Childhood GPA, EGPA, and MPA.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a term used to describe rare primary systemic vasculitides affecting small and medium-sized blood vessels. AAV diseases which include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), Microscopic Polyangiitis (MPA) and renal limited ANCA vasculitis. These multisystemic disorders involve upper and lower respiratory tract and kidneys associated with organ damage and long term sequelae. Newer understanding of pathogenesis in AAV have paved the way for clinical research with different biologic therapies. In spite of the paucity of clinical trials in pediatric AAV, the long-term survival of patients with AAV has improved dramatically. International collaborations will help to conduct clinical trials in pediatric AAV and help in better understanding of remission rates, relapse rates, and other outcomes. This article aims to provide a comprehensive review of pediatric AAV with a focus on epidemiology, disease pathogenesis, treatment trials, and prognosis.

World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified, (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of the therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Advances in the diagnosis and treatment of eosinophilia.

PURPOSE OF REVIEW: Eosinophils play an important role in the pathogenesis of allergic, infectious and malignant diseases. Over the last decade, new diagnostic tools and treatment modalities have led to the re-evaluation of the existing definition of eosinophilic disorders. This review discusses a recent proposal for new terminology and classification of hypereosinophilia. The results of targeted therapy for hypereosinophilia-related disorders are also summarized. RECENT FINDINGS: A panel of multidisciplinary experts agreed on unifying definitions and criteria of eosinophilia-associated disorders and created a new classification of hypereosinophilia-related conditions based on clinical, haematological and laboratory findings as well as the underlying cause of hypereosinophilia. Recent results of the treatment of idiopathic hypereosinophilic syndrome (HES) with the anti-interleukin 5 monoclonal antibody mepolizumab showed its efficacy and manageable safety profile. The treatment of platelet-derived growth factor alpha (PDGFRA)-positive HES with imatinib demonstrated long-lasting efficacy and low likelihood of drug resistance. SUMMARY: The unifying terminology and definitions should aid physicians caring for patients with hypereosinophilia. Despite much progress, serum biomarkers correlate with disease severity and predict responses to treatment that are needed. There is also a great need for understanding and specific therapy for PDGFRA-negative HES.

World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3)) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited number of patients. Although clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Persistent hypereosinophilia with Wells syndrome.

Since Wells and Smith first described cases of eosinophilic cellulitis (Wells syndrome; WS) in 1979, it has been noted that some but not all patients with WS present with eosinophilia. In the face of idiopathic persistent eosinophilia patients will also then fall within the hypereosinophilic syndrome (HES), which represents a multifarious spectrum of disorders of varying severity, causes and outcomes. In this article we propose that patients who present within the HES spectrum with cutaneous findings of WS and with no extracutaneous disease be classified as having 'persistent hypereosinophilia with Wells syndrome' (PHEWS).

Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes.

Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

Mucosal-type eosinophilic gastroenteritis in Thailand: 12-year retrospective study.

OBJECTIVE: To evaluate the clinical features and natural course of disease among patients with mucosal-type eosinophilic gastroenteritis in Thailand. MATERIAL AND METHOD: The present study was conducted by retrospectively searching for the ICD-10 code for eosinophilic gastroenteritis (EGE) among medical records for the period 2001-2012. Clinical and pathological specimens were reviewed using the same diagnostic criteria. Appropriate tests were conducted to exclude other secondary causes of EGE. All patients had to have either received empirical treatment for parasitic infections or were tested for parasites in the stool. After the diagnosis had been established, each patient received 30-40 mg/day of oral prednisoloneforfour weeks, which was tapered down as clinical status improved. All patients were followed up by monitoring clinical symptoms and relevant laboratory findings. Patients who did not maintain follow-up appointments were contacted by telephone and asked about their clinical symptoms. RESULTS: Seventeen patients with a diagnosis of mucosal-type E (6 male, 11 female, M:F ratio 1:1.83) were found. Mean age at the time of presentation was 52.5 +/- 13.04 years. Four patients (23.5%) had either allergic or atopic conditions. Chronic diarrhea and weight loss were the most common initial presentation in 16 patients (94.1%). Microscopically and macroscopically, bloody diarrhea was observed in 13 cases (76.5%). Four patients were found to have protein-losing enteropathy. Peripheral eosinophilia was found in 10 patients (58.8%) with absolute eosinophil counts between 744 and 23,550 cells/mm3. Eight of these had an absolute eosinophil count in the hypereosinophilic range (> 1,500 cells/mm3). All patients treated with prednisolone treatment showed symptomatic improvement within four weeks. One patient's symptom resolved spontaneously, without treatment. Thirteen patients relapsed during the tapering-off of prednisolone. Seven patients showed complete remission. Three patients subsequently developed cancer (lung, breast, and bladder) after EGE was diagnosed. CONCLUSION: EGE, although uncommon, is present in Thailand, where parasitic infections continue to be a significant public-health problem.

Update on the classification and treatment of localized scleroderma.

Morphea or localized scleroderma is a distinctive inflammatory disease that leads to sclerosis of the skin and subcutaneous tissues. It comprises a number of subtypes differentiated according to their clinical presentation and the structure of the skin and underlying tissues involved in the fibrotic process. However, classification is difficult because the boundaries between the different types of morphea are blurred and different entities frequently overlap. The main subtypes are plaque morphea, linear scleroderma, generalized morphea, and pansclerotic morphea. With certain exceptions, the disorder does not have serious systemic repercussions, but it can cause considerable morbidity. In the case of lesions affecting the head, neurological and ocular complications may occur. There is no really effective and universal treatment so it is important to make a correct assessment of the extent and severity of the disease before deciding on a treatment approach.

World Health Organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management.

DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. DIAGNOSIS: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1," chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

Eosinophilic disorders in various diseases.

Peripheral and tissue eosinophilia are usually associated with a variety of inflammatory, malignant, and infectious conditions. As the presence of eosinophils in the tissues may cause significant cellular damage to vital organs such as the heart, tissue eosinophilia should be diagnosed and treated promptly. One operative way to evaluate eosinophilic disorders is to classify them into extrinsic and intrinsic. While extrinsic eosinophilic disorders are usually due to the production of eosinopoietic factors derived from T cells or tumor cells, the intrinsic types generally are the result of genetic mutations in the eosinophilic lineage. As we understand more the biology of eosinophils, only a few eosinophilic disorders remain idiopathic. The purpose of this article is to help the clinician classify in an operational manner most eosinophilic disorders, using the extrinsic and intrinsic model. This may facilitate not only a better understanding of the role of eosinophils in these disorders, but also help the systematic clinical work-up and potential treatment of affected patients.

Asthma phenotypes: consistency of classification using induced sputum.

BACKGROUND AND OBJECTIVE: Asthma can be classified as eosinophilic or non-eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens. METHODS: Clinically stable, non-smoking, asthmatic adults were enrolled in one of two studies. In study one, induced sputum cell counts from 28 subjects were analysed after 4 weeks without corticosteroid treatment and after 6 week treatments with placebo, regular inhaled beta-agonist, inhaled corticosteroid, and combined beta-agonist and corticosteroid. In study two, sputum from 26 subjects with non-eosinophilic asthma was analysed after 12 weeks of placebo and after four 2-week corticosteroid washouts. Sputum with <2% eosinophils was classified as non-eosinophilic. RESULTS: Sputum classification changed frequently in both studies. In study one, only one of eight participants with non-eosinophilic sputum after placebo treatment remained non-eosinophilic throughout. In study two, all of participants had at least one eosinophilic sputum sample, despite the fact that all had been non-eosinophilic at recruitment. Neutrophilic asthma was uncommon in both studies and was also inconsistent. CONCLUSIONS: The phenotypic classification of asthma changes frequently. A diagnosis of non-eosinophilic asthma should not be based on a single sputum sample.

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities-some defined principally by genetic features-that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.

Eosinophilic Gastroenteritis: Using Presenting Findings to Predict Disease Course.

INTRODUCTION: Studies on eosinophilic gastroenteritis have identified broad spectrums of disease. We aimed to characterize subtypes of disease and ascertain outcomes of each group. METHODS: This is a retrospective cohort study from a large tertiary medical center including 35 patients diagnosed with eosinophilic gastroenteritis from 2007 to 2018. We defined 2 groups of patients based on clinical and laboratory findings at presentation. Severe disease was defined as having weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis. The remaining patients were labeled as mild disease group. We collected and compared demographic data, clinical features, laboratory findings, an allergy history, and disease course of both cohorts. RESULTS: Among 35 patients with eosinophilic gastroenteritis, 18 patients met the criteria for severe disease and 17 patients for mild disease. Of the patients with severe eosinophilic gastroenteritis, 6 (38%) had remission without chronic symptoms, whereas 10 (63%) had chronic symptoms requiring chronic medical therapy. Of the mild group, 12 patients (80%) had disease remission without chronic medications. An allergy history was more common in the severe disease group (83%) compared with the mild disease group (45%). Prednisone and open capsule budesonide were the most commonly used treatment medications in both groups. DISCUSSION: Patients with eosinophilic gastroenteritis may be characterized into 2 forms. Patients with weight loss at time of presentation, hypoalbuminemia at presentation, serosal disease involvement, or anemia at diagnosis were associated with a chronic disease course requiring chronic medications.

Eosinophilic colitis in adults.

Eosinophilic colitis (EoC) is a pathological entity associated with abnormal infiltration of colonic mucosa by eosinophilic polynuclear cells (Eo). This is a relatively common pathology in infants and children under 2 years old, but is more rare and has been less studied in adults. EoC can be classified as primary or secondary. Primary EoC is, in the majority of cases, related to an allergic reaction, either IgE-mediated and capable of causing an anaphylactic-type food allergy, or not mediated by IgE and capable of giving rise to food enteropathy. The symptoms for adults with EoC are variable and non-specific, diarrhoea and abdominal pain being the most common signs. There is no histological consensus for the diagnosis of EoC. The presence of over 40 Eo per high-power field (×400) in at least two different colonic segments could be suggested as the criterion for the diagnosis. In adults with primary EoC, skin tests are of limited value and the response to a restrictive diet is less effective than in young children, given that IgE or non-IgE-mediated allergic reactions are rarely identified and EoC generally require medical treatment. There is no consensus on the treatment of EoC, but the potential efficacy of corticosteroids and budesonide has been demonstrated in the vast majority of cases studied.

[Classification of chronic rhinosinusitis with nasal polyps based on eosinophilic inflammation].

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disorder characterized by chronic sinonasal mucosal inflammation. CRSwNP can be subdivided into two types based on eosinophilic inflammation: eosinophilic CRSwNP (Eos CRSwNP) and non-eosinophilic CRSwNP (Non-Eos CRSwNP). Eos CRSwNP and Non-Eos CRSwNP demonstrate distinct clinical manifestations, treatment outcomes, and cellular and immunopathologic characteristics. However, currently, there is no unified and generally accepted standard to define the Eos CRSwNP. The aim of this review is to compare the advantages and disadvantages of current methods used to classify Eos CRSwNP, in order to lay foundation for further study.

Classification of eosinophilic gastrointestinal diseases.

Diagnosis of eosinophilic gastrointestinal diseases is based on morphological evaluation with regard to localization and density of eosinophil infiltration of the mucosa and/or deeper parts of the oesophagus, stomach, and bowel in biopsy or resection specimens. As with eosinophils in any tissue, in the majority of diseases they are probably a sequel of acute inflammation and do not indicate any specific disease. Eosinophil morphology includes intact cells with bilobated nuclei and eosinophil granules in the cytoplasm and extracellular tissue following activation/degranulation. There is no fixed number of eosinophils that can be used as a cut-off criterion to define disease. Associated histopathological features observed in eosinophilic gastrointestinal disease depend on the site of manifestation and primary disease. Eosinophils are typically increased in allergy-associated colitis in adults and allergic proctocolitis in infants, eosinophilic gastroenteritis and eosinophilic oesophagitis. Their presence can also suggest a drug-induced eosinophilia or the presence of a parasitic infection. In general, eosinophils are increased in inflammatory bowel disease (IBD). They are seen in reflux oesophagitis, coeliac disease, and microscopic and infectious colitis. Eosinophils may be a feature of polyarteriitis nodosa and Churg-Strauss syndrome, and can accompany connective-tissue disease as well as malignant lymphomas and adenocarcinomas of gastrointestinal mucosa.

Classification of eosinophilic disorders of the small and large intestine.

Eosinophilic gastrointestinal diseases (EGIDs), including eosinophilic gastroenteritis and eosinophilic colitis, have been increasing in prevalence in Western countries in recent years. Eosinophils are normally scanty in the gastrointestinal tract, and increased numbers of eosinophils can denote pathology. Normal values for tissue eosinophils vary widely between different segments of the colon, thus location of the biopsy is critically important for the interpretation of findings. However, no standard diagnostic criteria have been proposed for the diagnosis of eosinophilic gastroenteritis or eosinophilic colitis. Gut eosinophilia encompasses entitites that are predominantly immunoglobulin E (IgE)-mediated, the primary EGIDs and those that are secondary and not IgE-mediated. A final diagnosis of eosinophilic gastrointestinal diseases requires careful pathological assessment, clinical correlation and exclusion of several differential diagnoses.

[CME: Mepolizumab, an Additional Therapeutic Agent for Severe Asthma]. / CME: Mepolizumab, ein weiterer Baustein der individualisierten Therapie des schweren Asthma bronchiale.

CME: Mepolizumab, an Additional Therapeutic Agent for Severe Asthma Abstract. The challenging therapy of severe uncontrollable bronchial asthma aims primarily at sufficient symptom control and the minimization of the exacerbation rate. If, despite extended drug therapy, symptom control is very difficult to achieve, biologics should preferably be used instead of corticosteroid therapy. The aim of this article is to point out these different asthma therapy pathways and to describe diagnostic criteria as well as practical experiences through application in patients.

Eosinophilic gastroenteritis and other eosinophilic gut diseases distal to the oesophagus.

Under normal physiological conditions, eosinophils are present throughout the gastrointestinal tract distal to the squamous oesophagus. Increases in their numbers signify primary and secondary eosinophilic conditions. The rare primary eosinophilic diseases eosinophilic gastroenteritis and eosinophilic colitis affect fewer than ten in 100 000 people, and are characterised by numerous mucosal eosinophils, distributed in sheets and sometimes extending from the mucosa into the submucosa. Pathogenesis of these diseases is poorly understood, but food allergies and intestinal dysbiosis have been implicated. Presentation ranges from vague abdominal symptoms and systemic complaints to, rarely, an acute abdomen with intestinal obstruction. Diagnosis is made from mucosal biopsy samples taken at endoscopy or from surgically resected specimens that demonstrate substantially increased numbers of eosinophils. Eosinophilia secondary to other conditions, such as pathogenic infections, must be excluded. Subtle eosinophilia has also been identified in the duodenum in functional dyspepsia and in the colon in spirochaetosis. Treatment of eosinophilic gastroenteritis and eosinophilic colitis is based on evidence from case reports and small case series, and first-line therapy includes empirical food-elimination diets and single courses of steroids, whereas relapsing or refractory disease might respond to steroid-sparing immunosuppressive agents and biological agents. The progression of disease in eosinophilic gastroenteritis and eosinophilic colitis is variable: a considerable number of patients have just one episode without relapse, whereas others have relapsing-remitting or chronic disease. Primary and secondary eosinophilia in the gastrointestinal tract is increasingly recognised as a clinical conundrum waiting to be solved.