COVID-19 related multisystem inflammatory syndrome in children (MIS-C): A case series from Ethiopia

Background: One in hventy ofpeople qffected by the ongoing COVID-19 pandemic have been children and adolescents. A unique complication in this age group is the Multi-inflammatory syndrome associated Il'ith COVID-19 (MS-C). We report a single-center case series ofchildren diagnosed with MS-Cfrom Addis Ababa, Ethiopia. Case descriptions This case series describes the clinical presentation and treatment outcomes offour male patients presenting at a mean age of3 years and 11 months. Allfulfilled the World Health Organization case definition criteria for the Multi-inflammatomy syndrome associated 'Vith COVID-19. All "'ere not eligible for vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) at the time oftheir diagnosis. They were treated with varying combinations of intravenous immunoglobulin, aspirin, and corticosteroids, and all recovered upon completion oftheirfollow-up period. Conclusion: Cases of Multi-inflammatomy syndrome associated with COVID-19 are often misdiagnosed. This case series highlights when to consider such a diagnosis and its therapeutic options

O estado da arte das síndromes autoinflamatórias associadas à criopirina / The state of the art of cryopyrin-associated periodic syndromes

As síndromes autoinflamatórias associadas à criopirina (CAPS) compreendem um grupo espectral de doenças raras autoinflamatórias. Todas estas doenças estão relacionadas ao inflamassoma NLRP3, sendo que de 50-60% dos pacientes apresentam mutações ao longo do gene NLRP3. Clinicamente, febre recorrente associada à urticária neutrofílica e outros sintomas sistêmicos são o grande marco clínico, comum a todo o espectro. O bloqueio da interleucina-1 trouxe grande alívio ao tratamento destas desordens, mas variações na resposta clínica podem ser observadas, principalmente nos espectros mais graves. Neste trabalho os autores trazem uma revisão do estado da arte das doenças autoinflamatórias CAPS. Foi realizado levantamento de literatura e, ao final, 49 artigos restaram como base para construção do texto final. O trabalho traz de forma narrativa os principais pontos relacionados a imunofisiopatologia, manifestação clínica, diagnóstico, tratamento, complicações e novas armas diagnósticas, e terapia gênica.

Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of rare autoinflammatory disorders. They are all related to the NLRP3 inflammasome, and 50-60% of the patients harbor mutations along the NLRP3 gene. Clinically, recurrent fever associated with neutrophilic urticaria and other systemic symptoms are a hallmark of all the disorders in the spectrum. Biologic drugs that can block interleukin-1 were a milestone for the treatment of such rare diseases, although variability in clinical response to this therapeutic intervention were observed, especially in those affected by severe phenotypes. In this paper, the authors provide a state-of-the-art review of CAPS. A literature search was performed and, finally, 49 articles remained for the construction of the final manuscript. The article presents a narrative review focused on the topics related to immune pathophysiology, clinical manifestations, diagnosis, treatment, complications and new therapeutic options, and gene therapy.

Urticaria por frío en un adolescente / Urticaria caused by cold in an adolescent

Se presenta el caso clínico de un paciente blanco de 17 años de edad, campesino, con antecedente de rinitis alérgica desde hacía aproximadamente 4 años, quien acudió a la consulta de Alergología del Hospital Provincial Eduardo Agramonte Piña de Camagüey, por presentar un cuadro urticariforme exacerbado en el tiempo que, a pesar de la dieta y de las medidas generales, se mantenía. Se realizó una prueba de provocación específica que resultó positiva; por tanto, se diagnosticó una urticaria crónica inducible de tipo físico, específicamente por frío. Se le indicó tratamiento con ketotifeno y a los 6 meses se repitió la prueba que mostró un resultado favorable.

The case report of a 17 years peasant white patient, is presented with a history of allergic rhinitis for approximately 4 years, who visited the Alergology Service of Eduardo Agramonte Piña Provincial Hospital in Camagüey, to present a sustained urticariform pattern exacerbated with time in spite of the diet and general measures. An specific provocation test which was positive was carried out; therefore, an inducible chronic urticaria of physical type was diagnosed, caused specifically by cold. Treatment with ketotifen was indicated and 6 months later the test was repeated, showing a favorable result.

Clinical and inflammatory phenotypic features of asthmatic patients sensitive to cold stimulation / 南方医科大学学报

OBJECTIVE@#To explore the clinical symptoms, lung function and airway inflammation phenotype characteristics of asthmatic patients who are sensitive to cold stimulation.@*METHODS@#Eighty patients with newly diagnosed bronchial asthma or with mild to moderate acute exacerbation of previously diagnosed bronchial asthma but without regular treatment were selected. According to whether cold air stimulation could induce respiratory symptoms such as cough and wheeze, the patients were divided into cold-insensitive group (45 cases) and cold-sensitive group (35 cases). All the patients were treated with inhaled corticosteroid (ICS), long-acting β2 receptor agonist (LABA; salmeterol xinafoate and fluticasone propionate powder for inhalation, 50 μg/250 μg, twice daily) and montelukast sodium tablets (10 mg, once daily); short-acting β2 receptor agonist (SABA) and/or systemic glucocorticoid (prednisone acetate tablets, 10 mg, once daily; or injection of methylprednisolone sodium succinate, 40 mg) were given if necessary. Asthma Control Test (ACT) score before treatment and at 3 months of treatment was used to assess the clinical symptoms such as cough and wheeze; spirometry was performed to determine lung function impairment and recovery. Blood and induced sputum cell counts were examined to determine the characteristics of airway inflammation.@*RESULTS@#The two groups were comparable for age, gender, BMI, proportion of smokers and allergic rhinitis before treatment. The cold-sensitive patients experienced significantly more frequent acute exacerbations than the cold-insensitive patient within 1 year before the visit ( < 0.05), but the use of SABA and glucocorticoid for symptom control during the treatment did not differ significantly between the two groups ( > 0.05). The ACT scores of the cold-sensitive group were significantly lower than those of the cold-insensitive group both before and after the treatment ( < 0.01). Compared with the cold-insensitive patients, the cold-sensitive patients had more obvious impairment of FEV1/FVC% and FEV1%pred before treatment ( < 0.01), and also showed poorer recovery after treatment ( < 0.05). The percentages of eosinophils in blood and induced sputum samples did not differ significantly between the two groups either before and after the treatment, but the percentage of neutrophils was significantly higher in the cold-sensitive group ( < 0.01). In the induced sputum samples collected before treatment, the cell populations consisted mainly of eosinophilic subtype (60%) and neutrophilic subtype (20%) in the cold-insensitive group; in the cold-sensitive patients, the sputum neutrophilic subtype cells increased significantly to 42.86% (=0.03) and the eosinophilic subtype cells were lowered to 31.43% (=0.01).@*CONCLUSIONS@#The cold-sensitive asthmatic patients experience frequent recurrent and/or aggravated symptoms and have obvious lung function impairment. Different from that in patients with classic asthma, the airway inflammatory phenotype in these patients is characterized by the domination by neutrophilic subtype.

The First Case Series of Cryopyrin-Associated Periodic Syndrome in Korea

Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia. Thus far, however there have been no reports of CAPS in Korea. Herein, we report 3 cases of CAPS for the first time in Korea. The first case, a 28-year-old man with recurrent urticaria, arthralgia and fever induced by cold, all of which were observed in his father, showed elevated erythrocyte sedimentation rate and C-reactive protein. He exhibited a p.Gly303Asp variant of the NLPR3 gene. The second case, a 2-year-old girl who had recurrent urticaria, arthritis and oral and genital ulcers, was positive for HLA B51 and a p.Glu569Lys mutation in exon 3 of the NLRP3 gene. Administration of anakinra greatly improved her symptoms. The third case, a 4-year-old boy who presented with recurrent urticaria, arthralgia, and fever, exhibited a p.Val72Met mutation in exon 1 of the NLRP3 gene. Administration of tocilizumab improved all of his symptoms. This small case series suggests that clinicians consider CAPS and conduct genetic studies when arthralgia and fever are accompanied by urticaria in Korea.

Síndrome de griscelli: reporte de caso / Griscelli Syndrome: Case Report

El síndrome de griscelli es una rara entidad, se engloba dentro de los síndromes de pelos plateados y se caracteriza por albinismo parcial. Fue descrito en 1978 en dos pacientes por Griscelli et al. Desde entonces se han descrito más de 40 casos en la literatura. Es una enfermedad de carácter autosómico recesivo. Se clasifica en tres diferentes tipos. Su tratamiento y pronóstico dependerá de cada uno de ellos. Caso clínico: Se trata de paciente de 1 año de edad que ingresa al Hospital Mario Catarino Rivas con historia de presentar convulsiones y somnolencia, con cuadro respiratorio sobreagreado. Antecedente hospitalario por neumonía grave, y color de pelo plateado desde su nacimiento. Discusión: los casos de síndrome de griscelli en Honduras son sumamente raros, dicho paciente ingresa a esta institución por manifestaciones neurológicas secundarias a su enfermedad, al ver su fenotipo, se investigó por dicho síndrome...(AU)

Síndrome de Stevens-Johnson en edad pediátrica / Stevens Johnson Syndrome of a Pediatric Age Case

El síndrome de Stevens-Johnson (SSJ) es una enfermedad inflamatoria aguda, originada por una reacción de hipersensibilidad, secundaria a ingesta de medicamentos o infecciones, que afecta a la piel y las membranas mucosas produciendo lesiones características del síndrome, causadas por apoptosis y posterior necrosis de los queratinocitos; su forma más severa es la necrolisis epidérmica tóxica, que constituye junto al SSJ un espectro de la misma enfermedad, compartiendo aspectos etiológicos, patogenéticos, histológicos y terapéuticos que ponen en peligro la vida del paciente. La afección se caracteriza por una súbita erupción morfológicamente variable, acompañada de estomatitis y oftalmia.En el presente trabajo se presenta el caso de un niño de 8 años de edad,con diagnóstico clínico de síndrome de Stevens-Johnson, con manifestaciones cutáneas, oculares y de la mucosa oral, que iniciaron posterior a ingesta de ibuprofeno, se mantuvo con un protocolo de cuidados que incluyeron soporte de oxígeno, antibioticoterapia, analgesia, corticoides, nebulizaciones, limpieza de lesiones con solución salina, sin debridación y lubricante oftálmico; tras 8 días dehospitalización el paciente evoluciona satisfactoriamente sin complicaciones durante su estancia hospitalaria.

The Stevens-Johnson syndrome (SJS) is an acute inflammatory disease caused by a hypersensitivity reaction, secondary to medication intake or infections, that affects skin and mucous membranes producing characteristic wounds of the syndrome, caused by apoptosis and subsequent necrosis of keratinocytes; the major form of this disease, is toxic epidermal necrolysis, wich together with SJS is a spectrum of the same disease, sharing etiological pathogenetic, histological and therapeutic aspects, that endanger the patient's life. The affection is characterized by a sudden morphologically varying rash, accompanied bystomatitis and ophthalmic injure. In this work we show an 8 year old patient with a clinical diagnosis of Stevens-Johnson syndrome, involving skin, eye and oral mucosa manifestations, which began after the intake of ibuprofen , it was mantained with a protocol care based on oxygen support, antibiotic therapy, analgesia, corticosteroids, sprays, cleansing wounds with saline solution without debridement and ophthalmic lubricant, after 8 days of hospitalization, our patient has a satisfactory evolution without acute complications during their time at the hospital.

Dental Treatment in a Patient with CINCA Syndrome under General Anesthesia / 대한소아치과학회지

Chronic infantile neurological cutaneous articular (CINCA) syndrome periodically causes fever along with inflammation in multiple organs. Patients with this condition are vulnerable to dental problems due to systemic inflammation. For uncooperative patients, general anesthesia has been widely used to control negative behavior. However, caution should be exercised when administering general anesthesia in these patients because this syndrome is pro-inflammatory. The present case report describes the clinical considerations of the dental treatment of an uncooperative child with CINCA syndrome who was treated under general anesthesia.

The First Report on Clinical Manifestation of Cryopyrin-Associated Periodic Syndrome in Korean Children

PURPOSE: The aim of this study was to evaluate the clinical characteristics of children diagnosed as cryopyrin-associated periodic syndrome (CAPS) in Korea. METHODS: Diagnosis was made based on clinical features and confirmed by a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene. Especially, osteocartilaginous overgrowth in the patella or distal femur was so characteristic that its presence warranted a diagnosis of chronic infantile neurologic cutaneous and articular/NOMID. RESULTS: We observed the clinical features of 9 Korean CAPS patients. All the patients suffered from an urticarial rash with recurrent fever. Among the 9 patients, 6 presented with rash and 4 with fever on the 1st or 2nd days of birth. Eight patients showed myalgia, and 7 patients showed arthralgia in the joints, and 6 patients showed radiologic findings of arthropathy including cupping of the metaphysis, excessive growth of the epiphysis, osteopenia or overgrowth of the cartilage. Four patients showed brain atrophy, enlarged ventricles or leptomeningeal enhancement on magnetic resonance imaging. Intellectual disability was observed in 1 patient. Five patients had eye involvement as conjunctivitis, uveitis, chorioretinitis, avascular area or papillary edema, and 3 patients showed progressive hearing loss. All 9 patients showed increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). CONCLUSIONS: All the patients carried a mutation on exon 3 of the CIAS1 gene. After the anakinra (interleukin-1 receptor antagonist) therapy, the fever and rash immediately disappeared, and CRP and ESR were improved.

Uma nova classe de doenças: doenças autoinflamatórias / A new class of diseases: autoinflammatory diseases

As doenças autoinflamatórias sistêmicas são um grupo de doenças raras recentemente descritas, mas que vêm ganhando espaço no cenário clínico. Caracterizam-se por alterações da imunidade inata, portanto sem a presença de linfócito T autorreator ou autoanticorpo, e que respondem ao bloqueio de uma única citocina. Esta revisão tem como objetivo analisar a base imunofisiológica destas doenças e descrever brevemente cada uma delas com suas características clínicas mais importantes.

Systemic autoinflammatory diseases are a group of rare diseases only recently described but rapidly growing in importance in the clinical setting. They are characterized by innate immunity impairment, i.e., absence of autoreactive T lymphocytes or autoantibodies, and respond to individual cytokine blockade. The objective of this review was to analyze the immunophysiological basis of these diseases and to briefly describe each of them along with their most relevant clinical characteristics.

A Novel Mutation in the Pyrin Domain of the NOD-like Receptor Family Pyrin Domain Containing Protein 3 in Muckle-Wells Syndrome / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin (IL)-1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease. CAPS is associated with gain-of-function missense mutations in NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), the gene encoding NLRP3. Moreover, most mutations leading to MWS occurred in exon 3 of NLRP3 gene. Here, we reported a novel mutation occurred in exon 1 of NLRP3 gene in an MWS patient and attempted to explore the pathogenic mechanism.</p><p><b>METHODS</b>Genetic sequence analysis of NLRP3 was performed in an MWS patient who presented with periodic fever, arthralgia, and multiform skin lesions. NLRP3 was also analyzed in this patient's parents and 50 healthy individuals. Clinical examinations including X-ray examination, skin biopsy, bone marrow aspiration smear, and blood test of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum levels of IL-1β, immunoglobulin E (IgE), antineutrophil cytoplasmic antibodies, antinuclear antibodies, and extractable nuclear antigen were also analyzed. The protein structure of mutant NLRP3 inflammasome was calculated by SWISS-MODEL software. Proteins of wild type and mutant components of NLRP3 inflammasome were expressed and purified, and the interaction abilities between these proteins were tested by surface plasmon resonance (SPR) assay.</p><p><b>RESULTS</b>X-ray examination showed no abnormality in the patient's knees. Laboratory tests indicated an elevation of CRP (233.24 mg/L) and ESR (67 mm/h) when the patient had fever. Serum IL-1β increased to 24.37 pg/ml, and serum IgE was higher than 2500.00 IU/ml. Other blood tests were normal. Bone marrow aspiration smear was normal. A novel point mutation c.92A>T in exon 1 of NLRP3 gene was identified, which caused a p.D31V mutation in pyrin domain (PYD) of NLRP3. SPR assay showed that this point mutation may strengthen the interaction between the PYD of NLRP3 and the PYD of the apoptosis-associated speck-like protein. The mutation c.92A>T in exon 1 of the NLRP3 gene was not found in the patient's parents and 50 healthy individuals.</p><p><b>CONCLUSIONS</b>The mutation c.92A>T in exon 1 of the NLRP3 gene is a novel mutation associated with MWS. The p.D31V mutation might promote the activation of NLRP3 inflammasome and induce MWS in this patient.</p>

Síndromes periódicos asociados a criopirina: etiopatogenia, características clínicas, diagnóstico y tratamiento / Cryopiryn-associated peryodic syndrome: etiopathogenesis, clinical features, diagnosis and treatment

Los desórdenes autoinflamatorios monogénicos comprenden un grupo de enfermedades caracterizadas por episodios recurrentes y espontáneos de fiebre e inflamación sistémica, en ausencia de infección, autoanticuerpos o células T específicas para antígenos propios (autorreactivas). Estas condiciones se deben a mutaciones en genes que codifican para proteínas que son claves en la regulación de la respuesta inflamatoria innata y se consideran como inmunodeficiencias primarias. Las enfermedades que comprenden estos síndromes representan un espectro clínico de diferentes mutaciones, con ganancia de función, de un gen denominado NLRP3 o CIAS1 que codifica para la proteína criopirina, de ahí que estos desórdenes sean también conocidos con el nombre de criopirinopatías. Dentro de estos se encuentran los síndromes periódicos asociados a criopirina que incluyen tres enfermedades: el síndrome autoinflamatorio familiar inducido por frío; el síndrome de Muckle-Wells y el síndrome crónico, infantil, neurológico, cutáneo y articular. Clínicamente se caracterizan por rash tipo urticariano, fiebre periódica, inflamación a nivel del sistema nervioso central, artropatía, manifestaciones oculares y riesgo de amiloidosis como complicación a largo plazo. La función clave de la criopirina en la liberación de la IL-β sugiere el criterio racional de implementar terapias anti-IL-1 para el tratamiento de estos síndromes. La administración de drogas como anakinra, canakinumab y rilonacept muestra un efecto marcado sobre el control de las manifestaciones inflamatorias, clínicas y de los parámetros de laboratorio en estos síndromes. Se describe la etiopatogenia de estas entidades, sus principales características clínicas, el diagnóstico y el tratamiento(AU)

Monogenic autoinflammatory disorders encompass a group of diseases characterized by spontaneous and recurring fever and systemic inflammation in the absence of infection, autoantibodies or specific T cells for self antigens (self-reactive). These conditions are caused by mutations in genes encoding proteins that play a key role in the regulation of innate inflammatory response and are considered primary immunodeficiencies. Diseases comprising these syndromes represent a different clinical spectrum of mutations, with gain of function of a gene called NLRP3 or CIAS1 encoding cryopyrin protein, hence these disorders are also known under the name cryopyrinpathies. Among these are the cryopyrin-associated periodic syndrome which include three conditions: familial cold autoinflammatory syndrome; Muckle-Wells syndrome and chronic infantile neurological, cutaneous and articular syndrome. In clinical terms, it is characterized by urticarial rash, periodic fever, inflammation of central nervous system (CNS), arthropathy, ocular manifestations and risk of amyloidosis as a long-term complication. The key role of cryopirin in the release of IL-β suggests rational approach to implement anti-IL-1 therapy for the treatment of these syndromes. The administration of drugs such as anakinra, canakinumab, and rilonacept shows a marked effect on the control of inflammatory manifestations, as well as clinical and laboratory parameters in these syndromes effect. The pathogenesis of these entities, as well as their main clinical features, diagnosis and treatment are described(AU)

Diretrizes de conduta e tratamento de síndromes febris periódicas associadas à criopirina (criopirinopatias – CAPS) / Guidelines for the management and treatment of periodic fever syndromes

Resumo Objetivo: Estabelecer diretrizes baseadas em evidências científicas para manejo das síndromes periódicas associadas à criopirina (criopirinopatias – Caps). Descrição do método de coleta de evidência: A diretriz foi elaborada a partir de quatro questões clínicas que foram estruturadas por meio do PICO (Paciente, Intervenção ou Indicador, Comparação e Outcome), com busca nas principais bases primárias de informação científica. Após definir os estudos potenciais para sustento das recomendações, esses foram graduados pela força da evidência e pelo grau de recomendação. Resultado: Foram recuperados, e avaliados pelo título e resumo, 1.215 artigos e selecionados 42 trabalhos para sustentar as recomendações. Recomendações: 1. O diagnóstico de Caps é baseado na anamnese e nas manifestações clínicas e posteriormente confirmado por estudo genético. Pode se manifestar sob três fenótipos: FCAS (forma leve), MWS (forma intermediária) e Cinca (forma grave). Avaliações neurológica, oftalmológica, otorrinolaringológica e radiológica podem ser de grande valia na distinção entre as síndromes; 2. O diagnóstico genético com análise do gene NLRP3 deve ser conduzido nos casos suspeitos de Caps, isto é, indivíduos que apresentam, antes dos 20 anos, episódios recorrentes de inflamação expressa por urticária e febre moderada; 3. As alterações laboratoriais incluem leucocitose e elevação nos níveis séricos de proteínas inflamatórias; 4. Terapias alvo dirigidas contra a interleucina 1 levam a rápida remissão dos sintomas na maioria dos pacientes. Contudo, existem limitações importantes em relação à segurança em longo prazo. Nenhuma das três medicações anti-IL1β evita progressão das lesões ósseas.

Abstract Objective: To establish guidelines based on cientific evidences for the management of cryopyrin associated periodic syndromes. Description of the evidence collection method: The Guideline was prepared from 4 clinical questions that were structured through PICO (Patient, Intervention or indicator, Comparison and Outcome), to search in key primary scientific information databases. After defining the potential studies to support the recommendations, these were graduated considering their strength of evidence and grade of recommendation. Results: 1215 articles were retrieved and evaluated by title and abstract; from these, 42 articles were selected to support the recommendations. Recommendations: 1. The diagnosis of CAPS is based on clinical history and clinical manifestations, and later confirmed by genetic study. CAPS may manifest itself in three phenotypes: FCAS (mild form), MWS (intermediate form) and CINCA (severe form). Neurological, ophthalmic, otorhinolaryngological and radiological assessments may be highly valuable in distinguishing between syndromes; 2. The genetic diagnosis with NLRP3 gene analysis must be conducted in suspected cases of CAPS, i.e., individuals presenting before 20 years of age, recurrent episodes of inflammation expressed by a mild fever and urticaria; 3. Laboratory abnormalities include leukocytosis and elevated serum levels of inflammatory proteins; and 4. Targeted therapies directed against interleukin-1 lead to rapid remission of symptoms in most patients. However, there are important limitations on the long-term safety. None of the three anti-IL-1β inhibitors prevents progression of bone lesions.

A Rare Case of Acute Ocular Hypertensive Episode in a Patient with Chronic Infantile Neurological Cutaneous Articular Syndrome

No abstract available.

Report of a child with neonatal-onset multisystem inflammatory disease and review of the literature / 中华儿科杂志

<p><b>OBJECTIVE</b>Neonatal-onset multisystem inflammatory disease (NOMID) is not widely recognized in China. This study aimed to investigate the diagnosis and treatment of NOMID.</p><p><b>METHOD</b>To analyze the clinical characteristics and laboratory results including skin biopsy, gene analysis and serum interleukin 1β of a boy admitted to Peking University First Hospital in November of 2013. Reports on NOMID were searched and the clinical and laboratory characteristics of reported cases were summarized.</p><p><b>RESULT</b>The patient was a 1-year-old boy. He had urticaria since 2 days after birth, and presented with episodes of fever, aseptic meningitis, symptoms of joints, short statue, hearing loss, abnormal fundus findings, and leucocytosis, high level of c-reactive protein (CRP) and abnormal findings of head MRI including ventriculomegaly and white matter dysplasia. Urticaria was confirmed by skin biopsy. Gene analysis showed T1702T/A in exon 4 of NLRP3 gene, which causes Phe568lle. Serum interleukin 1β increased dramatically. The boy was diagnosed as NOMID. He did not respond to antibiotic therapy and anti-allergy therapy. Corticosteroid therapy induced normalization of body temperature, and alleviation of rash, but not improvement in cerebrospinal fluid cell numbers. After searching reports of NOMID at PubMed, and Chinese literature published before November 2013, we summarized cases from 8 reports and reviewed 148 cases. The results showed that fever, urticaria, meningitis and arthropathy are the most common manifestations of NOMID, only 57% (69/122) of patients had mutation of NLRP3.</p><p><b>CONCLUSION</b>This is a rare report of NOMID in children in China. Fever, urticaria, aseptic meningitis and persistently high level of CRP are characteristics of NOMID. Gene analysis and serum interleukin-1β detection can aid in diagnosis.</p>

Canaquinumabe para o tratamento da síndrome periódica associada à criopirina - CAPS / Canaquinumab for the treatment of periodic syndrome associated with cryopyrin - CAPS

Tecnologia: CANAQUINUMABE (ILARIS®). Indicação: SÍNDROMES PERIÓDICAS ASSOCIADAS À CRIOPIRINA (CAPS). Demandante: NOVARTIS BIOCIÊNCIAS S.A. Contexto: a síndrome periódica associada à criopirina (CAPS) compreende um conjunto de doenças, ditas autoinflamatórias, causadas por mutações no gene cold induced autoinflammatory syndrome 1 (CIAS1), que codifica a proteína criopirina (NALP3 ou PYPAF1). Essa mutação provoca uma superexpressão de IL-1ß, o que provoca episódios recorrentes de inflamação sistêmica nos pacientes afetados. Trata-se de uma doença rara, com menos de 30 casos identificados no Brasil. O tratamento oferecido atualmente no SUS baseia-se em medicamentos não específicos para a doença, com vistas a suprimir os componentes inflamatórios da CAPS, a fim de controlar os episódios autoinflamatórios agudos e aliviar os sintomas, diminuindo a duração e frequência de eventos e evitando complicações graves em longo prazo. São eles: antiinflamatórios não-esteroidais, bloqueadores de fator de necrose tumoral, glicocorticoides, anti-histamínicos e imunossupressores. Pergunta: a pergunta formulada pelo demandante envolve o uso de canaquinumabe para tratamento de pacientes pediátricos e adultos com CAPS, em busca de desfechos de eficácia e segurança (sem restrição), além dos aspectos econômicos associados à introdução desta terapia. Restringiu-se a busca na literatura por metanálises, revisões sistemáticas, ensaios clínicos, estudos observacionais e avaliações econômicas. Evidências científicas: pesquisa nas bases de dados Cochrane, Medline, Lilacs e Embase, além de buscas em sítios eletrônicos de agências de ATS e suas bases de dados foram realizadas. Após análise de qualidade, 5 artigos foram incluídos. Tratam-se de estudos fase II e fase III com duração média de 24 semanas e um deles com 2 anos de seguimento, todos comparando o canaquinumabe a placebo ou a nenhum tratamento, além de um estudo que avaliou a qualidade de vida relacionada à saúde da população acompanhada em um dos estudos avaliados. Os desfechos mensurados na maioria dos estudos foram: melhora global de sintomas percebida por médico e paciente, remissão de sintomas e tempo de ausência das manifestações. Podem-se citar como principais limitações dos estudos a falta de um grupo comparador, o número amostral pequeno de pacientes e a curta duração da fase duplo-cego nos estudos, impossibilitando a avaliação em médio e longo prazo de desfechos definitivos da doença, além de resultados relacionados à prevenção de complicações da doença em longo prazo. Avaliação econômica: um modelo de Markov foi demonstrado, compreendendo quatro estados de saúde na progressão da doença dos pacientes com CAPS: CAPS, CAPS com amiloidose (AA), CAPS com insuficiência renal em fase terminal e morte, em pacientes adultos e pediátricos com CAPS a partir do início do tratamento até a morte, ou 100 anos. Foram considerados dois horizontes de tempo de tratamento, nos quais os pacientes iniciavam o tratamento com 4 ou 38 anos de idade. Através dos modelos matemáticos apresentados, o demandante afirma que o tratamento iniciado aos 4 e aos 38 anos de idade, trazem um benefício clínico de 13,7 e 10,3 anos de vida ganho, respectivamente, em relação ao não-tratamento. Discussão: a falta de estudos comparativos e com maior tempo de seguimento dos pacientes resulta em poucos subsídios para fornecer uma adequada avaliação dos benefícios e riscos no uso do medicamento em longo prazo, ou mesmo, se o medicamento seria eficaz em evitar ou reverter danos em pacientes afetados pela amiloidose em relação aos tratamentos já disponibilizados pelo SUS. O modelo econômico apresentou limitações importantes, pois calculou o benefício clínico em relação a nenhum tratamento, enquanto que os custos foram comparados com as alternativas disponíveis no SUS, o que limita o cálculo da razão de custo-efetividade incremental, que mesmo no modelo proposto foi bastante elevado. Decisão: a recomendação inicial da CONITEC foi pela não incorporação da tecnologia. A consulta pública recebeu 18 contribuições e, após a análise das mesmas, o plenário decidiu por manter a recomendação de não incorporação do canaquinumabe para o tratamento das síndromes periódicas associadas à criopirina - CAPS. No entanto, o plenário sugeriu que o tema seja remetido para estudo junto à área técnica da Secretaria de Atenção à Saúde do Ministério da Saúde responsável pela estruturação da Política Nacional de Atenção às Pessoas com Doenças Raras no SUS, a fim de avaliar o uso do medicamento no tratamento da condição (fenótipo) mais grave da doença (CINCA/NOMID).

Enfermedades auto inflamatorias (EAI) en pediatría / Autoinflammatory diseases in children

Las enfermedades autoinmunes son un grupo de enfermedades de relativo reciente conocimiento. Muchas de ellas están genéticamente determinadas (excepto el síndrome de PFAPA). Se caracterizan por episodios recurrentes de fiebre asociada a síntomas que generalmente pueden comprometer la piel, sistema músculo esquelético y gastrointestinal. A pesar de su baja prevalencia, el descubrimiento de los genes comprometidos en algunas de ella, ha permitido una mejor comprensión de los mecanismos de la respuesta inmune innata y en especial del rol de los llamados inflamosomas. Estos avances han permitido terapias más específicas, lo que ha llevado a disminuir en forma importante la morbilidad asociada, tanto a corto como a largo plazo. En el área pediátrica, el síndrome de PFAPA debe ser incluido como alternativa en el diagnóstico diferencial.

Autoimmune diseases are an emerging group of genetically determined diseases (except PFAPA) that affect innate immune system. They are characterized by recurrent episodes of fever associated with symptoms affecting skin, musculoskeletal and gastrointestinal system. Although unfrequent, the discovery of affected genes has allowed a better understanding of molecular mechanisms of innate immune response, specially about the role of inflammasomes. Subsequent targeted therapies have allowed a great improvement in short term and long term morbidity of most of these diseases. In children, PFAPA must be included in the analysis of differential diagnosis.

A Case Report of Glomus Tumor of the Nasal Columella

PURPOSE: Glomus tumor is a benign neoplasm of the normal glomus body, occurring as painful subcutaneous nodules, frequently located in the subungual area. There are few cases of facial glomus tumor reported and we report a case of glomus tumor developing on the columella of nose. METHODS: A 68-year-old female presented with a mass of the columella grown for 2 years. The nodule was 0.6 cm in diameter, red-colored without any symptoms such as pain, tenderness and cold hypersensitivity. The pathologic result after punch biopsy was hemangiopericytoma. Excision with local anesthesia was executed. RESULTS: The postoperative recovery of the patient was uneventful, Histopathological examination indicated a glomus tumor. Immunostaining revealed positivity for vimentin, actin, and negativity for desmin, CD-34. After 8 months follow up, there is neither complication nor evidence of local recurrence on clinical examination. CONCLUSION: To accomplish an accurate diagnosis of glomus tumor, the histopathological examination is essential together with immunochemical studies. The differential diagnosis include hemangioma, lipoma, epidermal inclusion cyst, dermoid cyst and arteriovenous malformation in this region. We report a case of glomus tumor on the face with uncommon clinical features.

Pyrin Domain (PYD)-containing Inflammasome in Innate Immunity

Inflammasome is a cytosolic multiprotein complex to activate caspase-1 leading to the subsequent processing of inactive pro-interleukin-1-beta (Pro-IL-1beta) into its active interleukin-1 beta (IL-1beta) in response to pathogen- or danger-associated molecular pattern. In recent years, a huge progress has been made to identify inflammasome component as a molecular platform to recruit and activate caspase-1. Nucleotide-binding oligomerization domain-like receptor (NLR) family proteins such as NLRP1, NLRP3 or interleukin-1beta-converting enzyme (ICE)-protease activating factor (IPAF) have been first characterized to form inflammasome complex to induce caspase-1 activation. More recently, non-NLR type, pyrin-domain (PYD)-containing proteins such as pyrin or absent in melanoma2 (AIM2) were also proposed to form caspase-1-activating inflammasome machinery with apoptosis-associated speck-like protein containing a CARD (ASC), an essential adaptor molecule. Inflammasome pathways were shown to be crucial for protecting host organisms against diverse pathogen infections, but accumulating evidences also suggest that excessive activation of inflammasome/caspase-1 might be related to the pathogenesis of inflammation-related diseases. Indeed, mutations in NLRP3 or pyrin are closely associated with autoinflammatory diseases such as familial Mediterranean fever (FMF) syndrome or Muckle-Wells syndrome (MWS), indicating that the regulation of caspase-1 activity by inflammasome is a central process in these hereditary inflammatory disorders. Here, recent advances on the molecular mechanism of caspase-1 activation by PYD-containing inflammasomes are summarized and discussed.

Síndrome de Muckle-Wells em quatro membros de uma família / Four cases of Muckle-Wells syndrome within the same family

A síndrome de Muckle-Wells é doença autossômica dominante rara, incluída no grupo das síndromes febris hereditárias. Caracteriza-se por episódios recorrentes e autolimitados de febre, urticária, artralgia, mialgia e conjuntivite, desde a infância, relacionados com a exposição ao frio. Mais tardiamente, há perda auditiva neurossensorial progressiva. Amiloidose, a principal complicação, desenvolve-se em cerca de 25 por cento dos casos. Associa-se a mutações no gene NLRP3 (antes CIAS1) que codifica a criopirina, proteína reguladora da produção de citocinas pró-inflamatórias, como a interleucina-1beta. Relata-se a ocorrência dessa doença incomum em quatro membros de uma única família.

Muckle-Wells syndrome is a rare autosomal dominant disease that belongs to a group of hereditary febrile syndromes. It is characterized by recurrent and self-limited episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis since childhood, which are related to exposure to cold temperatures. Lately, progressive sensorineural hearing loss occurs. Amyloidosis is the main complication and can be found in about 25 percent of the cases. It has been demonstrated that there is an association with mutations in the NLRP3 gene, which codifies cryopyrin, a protein responsible for regulating the production of proinflammatory cytokines, such as interleukin-1Beta. The authors report four cases of the disease within a family.