL Medizin, Novartis, Sanofi‐Aventis and Sanofi‐Genzyme, Med Update Europe GmbH, streamedup! GmbH, John Wiley and Sons, AS, Paul‐Martini‐Stiftung (PMS), Regeneron Pharmaceuticals Inc., RG Aerztefortbildung, Institut für Disease Management, Springer GmbH, AstraZeneca, IQVIA Commercial, Ingress Health, grants from Pohl‐Boskamp, Inmunotek S.L., Biomay, Circassia. NGPapadopoulos reports personal fees from Novartis, Nutricia, HAL, MENARINI/FAES FARMA, SANOFI, MYLAN/MEDA, BIOMAY, AstraZeneca, GSK, MSD, ASIT BIOTECH, Boehringer Ingelheim, grants from Gerolymatos International SA, Capricare. ATB reports personal fees from AstraZeneca, GSK, Novartis, IQVIA/Abbvie, Mylan, Bial, Leti, grants and personal fees from Teva. STS reports personal fees from ERT, Roche products, Novartis, Sanofi Pharma, AstraZeneca, ALK‐ Abelló grants from Glaxo Smith Kline. IT reports grants from GSK, Boehringer Ingelheim, AZ, personal fees from Novartis, Astra Zeneca, Chiesi, TZ reports Organizational affiliations: Committee member: WHO‐Initiative “Allergic Rhinitis and Its Impact on Asthma” (ARIA); Member of the Board: German Society for Allergy and Clinical Immunology (DGAKI); Head: European Centre for Allergy Research Foundation (ECARF). President: Global Allergy and Asthma European Network (GA2LEN); Member: Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). Funding Information: MASK‐air® has been supported by EU grants (POLLAR, EIT Health; Structural and Development Funds, Twinning, EIP on AHA and H2020) and educational grants from Mylan‐Viatris, ALK, GSK, Novartis and Uriach 1 1 Publisher Copyright: © 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. Background: Different treatments exist for allergic rhinitis (AR), including pharmacotherapy and allergen immunotherapy (AIT), but they have not been compared using direct patient data (i.e., “real-world data”). We aimed to compare AR pharmacological treatments on (i) daily symptoms, (ii) frequency of use in co-medication, (iii) visual analogue scales (VASs) on allergy symptom control considering the minimal important difference (MID) and (iv) the effect of AIT. Methods: We assessed the MASK-air® app data (May 2015–December 2020) by users self-reporting AR (16–90 years). We compared eight AR medication schemes on reported VAS of allergy symptoms, clustering data by the patient and controlling for confounding factors. We compared (i) allergy symptoms between patients with and without AIT and (ii) different drug classes used in co-medication. Results: We analysed 269,837 days from 10,860 users. Most days (52.7%) involved medication use. Median VAS levels were significantly higher in co-medication than in monotherapy (including the fixed combination azelastine-fluticasone) schemes. In adjusted models, azelastine-fluticasone was associated with lower average VAS global allergy symptoms than all other medication schemes, while the contrary was observed for oral corticosteroids. AIT was associated with a decrease in allergy symptoms in some medication schemes. A difference larger than the MID compared to no treatment was observed for oral steroids. Azelastine-fluticasone was the drug class with the lowest chance of being used in co-medication (adjusted OR = 0.75; 95% CI = 0.71–0.80). Conclusion: Median VAS levels were higher in co-medication than in monotherapy. Patients with more severe symptoms report a higher treatment, which is currently not reflected in guidelines. publishersversion published

Low air quality in Poland is a problem of particularly high urgency. Therefore, Poles must be aware of air quality levels, also during the COVID-19 pandemic. The study aimed to compare air-pollution-related information-seeking behaviour between the pre- and intra-pandemic periods as well as between the actual and theoretical machine-learning-forecasted intra-pandemic models. Google Trends search volumes (GTSVs) in Poland for air-pollution-related keywords were collected between January 2016 and January 2022. To investigate the changes that would have occurred without the outbreak of the pandemic, Seasonal Autoregressive Integrated Moving Average (SARIMA) machine-learning models were trained. Approximately 4,500,000 search queries were analysed. Between pre- and intra-pandemic periods, weighted mean GTSVs changed by −39.0%. When the actual intra-pandemic weighted mean GTSVs were compared to the intra-pandemic forecasts, the actual values were lower by −16.5% (SARIMA’s error = 6.2%). Compared to the pre-pandemic period, in the intra-pandemic period, the number of search queries containing keywords connected with air pollution decreased. Moreover, the COVID-19 pandemic might have facilitated the decrease. Possible causes include an attention shift towards everyday problems connected to the pandemic, worse mental health status and lower outdoor exposure that might have resulted in a lower intensity of non-pandemic-related active information-seeking behaviour.

The document prepared by the expert panel of allergy/immunology specialists representing Polish Allergy Society intends to provide allergists with recommendations with respect to proper management of allergic patients during SARS-CoV-2 pandemics Allergist should aim at reducing patient’s social interactions by replacing face-to-face visits with communication via telephone or internet In parallel allergist is responsible for assuring that the patient is receiving proper care of underlying allergic disease The experts panel provides eighteen recommendations for management of patients with asthma and allergic diseases during pandemics, indicating that in majority of patients asthma treatment (including inhaled corticosteroids) and allergy treatment should be continued Specific recommendations for treatment with allergen immunotherapy and with biologics are discussed in details

Advanced systemic mastocytosis (AdvSM) is characterized by the presence of KIT D816V and other somatic mutations (eg, in SRSF2, ASXL1, and RUNX1) in 95% and 60% to 70% of patients, respectively. The biological and clinical consequences of AdvSM include multilineage involvement (eg, associated hematologic neoplasm) in 60% to 80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow and visceral organs through affected mast cell (MC) and non-MC lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KIT inhibitor midostaurin and the selective KIT D816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed to better capture clinical benefit (eg, improved responses and progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases investigators that use a tiered approach to segregate the effects of histopathologic (eg, bone marrow MC burden, tryptase), molecular (eg, KIT D816V variant allele frequency), clinical (eg, C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KIT inhibitors and other novel agents., J. Gotlib expresses gratitude to the Charles and Ann Johnson Foundation and the Stanford Cancer Institute Clinical Innovation Fund for their support of mastocytosis research at Stanford. J. Schwaab, J. Lübke, and A. Reiter were supported by Deutsche José Carreras Leukämie-Stiftung Grant No. DJCLS 08R/2020. M.C. Carter, J.J. Lyons, and D.D. Metcalfe are supported by federal funds from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National

In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels

Data de publicació electrònica: 03-11-2022 Introduction: Data from mHealth apps can provide valuable information on rhinitis control and treatment patterns. However, in MASK-air®, these data have only been analyzed cross-sectionally, without considering the changes of symptoms over time. We analyzed data from MASK-air® longitudinally, clustering weeks according to reported rhinitis symptoms. Methods: We analyzed MASK-air® data, assessing the weeks for which patients had answered a rhinitis daily questionnaire on all 7 days. We firstly used k-means clustering algorithms for longitudinal data to define clusters of weeks according to the trajectories of reported daily rhinitis symptoms. Clustering was applied separately for weeks when medication was reported or not. We compared obtained clusters on symptoms and rhinitis medication patterns. We then used the latent class mixture model to assess the robustness of results. Results: We analyzed 113,239 days (16,177 complete weeks) from 2590 patients (mean age ± SD = 39.1 ± 13.7 years). The first clustering algorithm identified ten clusters among weeks with medication use: seven with low variability in rhinitis control during the week and three with highly-variable control. Clusters with poorly-controlled rhinitis displayed a higher frequency of rhinitis co-medication, a more frequent change of medication schemes and more pronounced seasonal patterns. Six clusters were identified in weeks when no rhinitis medication was used, displaying similar control patterns. The second clustering method provided similar results. Moreover, patients displayed consistent levels of rhinitis control, reporting several weeks with similar levels of control. Conclusions: We identified 16 patterns of weekly rhinitis control. Co-medication and medication change schemes were common in uncontrolled weeks, reinforcing the hypothesis that patients treat themselves according to their symptoms.

Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual’s baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.

In recent years, knowledge about mechanisms underlying mast cell activation (MCA) and accumulation in various pathologic conditions increased substantially. In addition, criteria and a classification of MCA syndromes (MCASs) have been set forth. MCAS is defined by typical clinical symptoms, a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase, and a response of the symptoms to drugs targeting mast cells, mediator production, and/or mediator effects. Alternative diagnostic criteria of MCAS have also been suggested, but these alternative criteria often lack specificity and validation. In this report, we critically review the contemporary literature relating to MCAS and compare the specificity, sensitivity, and strength of MCAS-related parameters within proposals to diagnose and classify MCAS and its variants. Furthermore, we highlight the need to apply specific consensus criteria in the evaluation and classification of MCAS in individual patients. This is an urgent and important medical necessity because as an increasing number of patients are being given a misdiagnosis of MCAS based on nonspecific criteria, which contributes to confusion and frustration by patients and caregivers and sometimes may delay recognition and treatment of correct medical conditions that often turn out to be unrelated to MCA. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.

Background Mastocytosis is a clinically heterogeneous, usually acquired disease of the mast cells with a survival time that depends on the onset of the disease and ranges from skin-limited to systemic disease, including indolent and more aggressive variants. The crucial element in pathogenesis is the presence of oncogenic KIT somatic mutation D816V. Further epigenetic alterations are responsible for regulating the expression of genes. It is essential to identify indicators of disease progression, and the specific clinical picture to establish an appropriate therapeutic strategy. Objective The aim of this study was to analyze the relation of mastocytosis symptoms and epigenetic changes, and to identify epigenetic predictors of the disease. Methods Global DNA methylation profile analysis was performed in peripheral blood collected from 73 patients with indolent systemic mastocytosis (ISM) and 43 healthy adult volunteers. Levels of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) were determined using an ELISA-based method, while the methylation of the Alu and LINE-1 repeats were assayed with the quantitative methylation-specific PCR technique. A questionnaire interview was conducted among the study participants to collect data on possible epigenetic modifiers. Additionally, the methylation profile was compared between three human mast cell lines: ROSA KIT D816V, ROSA KIT WT, and HMC-1.1 KIT V560G, in order to assess the association between KIT mutations and methylation profile. Results A significantly lower level of DNA hydroxymethylation (5-hmC) in the blood was found in patients with ISM as compared to the controls (0.022% vs. 0.042%, p = 0.0001). Differences in the markers of global DNA methylation (5-mC, Alu, LINE-1) were not statistically significant, although they did indicate generally higher DNA methylation in patients with mastocytosis. The 5-hmC level was significantly associated with allergy (p = 0.011) in patients with ISM, showing a higher level of 5-hmC in patients with allergy as compared to patients without allergy. The in vitro study revealed significant differences between the studied cell lines at the level of 5-mC, Alu, and LINE-1. Conclusions This study confirms that epigenetic changes are involved in mastocytosis, and suggests that allergy may be an important epigenetic modifier of the disease. A possible association between KIT mutations and methylation status observed in human mast cell lines requires further investigation in human studies. Clinical implications Epigenetic alterations are involved in mastocytosis pathology. The possible role of allergy as an important epigenetic modifier suggests the more impaired function of mast cells in ISM patients without allergy. Capsule summary Decreased DNA demethylation in the blood DNA of patients with ISM confirms that epigenetic alterations are involved in mastocytosis pathology. We observed a possible role of allergy as an important epigenetic modifier. There is a possible association between KIT mutations and the methylation status observed in human mast cell lines.

Background: Several studies have suggested an impact of allergic rhinitis on academic productivity. However, large studies with real-world data (RWD) are not available. Objective: To use RWD to assess the impact of allergic rhinitis on academic performance (measured through a visual analog scale [VAS] education and the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific [WPAI+CIQ:AS] questionnaire), and to identify factors associated with the impact of allergic rhinitis on academic performance. Methods: We assessed data from the MASK-air mHealth app of users aged 13 to 29 years with allergic rhinitis. We assessed the correlation between variables measuring the impact of allergies on academic performance (VAS education, WPAI+CIQ:AS impact of allergy symptoms on academic performance, and WPAI+CIQ:AS percentage of education hours lost due to allergies) and other variables. In addition, we identified factors associated with the impact of allergic symptoms on academic productivity through multivariable mixed models. Results: A total of 13,454 days (from 1970 patients) were studied. VAS education was strongly correlated with the WPAI+CIQ:AS impact of allergy symptoms on academic productivity (Spearman correlation coefficient = 0.71 [95% confidence interval (CI) = 0.58; 0.80]), VAS global allergy symptoms (0.70 [95% CI = 0.68; 0.71]), and VAS nose (0.66 [95% CI = 0.65; 0.68]). In multivariable regression models, immunotherapy showed a strong negative association with VAS education (regression coefficient = -2.32 [95% CI = -4.04; -0.59]). Poor rhinitis control, measured by the combined symptom-medication score, was associated with worse VAS education (regression coefficient = 0.88 [95% CI = 0.88; 0.92]), higher impact on academic productivity (regression coefficient = 0.69 [95% CI = 0.49; 0.90]), and higher percentage of missed education hours due to allergy (regression coefficient = 0.44 [95% CI = 0.25; 0.63]). Conclusion: Allergy symptoms and worse rhinitis control are associated with worse academic productivity, whereas immunotherapy is associated with higher productivity.

The role of mast cell (MC) activity in pathophysiology is complex and challenging and its clinical effects are difficult to predict. Apart from the known role of MCs in basic immunological processes and allergy, underlined is their importance in bone mineralization and in regulation of autoimmune reactions. Mast cell mediators, especially those released from mast cells in degranulation, but also those released constitutively, are important both in metabolic and immunological processes. Mastocytosis is a heterogeneous group of disorders characterized by accumulation of MC in one or more organs. There are scientific data indicating that mastocytosis patients are at increased risk of osteoporosis in the systemic form of the disease and children with cutaneous mastocytosis have a higher rate of hypogammaglobulinemia. Moreover, the origin of osteoporosis in patients with allergy is no longer considered as linked to steroid therapy only, but to the mast cell mediators' activity as well. There are indications that osteoporosis symptoms in this group of patients may develop independently of the cumulative steroids' dose. Thus, the influence of mast cells on metabolic and immunologic processes in allergic patients should be investigated. The assessment of mast cell activity and burden in mastocytosis may be used to guide clinical management of patients with allergy.

Integrated health care plays a pivotal role in allergic diseases. It identifies key actions (based on guidelines) in the management of allergy patients that are transferred to the local level and implemented in clinical practice. It is particularly important for allergic rhinitis to develop a new generation of guidelines for pharmacotherapy and allergen immunotherapy. Allergen-specific immunotherapy is a parallel therapy that has a preventive (or prophylactic) character and not a method indicated for those who do not respond to pharmacotherapy.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future. (C) 2019 American Academy of Allergy, Asthma & Immunology

Mastocytosis is a myeloid neoplasm defined by expansion and focal accumulation of clonal mast cells (MCs) in one or more organs. The disease exhibits a complex pathology and may be complicated by MC activation, bone abnormalities, neurological problems, gastrointestinal symptoms, and/or hematologic progression. The World Health Organization divides mastocytosis into cutaneous forms, systemic mastocytosis (SM) and MC sarcoma. In most patients with SM, somatic mutations in KIT are detected. Patients with indolent SM have a normal to near-normal life expectancy, whereas patients with advanced SM, including aggressive SM and MC leukemia, have a poor prognosis. In those with advanced SM, multiple somatic mutations and an associated hematologic neoplasm may be detected. Mediator-related symptoms can occur in any type of mastocytosis. Symptoms may be mild, severe, or even life-threatening. In patients with severe acute symptoms, an MC activation syndrome may be diagnosed. In these patients, relevant comorbidities include IgE-dependent and IgE-independent allergies. Management of patients with SM is an emerging challenge in daily practice and requires in-depth knowledge and a multidisciplinary and personalized approach with selection of appropriate procedures and interventions. In this article, we review the current knowledge on SM and MC activation syndrome, with emphasis on multidisciplinary aspects in diagnosis and patient-specific management. In addition, we provide a user’s guide for application of markers, algorithms, prognostic scores, and treatments for use in daily practice., This work was supported in part by the Austrian Science Fund (FWF; projects F4704 and P32470-B to P.V.) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (to M.C.C. and D.D.M.). The content is solely the responsibility of the authors and does not represent the official views of the NIH.

Mastocytosis is a heterogeneous group of hematologic neoplasms defined by an accumulation of neoplastic mast cells (MC) in the skin, bone marrow, and other visceral organs [...]

IntroductionRespiratory status is one of the main factors affecting the length of survival in patients with Duchenne muscular dystrophy (DMD) – the most common, severe, progressive muscular dystrophy.The aim: (1) to assess pulmonary function in DMD patients using the z-score method and (2) to identify factors affecting it, irrespective of the disease progress.Material and methodsWe evaluated 55 boys (aged 5 – 18 years) with DMD. The spirometry was performed with: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF) analysis as absolute values (in litres or litres/min), % predicted value (%pv) and z-scores [z]. The need of ventilation support, ambulatory status, steroid therapy were collected.Results25(45%) subjects were non-ambulatory, 38(69%) used steroid therapy. Mean FVC[z] -2.4±2.2, FEV1[z] -2.0±1.9, PEF[z] -1.5±1.3 value significantly decrease with age (r=-0.62/-0.65/-0.55; pConclusionsAnalysis of pulmonary function test based on z-score shows that deterioration of pulmonary function in DMD males may appear earlier than we thought measured by %pv and absolute values. Early loss of ambulation, lack of or delayed steroid therapy are risk factors for worse pulmonary outcomes. To confirm these findings cohort longitudinal studies are necessary.