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Type 2 and Non-type 2 Inflammation in the Upper Airways: Cellular and Molecular Alterations in Olfactory Neuroepithelium Cell Populations. 上呼吸道的 2 型和非 2 型炎症:嗅觉神经上皮细胞群的细胞和分子变化。
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-04-01 Epub Date: 2024-03-16 DOI: 10.1007/s11882-024-01137-x
Concepció Marin, Isam Alobid, Mauricio López-Chacón, Camilo R VanStrahlen, Joaquim Mullol

Purpose of review: Neurogenesis occurring in the olfactory epithelium is critical to continuously replace olfactory neurons to maintain olfactory function, but is impaired during chronic type 2 and non-type 2 inflammation of the upper airways. In this review, we describe the neurobiology of olfaction and the olfactory alterations in chronic rhinosinusitis with nasal polyps (type 2 inflammation) and post-viral acute rhinosinusitis (non-type 2 inflammation), highlighting the role of immune response attenuating olfactory neurogenesis as a possibly mechanism for the loss of smell in these diseases.

Recent findings: Several studies have provided relevant insights into the role of basal stem cells as direct participants in the progression of chronic inflammation identifying a functional switch away from a neuro-regenerative phenotype to one contributing to immune defense, a process that induces a deficient replacement of olfactory neurons. The interaction between olfactory stem cells and immune system might critically underlie ongoing loss of smell in type 2 and non-type 2 inflammatory upper airway diseases. In this review, we describe the neurobiology of olfaction and the olfactory alterations in type 2 and non-type 2 inflammatory upper airway diseases, highlighting the role of immune response attenuating olfactory neurogenesis, as a possibly mechanism for the lack of loss of smell recovery.

综述的目的:嗅觉上皮的神经发生对于不断替换嗅觉神经元以维持嗅觉功能至关重要,但在上呼吸道的慢性 2 型和非 2 型炎症期间会受到损害。在这篇综述中,我们描述了嗅觉的神经生物学以及慢性鼻炎伴鼻息肉(2 型炎症)和病毒后急性鼻炎(非 2 型炎症)中嗅觉的改变,强调了免疫反应削弱嗅觉神经发生的作用可能是这些疾病中嗅觉丧失的机制:一些研究对基底干细胞作为慢性炎症进展的直接参与者的作用提供了相关见解,确定了从神经再生表型到有助于免疫防御表型的功能转换,这一过程会诱导嗅觉神经元的不足替代。嗅觉干细胞与免疫系统之间的相互作用可能是2型和非2型上气道炎症性疾病持续丧失嗅觉的关键原因。在这篇综述中,我们描述了嗅觉神经生物学以及2型和非2型上气道炎症性疾病中的嗅觉改变,强调了免疫反应削弱嗅觉神经发生的作用,这可能是嗅觉丧失无法恢复的机制。
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引用次数: 0
The Future of Food Allergy Management: Advancements in Therapies. 食物过敏管理的未来:疗法的进步。
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-04-01 Epub Date: 2024-02-23 DOI: 10.1007/s11882-024-01133-1
Idil D Ezhuthachan, Michele Beaudoin, Anna Nowak-Wegrzyn, Brian P Vickery

Purpose of review: To review current and future treatment options for IgE-mediated food allergy.

Recent findings: Recent years have seen major developments in both allergen-specific and allergen-non-specific treatment options, with the first FDA-approved peanut oral immunotherapy (OIT) product becoming available in 2020. In addition to OIT, other immunotherapy modalities, biologics, adjunct therapies, and novel therapeutics are under investigation. Food allergy is a potentially life-threatening condition associated with a significant psychosocial impact. Numerous products and protocols are under investigation, with most studies focusing on OIT. A high rate of adverse events, need for frequent office visits, and cost remain challenges with OIT. Further work is needed to unify outcome measures, develop treatment protocols that minimize adverse events, establish demographic and clinical factors that influence candidate selection, and identify patient priorities.

综述目的回顾 IgE 介导的食物过敏目前和未来的治疗方案:近年来,过敏原特异性治疗方案和过敏原非特异性治疗方案都取得了重大进展,美国食品及药物管理局批准的首个花生口服免疫疗法(OIT)产品将于 2020 年上市。除口服免疫疗法外,其他免疫疗法方式、生物制剂、辅助疗法和新型疗法也在研究之中。食物过敏是一种可能危及生命的疾病,会对社会心理产生重大影响。目前正在对许多产品和方案进行研究,其中大多数研究侧重于 OIT。不良反应发生率高、需要频繁就诊以及成本问题仍然是 OIT 面临的挑战。我们需要进一步开展工作,以统一结果衡量标准,制定可最大限度减少不良反应的治疗方案,确定影响候选者选择的人口和临床因素,并确定患者的优先权。
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引用次数: 0
Recent Insights into the Environmental Determinants of Childhood Asthma 对儿童哮喘环境决定因素的最新认识
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-03-18 DOI: 10.1007/s11882-024-01140-2

Abstract

Purpose of Review

Ubiquitous environmental exposures, including ambient air pollutants, are linked to the development and severity of childhood asthma. Advances in our understanding of these links have increasingly led to clinical interventions to reduce asthma morbidity.

Recent Findings

We review recent work untangling the complex relationship between air pollutants, including particulate matter, nitrogen dioxide, and ozone and asthma, such as vulnerable windows of pediatric exposure and their interaction with other factors influencing asthma development and severity. These have led to interventions to reduce air pollutant levels in children’s homes and schools. We also highlight emerging environmental exposures increasingly associated with childhood asthma. Growing evidence supports the present threat of climate change to children with asthma.

Summary

Environmental factors play a large role in the pathogenesis and persistence of pediatric asthma; in turn, this poses an opportunity to intervene to change the course of disease early in life.

摘要 综述目的 无所不在的环境暴露(包括环境空气污染物)与儿童哮喘的发生和严重程度有关。随着我们对这些联系的认识不断加深,我们越来越多地采取临床干预措施来降低哮喘发病率。 最近的研究结果 我们回顾了最近的研究工作,这些工作揭示了空气污染物(包括颗粒物、二氧化氮和臭氧)与哮喘之间的复杂关系,例如儿童接触污染物的易感窗口及其与影响哮喘发展和严重程度的其他因素之间的相互作用。这些因素促使我们采取干预措施,降低儿童家庭和学校的空气污染物水平。我们还强调了与儿童哮喘日益相关的新出现的环境暴露。越来越多的证据表明,气候变化对哮喘儿童构成了威胁。 摘要 环境因素在小儿哮喘的发病和持续发展中起着重要作用;反过来,这也为我们提供了在生命早期进行干预以改变疾病进程的机会。
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引用次数: 0
Multidisciplinary Decision-Making-ITAlian Consensus After Two Years of Real Practice on the Management of Severe Uncontrolled CRSwNP by Biologics (ITACA Study). 生物制剂治疗严重失控的 CRSwNP(ITACA 研究)两年后的多学科决策--ITACA 共识。
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-03-01 Epub Date: 2024-03-12 DOI: 10.1007/s11882-024-01135-z
Eugenio De Corso, Carlotta Pipolo, Marco Caminati, Elena Cantone, Veronica Seccia, Lorenzo Cecchi, Eustachio Nettis, Massimiliano Garzaro, Giancarlo Ottaviano, Matteo Gelardi, Carlo Cavaliere, Enrico Heffler, Fabio Pagella, Ernesto Pasquini, Matteo Trimarchi, Stefania Gallo, Ignazio La Mantia, Sara Torretta, Davide Mattavelli, Cristiano Caruso, Andrea Matucci, Alessandra Vultaggio, Gianluca Bellocchi, Matteo Alicandri Ciufelli, Passali Fm, Gianenrico Senna

Purpose of review: We aimed to reach an Italian multidisciplinary consensus on some crucial aspects of treatment decision making in CRSwNP, following 2 years of clinical experience in order to support specialists in the management of CRSwNP in clinical practice. We addressed issues relating to therapeutic decision-making and shared criteria for the treatment choice, as well as appropriate timing and criteria for evaluating treatment response, and highlighted the need for repeated multidisciplinary assessments.

Recent findings: A national survey has been conducted recently to understand how rhinology practice has changed in Italy with the advent of biologics and how this affects patients with uncontrolled, severe CRSwNP. Despite the many published consensus documents, practical recommendations, and protocols on the use of biologics in CRSwNP, heterogenous behaviors in practice are still observed mainly conditioned by the novelty of the topic. The consensus procedure followed a modified Delphi approach. The scientific board included 18 otorhinolaryngologists and 8 allergists, who selected the 4 main topics to be addressed and developed overall 20 statements. Consensus on these statements was sought by a larger group of 48 additional experts, through two rounds of voting, the first web-based, the second in presence with discussion and possible refinement of the statements. The statements reaching an average score ≥ 7 at the second voting round were approved. Five statements were proposed for each of the following topics: baseline evaluation of patients eligible for biologic therapy; choice between different therapeutic options; assessment of the response to biologic treatment; multidisciplinary management. At the first voting round, 19 out of the 20 statements reached a mean score ≥ 7. Following the discussion and a few consequent amendments, at the second round of voting all the 20 statements were approved.

综述目的:我们的目的是根据 2 年的临床经验,就 CRSwNP 治疗决策的一些关键方面达成意大利多学科共识,以支持专家在临床实践中管理 CRSwNP。我们讨论了与治疗决策和治疗选择共同标准有关的问题,以及评估治疗反应的适当时机和标准,并强调了反复进行多学科评估的必要性:最近开展了一项全国性调查,以了解随着生物制剂的出现,意大利鼻科治疗方法发生了怎样的变化,以及这对未得到控制的严重 CRSwNP 患者产生了怎样的影响。尽管已发布了许多关于在 CRSwNP 中使用生物制剂的共识文件、实用建议和方案,但在实践中仍可观察到不同的行为,这主要是受该主题的新颖性所制约。达成共识的程序采用了改良的德尔菲法。科学委员会包括 18 名耳鼻喉科专家和 8 名过敏症专家,他们选出了要讨论的 4 个主要议题,并制定了总共 20 项声明。由另外 48 名专家组成的更大的小组通过两轮投票就这些声明达成共识,第一轮在网上进行,第二轮在现场进行,并对声明进行讨论和可能的改进。在第二轮投票中平均得分≥ 7 分的声明获得通过。针对以下主题各提出了五项声明:符合生物治疗条件患者的基线评估;不同治疗方案之间的选择;生物治疗反应评估;多学科管理。在第一轮投票中,20 项声明中有 19 项的平均得分≥ 7 分。经过讨论和随后的一些修正,在第二轮投票中,所有 20 项声明均获得通过。
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引用次数: 0
The Natural History and Risk Factors for the Development of Food Allergies in Children and Adults. 儿童和成人食物过敏的自然史和风险因素。
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-03-01 Epub Date: 2024-02-28 DOI: 10.1007/s11882-024-01131-3
Eric C K Lee, Brit Trogen, Kathryn Brady, Lara S Ford, Julie Wang

Purpose of review: This narrative review explores food allergy prevalence and natural history stratified by life stages, especially in context of evolving knowledge over the last few decades.

Recent findings: The prevalence of food allergy remains highest in early childhood with common food triggers being cow's milk, soy, hen's egg, wheat, peanut, tree nuts, sesame, fish, and shellfish. This correlates with certain risk factors especially pertinent in the postnatal period which appear to predispose an individual to developing a food allergy. Some allergies (such as milk and egg) were previously thought to be easily outgrown in early life; however, recent studies suggest increasing rates of persistence of these allergies into young adulthood; the reason behind this is unknown. Despite this, there is also evidence demonstrating that food allergies can be outgrown in adolescents and adults. An understanding of the paradigm shifts in the natural history of food allergy allows clinicians to provide updated, age-appropriate, and tailored advice for patients on the management and prognosis of food allergy.

综述的目的:这篇叙述性综述探讨了食物过敏的患病率和按生命阶段划分的自然史,尤其是在过去几十年中不断发展的知识背景下:食物过敏的发病率在幼儿期仍然最高,常见的食物诱因包括牛奶、大豆、鸡蛋、小麦、花生、树坚果、芝麻、鱼类和贝类。这与某些风险因素有关,尤其是与产后有关的风险因素,这些因素似乎容易使人患上食物过敏症。有些过敏症(如牛奶和鸡蛋)以前被认为很容易在幼年时期消失,但最近的研究表明,这些过敏症在成年后持续存在的比例越来越高,其背后的原因尚不清楚。尽管如此,也有证据表明,食物过敏在青少年和成年人中也会逐渐消失。了解了食物过敏自然史的范式转变,临床医生就能为患者提供最新的、适合其年龄的、有针对性的食物过敏管理和预后建议。
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引用次数: 0
Epidemiology and the Growing Epidemic of Food Allergy in Children and Adults Across the Globe. 全球儿童和成人食物过敏的流行病学和日益严重的流行病。
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-03-01 Epub Date: 2024-01-12 DOI: 10.1007/s11882-023-01120-y
Christopher M Warren, Shruti Sehgal, Scott H Sicherer, Ruchi S Gupta

Purpose of review: Food allergies are immune-mediated, complex disorders, which are the source of increasing health concern worldwide. The goal of this review is to present an updated summary of the food allergy (FA) burden among children and adults across different populations, focusing on research from the past 5 years.

Recent findings: FAs impact a growing number of global residents-particularly those residing in higher-income, industrialized regions. Moreover, growing epidemiologic evidence suggests that the population health burden of non-IgE-mediated FAs, such as food protein-induced enterocolitis syndrome, may also be higher than previously reported. FA is a complex trait that impacts infants, children, as well as adults across the globe. The population health burden of both IgE- and non-IgE-mediated FAs is likely to grow in the absence of rapid advances and widespread implementation of effective FA prevention and treatment interventions. Systematic epidemiological research initiatives are needed, both nationally and globally, to better understand and reduce the burden of these allergic diseases.

综述的目的:食物过敏是一种由免疫介导的复杂疾病,是全球日益关注的健康问题的根源。本综述旨在对不同人群中儿童和成人的食物过敏(FA)负担进行最新总结,重点关注过去 5 年的研究结果:食物过敏影响着越来越多的全球居民,尤其是那些居住在高收入、工业化地区的居民。此外,越来越多的流行病学证据表明,非 IgE 介导的 FAs(如食物蛋白诱发的小肠结肠炎综合征)对人群健康造成的负担可能也高于之前的报道。肠炎是一种影响全球婴儿、儿童和成人的复杂病症。如果不快速推进和广泛实施有效的 FA 预防和治疗干预措施,IgE 和非 IgE 介导的 FA 对人口健康造成的负担可能会越来越大。为了更好地了解和减轻这些过敏性疾病的负担,需要在国家和全球范围内开展系统的流行病学研究活动。
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引用次数: 0
Psychosocial Impact of Food Allergy on Children and Adults and Practical Interventions. 食物过敏对儿童和成人的社会心理影响及实用干预措施。
IF 5.4 2区 医学 Q1 ALLERGY Pub Date : 2024-03-01 Epub Date: 2024-01-23 DOI: 10.1007/s11882-023-01121-x
Theresa A Bingemann, Jennifer LeBovidge, Lisa Bartnikas, Jennifer L P Protudjer, Linda J Herbert

Purpose of review: IgE- and non-IgE-mediated food allergies are increasing in prevalence in children and adults worldwide. A food allergy diagnosis can be associated with a sense of overwhelm and stress and commonly has a negative impact on quality of life.

Recent findings: While there is an increased recognition of the psychosocial effects of food allergy, the current research reflects the experience of mostly White, well-educated wealthier populations. Some studies have now explored the psychosocial impact among other populations; however, further study is needed. It is important that physicians and allied health professionals screen for the potentially negative psychosocial effects of food allergy and provide education to promote safety and self-efficacy at each visit; however, time may be a limiting factor. Numerous validated questionnaires are now available to help assess the psychosocial impact of food allergies. Allergy-friendly foods are typically more expensive, and thus, it is imperative that physicians screen for food insecurity as well. Educational resources should be offered regarding living well with food allergies at each visit. For patients and families experiencing anxiety or food allergy burden that is difficult to manage, referral to a mental health provider should be considered. Resources regarding programs to help accessing safe foods should also be available. Further research is needed among diverse populations focusing on interventions to best support patients and families with food allergy.

综述的目的:IgE 和非 IgE 介导的食物过敏在全球儿童和成人中的发病率越来越高。食物过敏的诊断可能会让人感到不知所措和压力,通常会对生活质量产生负面影响:虽然越来越多的人认识到食物过敏对社会心理的影响,但目前的研究主要反映的是受过良好教育的富裕白人的经历。目前已有一些研究对其他人群的社会心理影响进行了探讨,但仍需进一步研究。重要的是,医生和专职医疗人员应筛查食物过敏可能带来的负面社会心理影响,并在每次就诊时提供教育,以提高安全性和自我效能;然而,时间可能是一个限制因素。现在有许多经过验证的问卷可以帮助评估食物过敏对社会心理的影响。适合过敏体质的食物通常比较昂贵,因此,医生也必须对食物不安全情况进行筛查。每次就诊时,医生都应提供有关食物过敏患者如何生活的教育资源。对于焦虑或食物过敏负担难以承受的患者和家庭,应考虑将其转介给心理健康提供者。还应提供有关帮助获取安全食品的计划的资源。需要在不同人群中开展进一步研究,重点关注如何采取干预措施为食物过敏患者和家属提供最佳支持。
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引用次数: 0
Precautionary Allergen Labeling: Avoidance for All? 预防性过敏原标签:所有人都要避免?
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-03-01 Epub Date: 2024-01-25 DOI: 10.1007/s11882-024-01129-x
Allison Schaible, Jamie Kabourek, Wendy Elverson, Carina Venter, Amanda Cox, Marion Groetch

Purpose of review: Precautionary allergen labeling (PAL) suggests the risk of unintended allergen presence (UAP) in food but is unregulated in most countries and inconsistently applied by food manufacturers. This review evaluates the current use of PAL, its relevance to allergic consumers, and weighs possible advantages and disadvantages of avoiding products with PAL.

Recent findings: In most countries, manufacturers are free to decide whether, when, and how to apply PAL resulting in inconsistencies and consumer confusion. Patients with food allergy often interpret PAL incorrectly and without guidance from their health care providers. Health care providers are also prone to misinterpreting PAL, indicating a need for better education. Consumers desire guidance on whether to avoid products with PAL or not. Until further regulatory guidance is available, shared decision-making between patient and provider is required to offer individualized, rather than one-size-fits-all, approaches to PAL.

审查目的:预防性过敏原标签(PAL)提示了食品中存在意外过敏原(UAP)的风险,但大多数国家并未对其进行监管,食品制造商对其的应用也不一致。这篇综述评估了目前 PAL 的使用情况及其与过敏性消费者的相关性,并权衡了避免食用带有 PAL 的产品的利弊:在大多数国家,制造商可自由决定是否、何时以及如何使用 PAL,这导致了不一致和消费者的困惑。食物过敏患者常常在没有医疗服务提供者指导的情况下错误地解释 PAL。医疗服务提供者也容易误解 PAL,这表明需要加强教育。消费者希望在是否避免食用含有 PAL 的产品方面得到指导。在获得进一步的监管指导之前,需要患者和医疗服务提供者共同决策,以提供个性化而非一刀切的 PAL 方法。
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引用次数: 0
Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS? 胰蛋白酶较个人基线的可逆性升高:为什么它是严重系统性肥大细胞活化和 MCAS 的最佳生物标志物?
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-02-03 DOI: 10.1007/s11882-024-01124-2
Peter Valent, Cem Akin, Michel Arock

Purpose of Review

Mast cell (MC) activation syndromes (MCAS) are conditions defined by recurrent episodes of severe systemic anaphylaxis or similar systemic events triggered by MC-derived mediators that can be measured in biological fluids. Since some symptoms of MC activation may occur due to other, non-MC etiologies and lead to confusion over diagnosis, it is of crucial importance to document the involvement of MC and their products in the patients´ symptomatology.

Recent Findings

The most specific and generally accepted marker of severe systemic MC activation is an event-related, transient increase in the serum tryptase level over the individual baseline of the affected individual. However, baseline concentrations of serum tryptase vary among donors, depending on the genetic background, age, kidney function, and underlying disease. As a result, it is of critical importance to provide a flexible equation that defines the diagnostic increase in tryptase qualifying as MCAS criterion in all patients, all situations, and all ranges of baseline serum tryptase. In 2012, the consensus group proposed the 120% + 2 ng/ml formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase level.

Summary

This formula has been validated in subsequent studies and has proven to be a robust and consistent diagnostic criterion of MCAS. The present article is discussing the impact of this formula and possible limitations as well as alternative markers and mediators that may be indicative of MCAS.

乳腺细胞(MC)活化综合征(MCAS)是由可在生物体液中测量到的 MC 衍生介质引发的反复发作的严重全身性过敏性休克或类似全身性事件所定义的病症。由于 MC 激活的某些症状可能是由其他非 MC 病因引起的,从而导致诊断上的混淆,因此记录 MC 及其产物在患者症状中的参与情况至关重要。然而,血清胰蛋白酶的基线浓度因供体的遗传背景、年龄、肾功能和潜在疾病而异。因此,提供一个灵活的等式来定义所有患者、所有情况和所有血清胰蛋白酶基线范围内符合 MCAS 标准的胰蛋白酶诊断性升高至关重要。2012 年,共识小组提出了 120% + 2 ng/ml 的公式,该公式涵盖了绝大多数群体,包括基础血清胰蛋白酶水平较低、正常或升高的病例。本文将讨论该公式的影响和可能存在的局限性,以及可能提示 MCAS 的其他标记物和介质。
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引用次数: 0
Predictors of Clonality and Underlying Mastocytosis in Mast Cell Activation Syndromes. 肥大细胞活化综合征的克隆性和潜在肥大细胞增多症的预测因素
IF 5.5 2区 医学 Q1 ALLERGY Pub Date : 2024-02-01 Epub Date: 2024-01-25 DOI: 10.1007/s11882-023-01122-w
David Gonzalez-de-Olano, Iván Álvarez-Twose

Purpose of review: Mast cell (MC) activation can present with a wide range of symptoms. The mechanisms that cause such activation are varied. One of them is the presence of clonal MCs which is defined, within other possible changes, by the presence of a somatic, activating mutation in the KIT gene. The clinical course and prognosis of patients with this underlying disease may be different from other causes of MC activation (MCA). For this reason, it is important to early diagnose, or at least suspect, which patients with MCA are due to clonal MCs.

Recent findings: The diagnosis of clonality must be made in a comprehensive manner. However, this paper reviews chronologically each of the stages from the patient's first visit to the doctor's office which can be indicative of clonality: clinical presentation of MCA, physical examination, analytical determinations of tryptase, and/or KIT mutational analysis and bone involvement, among others. The different clonality predictive scores proposed are also reviewed and compared. Although the gold standard for the diagnosis of certainty of MC clonality is the performance of a bone marrow (BM) biopsy, there are clinical symptoms, signs, and biological parameters suggestive of clonality, as well as predictive scores, which can guide (or rule out) an early diagnosis and avoid unnecessary BM biopsies.

审查目的:肥大细胞(MC)活化可表现出多种症状。导致这种活化的机制多种多样。其中一种是克隆 MCs 的存在,这种克隆 MCs 除其他可能的变化外,还取决于 KIT 基因中是否存在激活性的体细胞突变。患有这种潜在疾病的患者的临床过程和预后可能不同于其他原因导致的 MC 激活(MCA)。因此,早期诊断或至少怀疑哪些 MCA 患者是由克隆 MCs 引起的非常重要:克隆性诊断必须全面进行。然而,本文按时间顺序回顾了从患者首次就诊开始的各个阶段,这些阶段可提示克隆性:MCA 的临床表现、体格检查、胰蛋白酶分析测定和/或 KIT 突变分析以及骨骼受累等。本文还对提出的不同克隆性预测评分进行了回顾和比较。虽然确诊 MC 克隆的金标准是进行骨髓(BM)活检,但有一些临床症状、体征和生物参数可提示克隆性,还有一些预测性评分,可指导(或排除)早期诊断,避免不必要的骨髓活检。
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引用次数: 0
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