[Experience of biological therapy in severe forms of chronic rhinosinusitis with nasal polyps in the conditions of regional healthcare]. / Opyt biologicheskoi terapii pri tyazhelykh formakh khronicheskogo polipoznogo rinosinusita v usloviyakh regional'nogo zdravookhraneniya.

Recurrent chronic rhinosinusitis with nasal polyps (CRSwNP) with a predominant Th2 endotype of inflammation, including associated with bronchial asthma and/or allergic rhinitis, aspirin triad, refers to diseases with an insufficient level of control, despite the use of a wide range of options for conservative and surgical treatment. OBJECTIVE: To analyze our own experience, clinical and organizational features of the application of the method of biological therapy in patients with severe forms of recurrent CRSwNP. MATERIAL AND METHODS: 25 patients with severe and moderate forms of CRSwNP were examined, who, in a round-the-clock hospital (model CSG 36.018) was treated with Dupilumab, in the form of subcutaneous injections of 300 mg/2 ml 1 every two weeks. The diagnosis was confirmed on the basis of anamnestic data, SNOT-22 quality of life questionnaires, visual endoscopic examination, evaluation of CT data (Lund-Mackay scale), laboratory data. The effectiveness of treatment was monitored after 16 weeks, based on endoscopic examination data, evaluation of CT and SNOT-22 data. In 3 observations, a study of pathomorphological material for tissue eosinophilia was performed. RESULTS: The duration of the course of treatment ranged from 10 to 56 weeks. The most striking clinical effect was observed for signs such as sense of smell and nasal breathing (in some cases-after the first injection). The degree of regression of polyps according to CT and endoscopic examination was more prolonged in time, the same dynamics was observed in the level of total IgE. In a number of patients, the phenomenon of eosinophilia growth was observed against the background of treatment (with regression of clinical symptoms). Pathomorphological examination confirmed a high level of tissue eosinophilia as one of the fundamental signs of Th2 inflammation. One patient with concomitant chronic tubar dysfunction had an improvement in hearing. All patients with AD noted a subjective improvement in disease control (a decrease in the frequency and severity of choking attacks). The cancellation (break in treatment) of treatment was accompanied by a gradual return of symptoms in all patients at various times. CONCLUSIONS: Patients who have not achieved an acceptable level of control of CRSwNP,that meets the criteria of Th2 inflammation can be considered as candidates for the use of targeted biological therapy. With strict compliance with the selection criteria, there is a good clinical effect, primarily in relation to nasal symptoms (sense of smell and nasal breathing) and improved control of asthma symptoms.

UVA-1 phototherapy as adjuvant treatment for eosinophilic fasciitis: in vitro and in vivo functional characterization.

INTRODUCTION: Eosinophilic fasciitis (EF) is a rare autoimmune disease causing progressive induration of dermal, hypodermal, and muscularis fascia. The exact pathogenesis is yet to be fully understood, and a validated therapy protocol still lacks. We here aimed to realize a clinical-functional characterization of these patients. MATERIALS AND METHODS: A total of eight patients (five males, 45 years average) were treated with adjuvant high-dose UVA-1 phototherapy (90 J/cm), after having received the standard systemic immunosuppressive protocol (oral methylprednisolone switched to methotrexate). Body lesion mapping, Localized Scleroderma Assessment Tool (LoSCAT), Dermatology Life Quality Index (DLQI), High-Resolution Ultrasound (HRUS) (13-17MHz), and ultra HRUS (55-70 MHz) were performed at each examination time taking specific anatomical points. Gene expression analysis at a molecular level and in vitro UVA-1 irradiation was realized on lesional fibroblasts primary cultures. RESULTS: The LoSCAT and the DLQI showed to decrease significantly starting from the last UVA-1 session. A significant reduction in muscularis fascia thickness (-50% on average) was estimated starting from 3 months after the last UVA-1 session and maintained up to 12 months follow-up. Tissues was detected by HRUS. The UVA-1 in vitro irradiation of lesional skin sites cells appeared not to affect their viability. Molecular genes analysis revealed a significant reduction of IL-1ß and of TGF-ß genes after phototherapy, while MMPs 1,2,9 gene expression was enhanced. COMMENT: These preliminary in vivo and in vitro findings suggest that UVA-1 phototherapy is a safe and useful adjuvant therapy able to elicit anti-inflammatory effects and stimulate tissue matrix digestion and remodeling at lesional sites.

Objective Assessment of Cough: An Early Marker of Response to Biological Therapies in Asthma?

Cough is an important symptom of asthma. The objective assessment of chronic cough has been enhanced by the development of ambulatory cough monitoring systems. Mepolizumab has been demonstrated to reduce exacerbations in eosinophilic asthmatics long-term. We evaluate the utility of objective cough count as an outcome measure in severe eosinophilic asthma treated with mepolizumab. Consecutive, consenting patients initiated on treatment with mepolizumab had a 24-h cough count recorded at baseline; this was repeated at 1, 3 and 6 months. Asthma control questionnaire (ACQ) scores and exacerbation frequency were also recorded. The mean 24-h cough count in 11 subjects (8 females, mean age 53.6 years) was 172.4 at baseline; at 1, 3 and 6 months following initiation of treatment this decreased to 101.4, 92 and 70.8, respectively (p < 0.02). Significant improvements were also observed in mean ACQ score (3-1.6, p < 0.01) and exacerbation frequency (5.5 per year - 1.3, p < 0.01). Objective cough measurement could be used as an early, precise and clinically relevant endpoint in assessing response to asthma therapy.

Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.

Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.

Eosinophilic Dermatoses: Recognition and Management.

Eosinophilic dermatoses encompass a broad spectrum of diseases of different etiologies hallmarked by eosinophilic infiltration of the skin and/or mucous membranes, with or without associated blood eosinophilia. The wide range of dermatological manifestations of this spectrum, including nodules and plaques, pustules, blisters, ulcers, and urticarial lesions, is reflected in a non-univocal classification system. We identified six groups of eosinophilic dermatoses based on the predominant anatomic level of involvement: (1) epidermal; (2) of the dermal-epidermal junction; (3) dermal; (4) of the hypodermis and muscle fascia; (5) of the pilosebaceous unit; and (6) vascular/perivascular. We review clinicopathologic features and management of diseases belonging to each group, particularly: (1) pemphigus herpetiformis and atopic dermatitis as prototypes of the epidermal group; (2) bullous pemphigoid as prototypic eosinophilic dermatosis of the dermal-epidermal junction; (3) eosinophilic cellulitis (Wells syndrome), hypereosinophilic syndromes, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, eosinophilic dermatosis of hematologic malignancy and chronic spontaneous urticaria as paradigmatic dermal eosinophilic dermatoses; (4) eosinophilic fasciitis as an eosinophilic dermatosis with predominant involvement of the hypodermis and muscle fascia; (5) eosinophilic pustular folliculitis as a model of the pilosebaceous unit involvement; and (6) granuloma faciale, angiolymphoid hyperplasia with eosinophilia, and eosinophilic granulomatosis with polyangiitis, belonging to the vascular/perivascular group.

Targeted Anti-IL-5 Therapies and Future Therapeutics for Hypereosinophilic Syndrome and Rare Eosinophilic Conditions.

Eosinophilic inflammation is a component of many atopic diseases such as asthma, and biologics targeting eosinophils have been shown to be effective in subsets of these patients. However, there also are conditions in which eosinophils are the key inflammatory cells responsible for driving tissue damage. In these eosinophilic diseases such as hyper-eosinophilic syndrome, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis (EGPA), the development of biologics inhibiting eosinophilic inflammation have offered targeted therapeutic strategies for patients that have not responded well to typical first line drugs, which often have significant adverse side effects with poor disease modification or recurrent relapse with significant morbidity. IL-5 has long been recognized as the key inflammatory cytokine involved in the priming and survival of eosinophils and their proliferation and maturation in eosinophilic disease. There are a number of trials and case series demonstrating the immunomodulatory benefits of anti-IL-5 therapies in these diseases with good clinical responses. Yet, due to the heterogeneity and rarity of these conditions, anti-IL-5 therapies have not resulted in disease remission for all patients. Clearly, further research into the use of anti-IL-5 therapies in various eosinophilic diseases is needed and ongoing investigation into other immune mechanisms underlying chronic eosinophilic diseases may provide alternative therapies for these challenging conditions.

Future therapies for eosinophilic gastrointestinal disorders.

OBJECTIVE: To review novel therapeutics in development for treatment of eosinophilic gastrointestinal disorders (EGIDs). DATA SOURCES: Clinical trial data (clinicaltrials.gov) and literature search on PubMed. STUDY SELECTIONS: Studies on treatment and clinical trials in EGIDs were included in this review. RESULTS: During the past decade, significant progress has been made in understanding disease mechanisms in EGIDs. As a result, a variety of novel therapeutics have been developed for treatment of these disorders. Several monoclonal antibodies against targets, including interleukin (IL) 4, IL-5, IL-13, integrins, and siglec-8, have shown promise in early trials. Novel formulations of corticosteroids are also in development. CONCLUSION: The field of EGID research has advanced rapidly, and disease-modifying therapeutics are closer to clinical application.

The effect of the inhalation of and topical exposure to zinc oxide nanoparticles on airway inflammation in mice.

Zinc oxide nanoparticles (ZnONPs) are widely used in the manufacturing of many commercial products. Workers exposed to ZnO particles may develop metal fume fever. Our previous study suggested that the oropharyngeal aspiration of ZnONPs could cause eosinophilic airway inflammation and increase T helper 2 (Th2) cytokine expression in the absence of allergens in mice. ZnO has been used topically as a sunscreen and a therapeutic agent for dermatological conditions. To understand whether inhalation and topically applied ZnONPs might cause or exert an adjuvant effect on the development of allergic airway inflammation in mice, C57BL/6 J mice were exposed to filtered air or 2.5 mg/m3 ZnONPs via whole-body inhalation for 5 h a day over 5 days, and BALB/c mice were topically exposed to ZnONPs using modified mouse models of atopic dermatitis (AD) and asthma. Ovalbumin (OVA) solution was used as an allergen in the topical exposure experiments. A significantly increased eosinophil count and mixed Th1/Th2 cytokine expression were detected in the bronchoalveolar lavage fluid (BALF) after ZnONP inhalation. However, only mild eosinophilia and low Th2 cytokine expression were detected in the BALF after oropharyngeal OVA aspiration in the high-dose ZnONP topical treatment group. These results suggest that ZnONP inhalation might play a role in the development of allergic airway inflammation in mice. However, topically applied ZnONPs only play a limited role in the development of allergic airway inflammation in mice.

Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGID) are a group of disorders characterized by pathologic eosinophilic infiltration of the esophagus, stomach, small intestine, or colon leading to organ dysfunction and clinical symptoms (J Pediatr Gastroenterol Nutr; Spergel et al., 52: 300-306, 2011). These disorders include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), eosinophilic enteritis (EE), and eosinophilic colitis (EC). Symptoms are dependent not only on the location (organ) as well as extent (layer invasion of the bowel wall). Common symptoms of EoE include dysphagia and food impaction in adults and heartburn, abdominal pain, and vomiting in children. Common symptoms of the other EGIDs include abdominal pain, nausea, vomiting, early satiety, diarrhea, and weight loss. These disorders are considered immune-mediated chronic inflammatory disorders with strong links to food allergen triggers. Treatment strategies focus on either medical or dietary therapy. These options include not only controlling symptoms and bowel inflammation but also on identifying potential food triggers. This chapter will focus on the clinical presentation, pathophysiology, and treatment of these increasingly recognized disorders.

Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD.

BACKGROUND: Asthma and COPD are complex, heterogeneous conditions comprising a wide range of phenotypes, some of which are refractory to currently available treatments. Elucidation of these phenotypes and identification of biomarkers with which to recognize them and guide appropriate treatment remain a priority. OBJECTIVE: This review describes the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes. The role of blood eosinophils in airway disease is described, as is their relevance in reflecting airway eosinophilia. Each disease is discussed separately as the manner in which blood eosinophils might be used as biomarkers differs. Focusing on patients with severe disease (persistent eosinophilic asthma and exacerbating COPD), we evaluate evidence examining eosinophils as biomarkers. RESULTS: In asthma, the rationale for using blood eosinophils to guide treatment is clearly defined, backed by prospective, well-controlled studies. Higher eosinophil counts identify patients with more severe disease and poorer outcomes, patients for whom biologic therapies targeting allergic and/or eosinophilic pathways are recommended. In COPD, the evidence is less robust. High blood eosinophil counts are a modest predictor of future exacerbations, and may predict a favourable response to ICS on top of LABA/LAMA, especially in patients with a history of frequent exacerbations. CONCLUSION: Before extensive application in clinical practice, further evaluation of these findings in prospective clinical studies, and standardization of the appropriate thresholds of clinically relevant eosinophilia are needed, together with establishing whether single or multiple measurements are required in different clinical settings.

Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis.

We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis.

Hematochezia caused by eosinophilic proctocolitis in a newborn before oral feeding: a case report.

BACKGROUND: Hematochezia is a frequent symptom in early infancy. However, it occurs very rarely within the immediate neonatal period, and its occurrence before any oral intake is particularly rare. Because of the "congenital" presentation of hematochezia in our patient, we initially considered our case to be a non-classical, potentially severe type of food protein-induced allergic proctocolitis. This diagnosis needs to be confirmed by an abnormal oral challenge test once the hematochezia has disappeared. If such a challenge cannot demonstrate an allergic origin, then the etiology of the hematochezia could be a neonatal transient eosinophilic colitis. Only two similar cases have been described so far. CASE PRESENTATION: We report the case of a black baby boy of African origin born at 36 weeks 5 days of gestational age who presented with massive hematochezia immediately after birth. A rectosigmoidoscopy revealed a severe inflammation associated with diffuse eosinophilic infiltration on biopsy. His clinical outcome was favorable after introduction of an amino acid formula diet. We initially considered our case to be a non-classical, potentially severe type of food protein-induced allergic proctocolitis but reintroduction of standard formula milk at the age of 3 months was successful. So, our patient is the first newborn in Europe who fits the diagnosis of "neonatal transient eosinophilic colitis." CONCLUSIONS: We discuss the possible etiology of "congenital" eosinophilic inflammation of the distal colon and conclude that hematochezia in well-looking neonates, in the absence of negative challenge tests later on, is more likely to be a neonatal transient eosinophilic colitis than an allergic proctocolitis. This new entity could be more frequent than previously thought, changing our medical care strategies for this kind of neonatal symptom.

Dramatic and early response to low-dose steroid in the treatment of acute eosinophilic myocarditis: a case report.

BACKGROUND: Eosinophilic myocarditis encompasses a variety of etiologies and the prognosis varies. For patients with a hypersensitive response to medications, high-dose corticosteroids and discontinuation of culprit medications are the main treatments. CASE PRESENTATION: We reported a young man with biopsy-proven eosinophilic myocarditis which was possibly induced by Chinese herbal medicine. His heart failure and left ventricular hypertrophy improved soon after low-dose corticosteroid. CONCLUSION: Low-dose corticosteroid may be effective in selected patients with eosinophilic myocarditis. Early echocardiographic follow-up is mandatory for evaluation of the clinical response.

Morphea and Eosinophilic Fasciitis: An Update.

Morphea, also known as localized scleroderma, encompasses a group of idiopathic sclerotic skin diseases. The spectrum ranges from relatively mild phenotypes, which generally cause few problems besides local discomfort and visible disfigurement, to subtypes with severe complications such as joint contractures and limb length discrepancies. Eosinophilic fasciitis (EF, Shulman syndrome) is often regarded as belonging to the severe end of the morphea spectrum. The exact driving mechanisms behind morphea and EF pathogenesis remain to be elucidated. However, extensive extracellular matrix formation and autoimmune dysfunction are thought to be key pathogenic processes. Likewise, these processes are considered essential in systemic sclerosis (SSc) pathogenesis. In addition, similarities in clinical presentation between morphea and SSc have led to many theories about their relatedness. Importantly, morphea may be differentiated from SSc based on absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes. The diagnosis of morphea is often based on characteristic clinical findings. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases. However, full-thickness skin biopsies, containing fascia and muscle tissue, are required for the diagnosis of EF. Monitoring of disease activity and damage, especially of subcutaneous involvement, is one of the most challenging aspects of morphea care. Therefore, data harmonization is crucial for optimizing standard care and for comparability of study results. Recently, the localized scleroderma cutaneous assessment tool (LoSCAT) has been developed and validated for morphea. The LoSCAT is currently the most widely reported outcome measure for morphea. Care providers should take disease subtype, degree of activity, depth of involvement, and quality-of-life impairments into account when initiating treatment. In most patients with circumscribed superficial subtypes, treatment with topical therapies suffices. In more widespread disease, UVA1 phototherapy or systemic treatment with methotrexate (MTX), with or without a systemic corticosteroid combination, should be initiated. Disappointingly, few alternatives for MTX have been described and additional research is still needed to optimize treatment for these debilitating conditions. In this review, we present a state-of-the-art flow chart that guides care providers in the treatment of morphea and EF.

Eosinophilic colitis.

A 57-year-old man, diagnosed with colon cancer stage III in July/2010, underwent surgery and received adjuvant chemotherapy with FOLFOX 4 (5-fluorouracil; calcium folinate and oxaliplatin), which ended in March/2011 after 12-cycles. It was then decided to maintain periodical surveillance. About 1 year later, the patient developed several episodes of diarrhoea, mainly during the night, and presented persistent peripheral eosinophilia in the blood count (range 585-1300 eosinophils/µL). Colonoscopy was performed, with the histological result showing eosinophilic infiltration of the colon, compatible with eosinophilic colitis. The patient was treated with a short course of budesonide, achieving resolution of symptoms, and has remained asymptomatic.

Atypical presentations of eosinophilic fasciitis.

Eosinophilic fasciitis is an uncommon connective tissue disease that may mimic and overlap with other sclerosing disorders such as morphea and lichen sclerosus. Herein, we report four patients (two men and two women, aged 16-64 yeas) with eosinophilic fasciitis. There was overlap with both morphea and lichen sclerosus in 2 patients and with morphoea alone in 1 patient. Magnetic resonance imaging (MRI) was used for diagnosis in three patients and for assessing treatment response in one patient. Eosinophilic fasciitis may co-exist with morhoea and lichen sclerosus. In view of the overlapping clinical and histopathological features of these disorders, MRI may be helful in delineating the conditions by detecting involvement of fascia.

Drug reaction with eosinophilia and systemic symptoms syndrome probably induced by a lamotrigine-ginseng drug interaction.

The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10-40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug's package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 × 10(3) /mm(3) , with a prominent eosinophilia of 3.04 × 10(3) /mm(3) ; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng.