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2.
J Exp Med ; 216(9): 1986-1998, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31235509

RESUMO

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.

4.
J Allergy Clin Immunol Pract ; 7(7): 2212-2217.e1, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30922988

RESUMO

BACKGROUND: Flucloxacillin is a narrow-spectrum, beta-lactamase-resistant penicillin. Type I (IgE-mediated) and type IV (T-cell-mediated) reactions are less frequently reported than with other penicillins. OBJECTIVE: To undertake a detailed clinical characterization of a cohort of patients referred with suspected flucloxacillin hypersensitivity. METHODS: We retrospectively analyzed demographic characteristics, presentation, investigation, and management of 108 patients presenting to 4 UK centers. Patients underwent skin prick and intradermal testing with flucloxacillin, major (benzylpenicilloyl poly-l-lysine) and minor determinants, amoxicillin, and benzylpenicillin with immediate and, where appropriate, delayed reading of the test. In the immediate group, a further 14 patients were tested to ampicillin and 16 to Augmentin (co-amoxiclav-combination of clavulanic acid and amoxicillin). Skin test-negative patients underwent oral drug provocation. A multistep protocol was used, depending on risk assessment. RESULTS: Forty of 108 (37%) patients were diagnosed with hypersensitivity to flucloxacillin, of whom 33 (82.5%) showed immediate and 7 (17.5%) nonimmediate hypersensitivity, respectively. In the immediate group, most reactions were severe: 19 of 33 (58%). Intradermal testing had a higher negative predictive value (86%) in the immediate group than in the nonimmediate group (67%). Only a minority of patients (6 of 17 [35%]) with IgE-mediated allergy were cross-sensitized on intradermal testing with other penicillins, compared with 3 of 4 (75%) in the delayed group. CONCLUSIONS: Immediate hypersensitivity reactions to flucloxacillin are more common than delayed. Cross-sensitization to other penicillins appears higher in delayed reactions than in immediate. The negative predictive value of intradermal testing is higher in the immediate group than in the nonimmediate group. Drug provocation testing remains the diagnostic criterion standard.

6.
J Clin Pathol ; 71(4): 316-322, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28844038

RESUMO

BACKGROUND: Faecal calprotectin (FC) measurement distinguishes patients with inflammatory bowel disease (IBD) from those with irritable bowel syndrome but evidence of its performance in primary care is limited. AIMS: To assess the yield of IBD from FC testing in primary care. METHODS: Retrospective review of hospital records to assess the outcome following FC testing in primary care. Investigations for all patients undergoing FC testing in a single laboratory for 6 months from 1 October 2013 to 28 February 2014 were reviewed. RESULTS: 410 patients (162 male; median age 42; range 16-91) were included. FC>50 µg/g was considered positive (FC+). 148/410 (36.1%; median age 44 (17-91)) were FC+ (median FC 116.5 µg/g (51-1770)). 122/148 FC-positive patients (82.4%) underwent further investigation. 97 (65.5%) underwent lower gastrointestinal endoscopy (LGIE), of which 7 (7.2%) had IBD. 49/262 (18.7%) FC-negative (FC-) patients (FC ≤50 µg/g) (median age 47 (19-76)) also underwent LGIE, of whom 3 (6.1%) had IBD.IBD was diagnosed in 11/410 (2.7%; 4 ulcerative colitis, 3 Crohn's disease, 4 microscopic colitis). 8/11 were FC+ (range 67-1170) and 3 FC-. At a 50 µg/g threshold, sensitivity for detecting IBD was 72.7%, specificity 64.9%, positive predictive value (PPV) 5.41% and negative predictive value 98.9%. Increasing the threshold to 100 µg/g reduced the sensitivity of the test for detecting IBD to 54.6%. CONCLUSIONS: FC testing in primary care has low sensitivity and specificity with poor PPV for diagnosing IBD. Its use needs to be directed to those with a higher pretest probability of disease. Local services and laboratories should advise general practitioners accordingly.


Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Atenção Primária à Saúde/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
7.
BMJ Open ; 7(4): e014777, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28442578

RESUMO

OBJECTIVE: The aims of this study were (1) to characterise the type of patient prescribed MP-AzeFlu (Dymista, a novel formulation of azelastine hydrochloride, fluticasone propionate and excipients in a single spray) in real life in the UK and physicians' reasons for prescribing it and (2) to quantify the personal and societal burden of allergic rhinitis (AR) in the UK prior to MP-AzeFlu prescription. DESIGN, SETTING AND PARTICIPANTS: This multicentre, non-interventional study enrolled patients (n=193) with moderate-to-severe AR and acute symptoms who were eligible to receive treatment with MP-AzeFlu according to its licensed indications. Information was gathered on patient demographics, AR history and symptom severity, symptomatology and AR treatments in the previous calendar year (prior to MP-AzeFlu prescription). Physicians also recorded the number of previous AR visits, specific reasons for these visits and their reason for prescribing MP-AzeFlu. RESULTS: Most patients had seasonal AR either alone (10.4%) or in combination with perennial AR (35.2%), but many had AR of unknown origin (35.8%). Prior to MP-AzeFlu prescription, patients reported troublesome symptoms (78.2%) and sleep disturbance (64.8%), with congestion considered the most bothersome (54.4%) and ocular symptoms reported by 68.4% of patients. The most frequent reason for MP-AzeFlu prescription was that other therapies were not sufficient in the past (78.8%) or not sufficient to treat acute symptoms (16.1%). 79.3% of patients reported using ≥2 AR therapies in the past year. An average of 1.6 (SD 1.9) doctor visits due to AR were reported prior to MP-AzeFlu prescription. CONCLUSIONS: In the UK, MP-AzeFlu was prescribed for individuals (≥12 years) with moderate/severe AR irrespective of (1) previous AR treatment (mono or multiple), (2) previous or likely treatment failure, (3) phenotype, (4) number of previous physician visits for AR and (5) for the relief of both acute symptoms and in anticipation of allergen exposure.


Assuntos
Fluticasona/administração & dosagem , Ftalazinas/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Criança , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica/epidemiologia , Reino Unido , Adulto Jovem
8.
J Allergy Clin Immunol Pract ; 5(4): 938-945, 2017 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28351785

RESUMO

A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).


Assuntos
Imunodeficiência de Variável Comum , Granuloma , Doenças Pulmonares Intersticiais , Instituições de Caridade , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico por imagem , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/patologia , Consenso , Granuloma/diagnóstico , Granuloma/diagnóstico por imagem , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Sociedades Médicas , Reino Unido
9.
Sci Transl Med ; 5(206): 206ra139, 2013 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-24107778

RESUMO

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire⁻/⁻ mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.


Assuntos
Autoantígenos/imunologia , Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/imunologia , Pulmão/patologia , Proteínas/metabolismo , Transferência Adotiva , Animais , Autoanticorpos/imunologia , Autoantígenos/metabolismo , Autoimunidade/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Genótipo , Humanos , Tolerância Imunológica/imunologia , Camundongos , Especificidade de Órgãos , Poliendocrinopatias Autoimunes/imunologia , Ensaio Radioligante , Reprodutibilidade dos Testes , Timo/imunologia , Timo/transplante , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
J Pediatr Gastroenterol Nutr ; 55(6): 733-5, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22744189

RESUMO

The updated ESPGHAN guidance on coeliac disease recommends the use of common multiples of the upper limit of normal (ULN) for IgA tissue transglutaminase antibodies (TG2) when deciding which diagnostic pathway to follow. The current lack of standardisation between assays makes it difficult to harmonise results between centres as different performance characteristics are observed with each assay. This variability is shown in data from external quality assessment distributions. As a result, the updated guidance is too generalised for use with all the commercial TG2 kits and is therefore not translatable for use in all centres.


Assuntos
Doença Celíaca/diagnóstico , Duodeno/patologia , Antígenos HLA-DQ/sangue , Imunoglobulina A/sangue , Transglutaminases/imunologia , Humanos
11.
Ann Clin Biochem ; 47(Pt 1): 8-16, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20040797

RESUMO

Cryoglobulins are serum immunoglobulins that precipitate at temperatures below 37 degrees C and re-dissolve on warming. Cryoglobulinaemia leads to variable symptoms including characteristic purpura, ischaemia of extremities, renal failure, peripheral neuropathy, abdominal pain secondary to intestinal ischaemia and arthralgias. Cryoglobulin testing is underutilized in clinical practice. It has been neglected in clinical laboratories and by clinicians due to several factors, such as the length of time it takes for serum cryoglobulin analysis to be performed in the laboratory, the perceived difficulty in getting optimal sampling conditions and a failure to appreciate that even apparently low levels of cryoglobulin can be associated with severe symptoms in some patients. The most important variable confounding standardization of cryoglobulin testing is improper sample handling. A recent report critically appraising the current practice of cryoglobulin evaluation in 137 laboratories in Europe by United Kingdom National External Quality Assurance Scheme (UKNEQAS) illustrated the wide variability in practice. Although many clinical laboratories perform cryoglobulin evaluation, there are widespread differences in the methodology used and the care with which this is carried out and this leads to considerable intralaboratory and interlaboratory variability. The most common sources of error are false-negative results due to loss of cryoprecipitate during transport and storage. Better standardization is needed to avoid missed diagnoses and improve the comparability of results. Laboratories should ensure that sample temperature is maintained at 37 degrees C until the serum is separated. In this article, we briefly review the classification and clinical features of cryoglobulins and suggest best practice guidelines for laboratory detection and identification of cryoglobulins.


Assuntos
Técnicas de Laboratório Clínico , Crioglobulinemia/diagnóstico , Crioglobulinas/análise , Guias de Prática Clínica como Assunto , Algoritmos , Coleta de Amostras Sanguíneas/métodos , Coleta de Amostras Sanguíneas/normas , Técnicas de Laboratório Clínico/normas , Crioglobulinemia/sangue , Crioglobulinemia/virologia , Hepacivirus/fisiologia , Humanos , Valores de Referência , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico
12.
Proc Natl Acad Sci U S A ; 106(11): 4396-401, 2009 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-19251657

RESUMO

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Brônquios/imunologia , Pneumopatias/imunologia , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Canais de Potássio/imunologia , Obstrução das Vias Respiratórias , Autoanticorpos/análise , Bronquíolos/imunologia , Bronquíolos/patologia , Causas de Morte , Células Epiteliais/imunologia , Biblioteca Gênica , Humanos , Imunoprecipitação , Pneumopatias/etiologia , Canais de Potássio/análise , Canais de Potássio/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , RNA Mensageiro/análise , Proteínas Recombinantes/imunologia
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