Interobserver variability in the classification of childhood maculopapular cutaneous mastocytosis.

BACKGROUND: Maculopapular cutaneous mastocytosis (MPCM) in children is classified in two variants: (i) monomorphic variant, presenting with the small macules or papules typically seen in adult patients; and (ii) polymorphic variant with larger lesions of variable size and shape, typically seen in children. The definition of polymorphic and monomorphic variants is mostly intuitive, and a validation of this classification has not been done. OBJECTIVE: To study interobserver variability in the classification of MPCM in two groups of observers: mastocytosis experts and general dermatologists. MATERIALS AND METHODS: Nineteen cases of childhood MPCM were shown blindly, for classification as monomorphic or polymorphic type, to 10 independent observers (eight dermatologists, one allergist and one haematologist) from Europe and North America with a vast experience in the management of paediatric mastocytosis. Also, the same cases were shown on a screen to 129 general dermatologists attending a meeting; their votes were registered by remote controls. The interobserver variability kappa coefficient (with 95% confidence interval) was calculated to measure the reliability of the correlation. RESULTS: The value of kappa interobserver variability coefficient for the group of 10 experts (95% confidence interval) was 0.39 (0.18-0.63), which is considered as 'fair'. The value of kappa interobserver variability coefficient for the group of 129 general dermatologists (95% confidence interval) was 0.17 (0.06-0.39), which is considered as 'slight'. A complete agreement of all 10 experts was achieved in only four of 19 cases (21.1%) The most voted choice was concordant between the two groups in only 11 of the 19 cases. CONCLUSIONS: We failed to validate the classification system of childhood MPCM in monomorphic and polymorphic types. While the rate of agreement was low for mastocytosis experts, it was nearly the agreement expected by chance in general dermatologists.

Síndrome de Kounis del tipo II inducido por amoxicilina-ácido clavulánico complicado con encefalopatía hipóxico-isquémica durante anestesia general / Amoxicillin-clavulanic acid-induced type II Kounis syndrome during general anaesthesia complicated with hypoxic-ischaemic encephalopathy

La anafilaxis es un síndrome multisistémico agudo grave que implica la liberación masiva del torrente sanguíneo de mastocitos y mediadores basófilos. Cuando las arterias coronarias son el objetivo principal, se puede sospechar el síndrome de Kounis o, más raramente, el llamado síndrome de Kounis cuando se trata de arterias cerebrales. Las lesiones isquémicas cerebrales pueden resultar de una presión arterial baja o de una acción mediadora proinflamatoria y/o vasoconstrictora directa en el sistema arterial cerebral. El diagnóstico es difícil en pacientes anestesiados. El tratamiento también es un reto, ya que la administración de adrenalina puede empeorar la isquemia. Presentamos un caso de síndrome de Kounis tipo II inducido por amoxicilina-ácido clavulánico bajo anestesia general, complicado con encefalopatía grave e irreversible de origen isquémico.(au)

Anaphylaxis is a severe acute multisystem syndrome involving massive mediator release from mast cells and basophils. Although the entire arterial system can be affected, when coronary arteries are the main targets, Kounis syndrome needs to be considered. Cerebral artery involvement has also been suggested in rarer MC-mediator release episodes; so-called ‘Kounis-like’ syndrome. Cerebral ischaemic lesions can then result from low blood pressure or direct proinflammatory and/or vasoconstrictive mediator action in the cerebral arterial system. Diagnosis can be difficult in anaesthetised patients, as low blood pressure can have multiple causes. Treatment is also challenging, as administering adrenaline can worsen ischaemia. We report the first case of amoxicillin-clavulanic acid-induced type II Kounis syndrome under general anaesthesia, complicated with severe, irreversible and subsequently fatal encephalopathy of ischaemic origin. This case can contribute to awareness of less common Kounis syndrome manifestations, including severe cerebral involvement, or other anaphylactic reactions with atypical presentations.(AU)

Amoxicillin-clavulanic acid-induced type II Kounis syndrome during general anaesthesia complicated with hypoxic-ischaemic encephalopathy. / Síndrome de Kounis del tipo II inducido por amoxicilina-ácido clavulánico complicado con encefalopatía hipóxico-isquémica durante anestesia general.

Anaphylaxis is a severe acute multisystem syndrome involving massive mediator release from mast cells and basophils. Although the entire arterial system can be affected, when coronary arteries are the main targets, Kounis syndrome needs to be considered. Cerebral artery involvement has also been suggested in rarer MC-mediator release episodes; so-called 'Kounis-like' syndrome. Cerebral ischaemic lesions can then result from low blood pressure or direct proinflammatory and/or vasoconstrictive mediator action in the cerebral arterial system. Diagnosis can be difficult in anaesthetised patients, as low blood pressure can have multiple causes. Treatment is also challenging, as administering adrenaline can worsen ischaemia. We report the first case of amoxicillin-clavulanic acid-induced type II Kounis syndrome under general anaesthesia, complicated with severe, irreversible and subsequently fatal encephalopathy of ischaemic origin. This case can contribute to awareness of less common Kounis syndrome manifestations, including severe cerebral involvement, or other anaphylactic reactions with atypical presentations.

WITHDRAWN: Amoxicillin-clavulanic acid-induced type II Kounis syndrome during general anaesthesia complicated with hypoxic-ischaemic encephalopathy.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.redar.2019.06.002. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Mast Cells as Key Players in Allergy and Inflammation.

Mast cells (MCs) are a key structural and functional component of both the innate and the adaptive immune systems. They are involved in many different processes, but play a major role in the response to infections and in inflammatory reactions. In addition, MCs are the main effector cells in allergy. MC biology is far more complex than initially believed. Thus, MCs may act directly or indirectly against pathogens and show a wide variety of membrane receptors with the ability to activate cells in response to various stimuli. Depending on where MCs complete the final stages of maturation, the composition of their cytoplasmic granules may vary considerably, and the clinical symptoms associated with tissue MC activation and degranulation may be also different. MCs are activated by complex signalling pathways characterized by multimolecular activating and inhibitory interactions. This article provides a comprehensive overview of MC biology, focusing predominantly on mechanisms of MC activation and the role of MCs in the pathogenesis of allergic diseases.

An Increase in Tryptase on the First Day of Hymenoptera Venom Immunotherapy Might Be a Predictor of Future Systemic Reactions During Treatment.

BACKGROUND AND OBJECTIVE: Serum tryptase (ST) decreases during long-term venom immunotherapy (VIT). ST also exhibits a circadian variation, with a small decrease after sting challenge. Both findings have been related to successful VIT. Objective: To assess whether variation (increase or decrease) in ST on the first day of VIT is associated with the likelihood of future systemic adverse reactions (SARs) during treatment. METHODS: We prospectively studied patients who underwent cluster VIT, which was continued for at least 6 months. ST was measured on the first day of VIT, before the first dose (pre-IT tryptase) and after the last dose (post-IT tryptase). Differences between patient groups (with and without SAR) were analyzed. RESULTS: A total of 160 courses of VIT were administered to 150 patients. The median baseline ST value was 4.3 µg/L. A total of 25 courses (15.6%) were associated with SAR. In 64% of the 25 patients with SAR, the post-IT tryptase value was higher than the pre-IT tryptase level; the median increment was 19% in these patients. We found a significant association between the increase in ST on the first day of VIT and future SARs (risk ratio, 7.6). This elevation was independent of the scheduled VIT day, severity of the SAR, and baseline ST value. CONCLUSIONS: A slight increase in tryptase on the first day of VIT is an independent variable that is strongly related to a high risk of future SAR. This simple biomarker could improve patient safety.

Characterization of CD34+ hematopoietic cells in systemic mastocytosis: Potential role in disease dissemination.

BACKGROUND: Recent studies show that most systemic mastocytosis (SM) patients, including indolent SM (ISM) with (ISMs+) and without skin lesions (ISMs-), carry the KIT D816V mutation in PB leukocytes. We investigated the potential association between the degree of involvement of BM hematopoiesis by the KIT D816V mutation and the distribution of different maturation-associated compartments of bone marrow (BM) and peripheral blood (PB) CD34+ hematopoietic precursors (HPC) in ISM and identified the specific PB cell compartments that carry this mutation. METHODS: The distribution of different maturation-associated subsets of BM and PB CD34+ HPC from 64 newly diagnosed (KIT-mutated) ISM patients and 14 healthy controls was analyzed by flow cytometry. In 18 patients, distinct FACS-purified PB cell compartments were also investigated for the KIT mutation. RESULTS: ISM patients showed higher percentages of both BM and PB MC-committed CD34+ HPC vs controls, particularly among ISM cases with MC-restricted KIT mutation (ISMMC ); this was associated with progressive blockade of maturation of CD34+ HPC to the neutrophil lineage from ISMMC to multilineage KIT-mutated cases (ISMML ). Regarding the frequency of KIT-mutated cases and cell populations in PB, variable patterns were observed, the percentage of KIT-mutated PB CD34+ HPC, eosinophils, neutrophils, monocytes and T cells increasing from ISMs-MC and ISMs+MC to ISMML patients. CONCLUSION: The presence of the KIT D816V mutation in PB of ISM patients is associated with (early) involvement of circulating CD34+ HPC and multiple myeloid cell subpopulations, KIT-mutated PB CD34+ HPC potentially contributing to early dissemination of the disease.

An increase in tryptase on the first day of hymenoptera venom immunotherapy might be a predictor of future systemic reactions during treatment

Background: Serum tryptase (ST) decreases during long-term venom immunotherapy (VIT). ST also exhibits a circadian variation, with a small decrease after sting challenge. Both findings have been related to successful VIT. Objective: To assess whether variation (increase or decrease) in ST on the first day of VIT is associated with the likelihood of future systemic adverse reactions (SARs) during treatment. Methods: We prospectively studied patients who underwent cluster VIT, which was continued for at least 6 months. ST was measured on the first day of VIT, before the first dose (pre-IT tryptase) and after the last dose (post-IT tryptase). Differences between patient groups (with and without SAR) were analyzed. Results: A total of 160 courses of VIT were administered to 150 patients. The median baseline ST value was 4.3 μg/L. A total of 25 courses (15.6%) were associated with SAR. In 64% of the 25 patients with SAR, the post-IT tryptase value was higher than the pre-IT tryptase level; the median increment was 19% in these patients. We found a significant association between the increase in ST on the first day of VIT and future SARs (risk ratio, 7.6). This elevation was independent of the scheduled VIT day, severity of the SAR, and baseline ST value. Conclusions: A slight increase in tryptase on the first day of VIT is an independent variable that is strongly related to a high risk of future SAR. This simple biomarker could improve patient safety

Antecedentes: Se ha observado una disminución progresiva del nivel de triptasa sérica (TS) basal durante la inmunoterapia con veneno de himenópteros (ITVH), así como la conservación de la variación circadiana de triptasa en pacientes que han tolerado una repicadura controlada. Ambos hallazgos se han relacionado con la eficacia del tratamiento. Objetivo: Estudiar si la variación (aumento o disminución) de la TS durante el primer día de ITVH se relaciona con un mayor riesgo de presentar reacciones adversas sistémicas (RAS) con futuras dosis de ITVH. Método: Estudio prospectivo de pacientes sometidos a ITVH en pauta de inicio agrupada y que continuaron con el tratamiento durante al menos 6 meses. Se determinó la TS el primer día de ITVH, antes de la primera dosis (triptasa pre-IT) y tras la última dosis (triptasa post-IT). Se analizaron las diferencias entre los dos grupos de pacientes (con o sin RAS). Resultados: Se administraron 160 ITVH a 150 pacientes. El valor medio de TS basal fue 4,3 μg/L, siendo > 11,4 μg/L en 4 casos. Un total de 25 ITVH (15,6%) presentaron RAS. En 64% de los 25 pacientes con RAS, el valor de triptasa post-IT fue más alto que el valor de triptasa pre-IT; el incremento medio fue del 19% en estos pacientes. Encontramos una relación significativa entre este aumento de triptasa el primer día de ITVH y la aparición de RAS con futuras dosis de ITVH (risk ratio 7,6). Esta elevación fue independiente del día de aparición de la reacción, de la gravedad de la misma, así como del valor basal de triptasa. Conclusiones: Un ligero aumento de triptasa el primer día de ITVH es una variable independiente, fuertemente relacionada con un alto riesgo de presentar una futura RAS. Este sencillo biomarcador podría ser útil para mejorar la seguridad de estos pacientes

Mast cells as key players in allergy and inflammation

Mast cells (MCs) are a key structural and functional component of both the innate and the adaptive immune systems. They are involved in many different processes, but play a major role in the response to infections and in inflammatory reactions. In addition, MCs are the main effector cells in allergy. MC biology is far more complex than initially believed. Thus, MCs may act directly or indirectly against pathogens and show a wide variety of membrane receptors with the ability to activate cells in response to various stimuli. Depending on where MCs complete the final stages of maturation, the composition of their cytoplasmic granules may vary considerably, and the clinical symptoms associated with tissue MC activation and degranulation may be also different. MCs are activated by complex signalling pathways characterized by multimolecular activating and inhibitory interactions. This article provides a comprehensive overview of MC biology, focusing predominantly on mechanisms of MC activation and the role of MCs in the pathogenesis of allergic diseases

Actualmente el mastocito (MC) es considerado como un componente estructural y funcional clave del sistema inmunitario, tanto innato como adquirido. El MC está involucrado en muchos procesos biológicos diferentes, pero juega un papel primordial en la respuesta inmune frente a infecciones y en las reacciones inflamatorias. Además, el MC es la principal célula efectora en los procesos alérgicos. La biología mastocitaria es mucho más compleja de lo que se podía pensar en un principio. Así, los MCs pueden actuar frente a patógenos tanto de forma directa como indirecta, y presentan una amplia variedad de receptores de membrana capaces de inducir la activación de la célula en respuesta a diferentes estímulos. Dependiendo del lugar donde los MCs completan los estadíos finales de su maduración, la composición de sus gránulos citoplasmáticos puede variar considerablemente, y los síntomas clínicos asociados a la activación y desgranulación de los MCs tisulares pueden ser también diferentes. La activación mastocitaria se produce como consecuencia de complejas vías de señalización caracterizadas por interacciones multimoleculares activadoras e inhibidoras. Este artículo muestra una revisión integral de la biología mastocitaria, predominantemente enfocado a los mecanismos de activación mastocitaria y en el papel que los MCs desempeñan en la patogenia de las enfermedades alérgicas

Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression.

Systemic mastocytosis (SM) is a heterogeneous disease with altered interleukin (IL)-6 and IL13 plasma levels. However, no study has simultaneously investigated the plasma levels of IL1ß, IL6, IL13, CCL23 and clusterin in SM at diagnosis and correlated them with disease outcome. Here we investigated IL1ß, IL6, IL13, CCL23 and clusterin plasma levels in 75 SM patients--66 indolent SM (ISM) and 9 aggressive SM--and analyzed their prognostic impact among ISM cases grouped according to the extent of hematopoietic involvement of the bone marrow cells by the KIT D816V mutation. Although increased IL1ß, IL6 and CCL23 levels were detected in SM patients versus healthy controls, only IL6 and CCL23 levels gradually increased with disease severity. Moreover, increased IL6 plasma levels were associated with ISM progression to more aggressive disease, in particular among ISM patients with multilineal KIT mutation (ISM-ML), these patients also showing a higher frequency of organomegalies, versus other ISM-ML patients. Of note, all ISM patients who progressed had increased IL6 plasma levels already at diagnosis. Our results indicate that SM patients display an altered plasma cytokine profile already at diagnosis, increased IL6 plasma levels emerging as an early marker for disease progression among ISM cases, in particular among high-risk ISM patients who carry multilineage KIT mutation.

Anaphylaxis as a clinical manifestation of clonal mast cell disorders.

Clonal mast cell disorders comprise a heterogeneous group of disorders characterized by the presence of gain of function KIT mutations and a constitutively altered activation-associated mast cell immunophenotype frequently associated with clinical manifestations related to the release of mast cells mediators. These disorders do not always fulfil the World Health Organization (WHO)-proposed criteria for mastocytosis, particularly when low-sensitive diagnostic approaches are performed. Anaphylaxis is a frequent presentation of clonal mast cell disorders, particularly in mastocytosis patients without typical skin lesions. The presence of cardiovascular symptoms, e.g., hypotension, occurring after a hymenoptera sting or spontaneously in the absence of cutaneous manifestations such as urticaria is characteristic and differs from the presentation of anaphylaxis in the general population without mastocytosis.

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis.

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.