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2.
PLoS One ; 14(5): e0215061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31042724

RESUMO

INTRODUCTION: The early identification of patients at risk of severe dengue infection (DI) is critical to guide clinical management. There is currently no validated laboratory test which can predict severe complications of DI. The Atypical lymphocyte count (ALC) is a research parameter generated at no extra cost when an automated Full Blood Count (FBC) is performed. The purpose of this study was to assess the association of ALC with the severity of DI. METHODS: We prospectively collected data on patients admitted to Nawaloka Hospital Sri Lanka (NH) with DI between December 2016 and November 2017. DI was diagnosed based on a positive Non-structural antigen 1 (NS1) or dengue IgM antibody. ALC (absolute ALC and percentage) data were extracted from the Sysmex XS500i automated full blood count (FBC) analyzer (Sysmex Corporation Kobe, Japan). Clinical data was recorded from medical records and the computerized data base maintained by NH. RESULTS: 530 patients were enrolled. Patients with clinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. Patients who presented with respiratory compromise had statistically significantly higher AL% compared to those without. (AL%; 8.65±12.09 vs 2.17±4.25 [p = 0.01]). Similarly, patients who developed hypotension had higher AL% compared to those who did not suffered from shock (AL%; 8.40±1.26 vs 2.18±4.25 [p = 0.001]). The AL% of dengue patients presenting with bleeding, at 4.07%, is also higher than those without bleeding complications, at 2.15%. There was a significant negative association between platelet count and AL% (p = 0.04). CONCLUSIONS: Clinical manifestations of severe dengue have a significantly higher AL % compared to dengue without warning signs. AL % at presentation may be predictive of severe DI and future larger prospective longitudinal studies should be done to determine if AL % on admission is predictive of the complications of DI.

3.
BMC Res Notes ; 11(1): 556, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30075812

RESUMO

OBJECTIVES: There has been a global increase in the incidence and prevalence of NAFLD. We assessed the knowledge and awareness of NAFLD among gastroenterology doctors in three state sector hospitals. RESULTS: 80 medical officers and 58 post-graduate trainee doctors/consultants responded. 110 (79.7%) considered NAFLD a major health problem whilst 97 (70.3%) thought the prevalence of NAFLD was 10-40%. 52.9% saw 12-24 patients with NAFLD/year. A vast majority knew the risk factors for NAFLD: 127 (92.7%) diabetes mellitus, 135 (97.8%) Obesity, 132 (95.7%) Dyslipidemia and 87 (63%) PCOS. The methods for diagnosis were recognized by: USS 132 (95.7%), MRI 34 (24.6%), transient elastography 23 (16.7%) and liver biopsy 88 (63.8%) while, 53 (38.4%) recognized the non-invasive methods available for diagnosis. The trends in referral were lower than expected: 85 (61.6%) refer to a Gastroenterologist/Physician, 53 (38.4%) to a Gym, 67 (48.6%) to a weight loss clinic and 45 (32.6%) to a dietician. Significantly more postgraduate trainee doctors: recognized the availability of non-invasive investigations for NAFLD (P = 0.01) and read guidelines on NAFLD (P = 0.02) compared to non-trainee doctors. As a whole, a majority (57.2%) had not attended a lecture or read a guideline on NAFLD. The barriers for management included: lack of confidence 70 (50.7%) and time constraints 58 (42%).

4.
Trans R Soc Trop Med Hyg ; 112(3): 144-153, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726966

RESUMO

Background: Sri Lanka experienced its largest dengue epidemic in 2017. This study describes the disease pattern of adult dengue patients from two hospitals in Sri Lanka. Methods: Demographic, clinical and investigation findings of adult dengue patients admitted to the two hospitals from June to August 2017 were collected and analysed. Results: A total of 1167 patients (777 males [66.2%], mean age 32.9 y) were studied. There were 775 (66.4%) patients with dengue fever (DF), 334 (28.6%) with dengue haemorrhagic fever grade I, 54 (4.6%) with DHF grade II and 4 (0.3%) with DHF grade III. DHF was significantly associated with abdominal symptoms/signs and bleeding manifestations (p<0.001). A considerable variation in time of onset of the critical phase was noted (day 3, 11.9%; day 4-5, 63.1%; day 6, 16.2%; day ≥7, 8.7%). Significantly lower platelet and white blood cell counts and elevated transaminase levels were found in DHF than DF (p<0.001). Other complications included myocarditis (two patients) and mild renal impairment (three patients). None had neurological manifestations. Conclusions: We found abdominal symptoms/signs, low platelet and white blood cell counts and high transaminase to be associated with DHF. The onset of the critical phase was variable and difficult to predict. Compiling data from various regions would help to understand disease patterns, which in turn would help in formulating evidence-based management guidelines and the allocation of limited health care resources.

5.
Rev Med Virol ; 28(2)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29465794

RESUMO

Dengue fever is the commonest viral haemorrhagic fever worldwide and is a leading cause of morbidity and mortality in the tropics. Dengue viral infections are frequently associated with varying degrees of liver injury. Liver injury is more severe in dengue haemorrhagic fever or severe dengue. We review the current knowledge on liver involvement following dengue viral infections and explore the links between clinical manifestations, pathogenesis, and their impact on management.


Assuntos
Vírus da Dengue/fisiologia , Dengue/complicações , Dengue/virologia , Hepatopatias/etiologia , Animais , Dengue/diagnóstico , Dengue/epidemiologia , Vírus da Dengue/classificação , Gerenciamento Clínico , Humanos , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Hepatopatias/terapia , Testes de Função Hepática
6.
J Clin Virol ; 101: 1-6, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29414180

RESUMO

Dengue is a significant health problem in many countries. In recent years, complications involving specific organ systems have been increasingly observed and appear to have important effects on overall dengue related morbidity and mortality. Renal involvement in dengue could potentially cause increased mortality and long term effects. We review the different renal manifestations associated with dengue virus infections and explore their potential underlying pathophysiological mechanisms. The serum electrolyte and urinary abnormalities seen in dengue are discussed and Acute Kidney Injury (AKI) due to acute glomerulonephritis, rhabdomyolysis and haemolytic uraemic syndrome following dengue are explored. Renal manifestations of dengue in patients with chronic kidney disease or a transplanted kidney provides new insights into the pathophysiology of the disease.

7.
J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29477724

RESUMO

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

9.
J Allergy Clin Immunol Pract ; 6(1): 159-168.e3, 2018 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28734862

RESUMO

BACKGROUND: Patients with common variable immunodeficiency (CVID) suffer frequent respiratory tract infections despite immunoglobulin replacement and are prescribed significant quantities of antibiotics. The clinical and microbiological nature of these exacerbations, the symptomatic triggers to take antibiotics, and the response to treatment have not been previously investigated. OBJECTIVES: To describe the nature, frequency, treatment, and clinical course of respiratory tract exacerbations in patients with CVID and to describe pathogens isolated during respiratory tract exacerbations. METHODS: We performed a prospective diary card exercise in 69 patients with CVID recruited from a primary immunodeficiency clinic in the United Kingdom, generating 6210 days of symptom data. We collected microbiology (sputum microscopy and culture, atypical bacterial PCR, and mycobacterial culture) and virology (nasopharyngeal swab multiplex PCR) samples from symptomatic patients with CVID. RESULTS: There were 170 symptomatic exacerbations and 76 exacerbations treated by antibiotics. The strongest symptomatic predictors for commencing antibiotics were cough, shortness of breath, and purulent sputum. There was a median delay of 5 days from the onset of symptoms to commencing antibiotics. Episodes characterized by purulent sputum responded more quickly to antibiotics, whereas sore throat and upper respiratory tract symptoms responded less quickly. A pathogenic virus was isolated in 56% of respiratory exacerbations and a potentially pathogenic bacteria in 33%. CONCLUSIONS: Patients with CVID delay and avoid treatment of symptomatic respiratory exacerbations, which could result in structural lung damage. However, viruses are commonly represented and illnesses dominated by upper respiratory tract symptoms respond poorly to antibiotics, suggesting that antibiotic usage could be better targeted.

10.
BMC Musculoskelet Disord ; 18(1): 310, 2017 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-28724365

RESUMO

BACKGROUND: The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. METHODS: Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. RESULTS: Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). CONCLUSIONS: Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. TRIAL REGISTRATION: The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Isoxazóis/administração & dosagem , Metotrexato/administração & dosagem , Rituximab/administração & dosagem , Adulto , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Leflunomida , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Heliyon ; 3(6): e00333, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28721392

RESUMO

Measurement of an individuals ability to respond to polysaccharide antigens is a crucial test to determine adaptive immunity. Currently the response to Pneumovax® is utilized but with the success of Prevnar®, measurement of the response to Pneumovax may be challenging. The aim of the study was to assess the response to Typhi Vi vaccination in both children and adult control groups and patients with primary immunodeficiency (PID). In the control groups, >95% of the individuals had pre Typhi Vi vaccination concentrations <100 U/mL and there was significant increase in concentration post Typhi Vi vaccination (p<0.0001) with>94% achieving ≥3 fold increase in concentration (FI). The response to Typhi Vi vaccination was significantly lower in both children (p = 0.006) and adult (p = 0.002) PID groups when compared to their control groups. 11% and 55% of the children and adult PID groups respectively did not obtain a response >3FI. There were no significant differences between the responses obtained in the children and adult PID groups. When all individuals with PID were separated into those with either hypogammaglobulinemia (HYPO) or common variable immunodeficiency (CVID), both groups had a significantly lower median FI than the control group (19, 95%CI 5-56 vs 59, 95%CI 7-237; p = 0.01 and 1, 95%CI 1-56 vs 32, 95%CI 5-136; p = 0.005). Further, a >3FI differentiated the antibody responses between both the CVID and HYPO groups and their control groups (AUC: 0.83, 95%CI: 0.65-1.00, p = 0.005 and 0.81, 95% CI: 0.65-0.97, p = 0.01). The data suggests that measurement of the response to Typhi Vi vaccination could represent a complementary assay for the assessment of the response to a polysaccharide vaccine.

12.
Toxicon ; 137: 27-35, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28712914

RESUMO

Diagnostic and therapeutic reagents are unavailable for anaphylaxis arising from stings by Apis dorsata. Venom profiles and cross-reactivity of A. dorsata and Apis mellifera were compared, to ascertain whether venom of A. mellifera can be used for diagnosis in A. dorsata allergy. Both venom profiles were similar by High Performance Liquid Chromatography and SDS-PAGE. Sera of 29 of 30 (96.7%) patients with anaphylaxis to A. dorsata stings had IgE to the phospholipase-2 (PLA2) doublet (15 and 16 kDa) of A. dorsata venom by immunoblot, compared to 26 of 30 (86.7%) with the PLA2 of A. mellifera and a purified preparation of PLA2. Twelve patients (40%) with severe anaphylaxis had IgE reactivity to a 39 kDa protein band of venom of both species, a third band, identified in immunoblot as hyaluronidase. The cross-reactivity of PLA2 and hyaluronidase of A. dorsata and A. mellifera were further confirmed by immunoblot inhibition results. Twenty five of 30 (83.3%) of our patients had positive venom specific IgE (>0.35 KUA/L) reactivity to Phadia ImmunoCAPs of A. mellifera venom. The observed IgE cross reactivity suggests the possibility of using A. mellifera venom as a diagnostic test for A. dorsata venom allergy.

13.
Am J Med Genet C Semin Med Genet ; 175(1): 226-236, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28261938

RESUMO

Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical mediators. After being recruited to connective tissues, resident MCs progenitors undergo further differentiation, under the influence of signals from surrounding microenvironment. It is the differential tissue homing and local maturation factors which result in a diverse population of resident MC phenotypes. An abundance of MC reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibers, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell populations, fibroblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs). This report reviews basic biology of mast cells and mast cell activation as well as recent research efforts, which implicate a role of MC dysregulation beyond atopic disorders and in a cluster of Ehlers-Danlos Syndromes, non-IGE mediated hypersensitivity disorders, and dysautonomia. © 2017 Wiley Periodicals, Inc.


Assuntos
Síndrome de Ehlers-Danlos/patologia , Mastócitos/patologia , Doenças do Sistema Nervoso Autônomo , Humanos , Hipersensibilidade
14.
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
15.
Trans R Soc Trop Med Hyg ; 111(9): 384-392, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351663

RESUMO

Dengue viral infections are endemic or epidemic in virtually all tropical countries. Among individuals infected with the dengue virus, severe dengue syndromes (i.e., dengue haemorrhagic fever and dengue shock syndromes) tend to affect only some and this may be due to a combination of host genetic susceptibility and viral factors. In this review article we analyse and discuss the present knowledge of non-human leucocyte antigen host genetic susceptibility to severe dengue syndromes. The relevance of genetic polymorphisms in the pathways of antigen recognition, uptake, processing and presentation, activation of interferon α responses, mast cell and complement activation and T cell activation and dengue disease severity has been reviewed and analysed.

16.
J Allergy Clin Immunol ; 139(4): 1282-1292, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27697500

RESUMO

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/mortalidade , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tempo , Adulto Jovem
17.
J Clin Immunol ; 36(7): 656-66, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27484504

RESUMO

Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications. Using a functional read-out, we previously identified a functional subgroup of CVID patients with plasmablasts (PBs) producing IgM only. We have now further characterized such CVID patients by a direct functional comparison with patients having genetically well-characterized CSR defects in CD40L, activation-induced cytidine deaminase (AID) and uracil N-glycosylase activity (UNG). The CSR-like CVID patients showed a failure in B cell activation patterns similar to the classical AID/UNG defects in three out of five CVID patients and distinct more individual defects in the two other CVID cases when tested for cellular activation and PB differentiation. Thus, functional categorization of B cell activation and differentiation pathways extends the expected variation in CVID to CSR-like defects of as yet unknown genetic etiology.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Fenótipo , Adolescente , Adulto , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Imunodeficiência de Variável Comum/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/metabolismo , Plasmócitos/patologia , Adulto Jovem
18.
Clin Infect Dis ; 63(1): 57-63, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27076567

RESUMO

BACKGROUND: Therapeutic immunoglobulins are used as replacement or immunomodulatory therapy, but can transmit clinically important molecules. We investigated hepatitis B virus (HBV) antibodies and galactomannan enzyme immunoassay (GM-EIA) positivity. Detection of HBV core antibody may prompt antiviral prophylaxis when commencing therapy such as rituximab; a positive GM-EIA result prompts investigation or treatment for invasive fungal disease. METHODS: We performed a cross-sectional analysis of HBV serology in 80 patients established (>6 months) on immunoglobulin therapy; prospective analysis of HBV serology in 16 patients commencing intravenous immunoglobulin (IVIG); and pre- and post-infusion analysis of GM-EIA in 37 patients receiving IVIG. RESULTS: Pre-IVIG, 9 of 80 patients tested positive for HBV surface antibody and 1 of 80 tested equivocal for HBV core antibody. On IVIG, 79 of 79 tested positive for surface antibody, 37 of 80 tested positive for core antibody, and 10 of 80 tested equivocal for core antibody. There were significant differences by product, but among patients receiving products that appear to transmit core antibody, negative results correlated with lower surface antibody titers and longer time since infusion, suggesting a simple concentration effect. There was a progressive increase with each infusion in the percentage of patients testing positive for HBV core antibody among patients newly commencing IVIG. Some patients "seroreverted" to negative during therapy. Certain IVIG products tested positive for GM-EIA and there were rises in index values in corresponding patient samples from pre- to post-infusion. Overall, 5 of 37 patient samples pre-infusion and 15 of 37 samples post-infusion tested positive for GM-EIA. CONCLUSIONS: HBV antibodies and GM-EIA positivity are common in patients receiving IVIG and confound diagnostic results.


Assuntos
Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Hepatite B/imunologia , Técnicas Imunoenzimáticas/métodos , Imunoglobulinas Intravenosas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Reações Falso-Positivas , Feminino , Humanos , Imunização Passiva , Técnicas Imunoenzimáticas/normas , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Mananas , Pessoa de Meia-Idade , Adulto Jovem
19.
J Clin Immunol ; 36(1): 73-84, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26604104

RESUMO

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.


Assuntos
Candidíase Mucocutânea Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Leucócitos Mononucleares/imunologia , Mutação/genética , Fator de Transcrição STAT1/metabolismo , Adulto , Candidíase Mucocutânea Crônica/genética , Células Cultivadas , Citocinas/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Linhagem , Fenótipo , Estrutura Terciária de Proteína/genética , Fator de Transcrição STAT1/genética
20.
J Allergy Clin Immunol ; 136(2): 382-91, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25772593

RESUMO

BACKGROUND: Hazelnut allergy is birch pollen-driven in Northern/Western Europe and lipid transfer protein-driven in Spain and Italy. Little is known about other regions and other allergens. OBJECTIVE: Establishing a molecular map of hazelnut allergy across Europe. METHODS: In 12 European cities, subjects reporting reactions to hazelnut (n = 731) were evaluated and sensitization to 24 foods, 12 respiratory allergen sources, and latex was tested by using skin prick test and ImmunoCAP. A subset (124 of 731) underwent a double-blind placebo-controlled food challenge to hazelnut. Sera of 423 of 731 subjects were analyzed for IgE against 7 hazelnut allergens and cross-reactive carbohydrate determinants by ImmunoCAP. RESULTS: Hazelnut allergy was confirmed in 70% of those undergoing double-blind placebo-controlled food challenges. Birch pollen-driven hazelnut sensitization (Cor a 1) dominated in most cities, except in Reykjavik, Sofia, Athens, and Madrid, where reporting of hazelnut allergy was less frequent anyhow. In Athens, IgE against Cor a 8 dominated and strongly correlated with IgE against walnut, peach, and apple and against Chenopodium, plane tree, and mugwort pollen. Sensitization to seed storage proteins was observed in less than 10%, mainly in children, and correlated with IgE to nuts, seeds, and legumes. IgE to Cor a 12, observed in all cities (10% to 25%), correlated with IgE to nuts, seeds, and pollen. CONCLUSIONS: In adulthood, the importance of hazelnut sensitization to storage proteins, oleosin (Cor a 12), and Cor a 8 is diluted by the increased role of birch pollen cross-reactivity with Cor a 1. Cor a 8 sensitization in the Mediterranean is probably driven by diet in combination with pollen exposure. Hazelnut oleosin sensitization is prevalent across Europe; however, the clinical relevance remains to be established.


Assuntos
Alérgenos/imunologia , Antígenos de Plantas/imunologia , Corylus/imunologia , Hipersensibilidade a Noz/epidemiologia , Adolescente , Adulto , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Betula/química , Betula/imunologia , Proteínas de Transporte/imunologia , Corylus/química , Reações Cruzadas , Método Duplo-Cego , Europa (Continente)/epidemiologia , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Hipersensibilidade a Noz/etiologia , Hipersensibilidade a Noz/imunologia , Hipersensibilidade a Noz/fisiopatologia , Pólen/imunologia , Testes Cutâneos
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