Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
1.
J Thromb Haemost ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587810

RESUMO

BACKGROUND: Persistent fatigue, breathlessness and reduced exercise tolerance have been reported following acute COVID-19 infection. Although immuno-thrombosis has been implicated in acute COVID-19 pathogenesis, the biological mechanisms underpinning Long COVID remain unknown. We hypothesized that pulmonary microvascular immuno-thrombosis may be important in this context. METHODS: 150 COVID-19 patients were reviewed at St James's Hospital Dublin between May and September 2020 at a median of 80.5 (range 44 - 155) days after initial diagnosis. These included patients hospitalized during initial illness (n=69) and others managed entirely as outpatients (n=81). Clinical examination, chest x-ray and 6-minute walk tests were performed. In addition, a range of coagulation and inflammatory markers were assessed. RESULTS: Increased D-dimer levels (>500ng/ml) were observed in 25.3% patients up to four months post-SARS-CoV-2 infection. On univariate analysis, elevated convalescent D-dimers were more common in COVID-19 patients who had required hospital admission and in patients aged more than 50 years (p<0.001). Interestingly, we observed that 29% (n=11) of patients with elevated convalescent D-dimers had been managed exclusively as out-patients during their illness. In contrast, other coagulation (PT, APTT, fibrinogen, platelet count) and inflammation (CRP, IL-6 and sCD25) markers had returned to normal in > 90% of convalescent patients. CONCLUSIONS: Elucidating the biological mechanisms responsible for sustained D-dimer increases may be of relevance in Long COVID pathogenesis and has implications for clinical management of these patients.

2.
J Clin Pharmacol ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33543766

RESUMO

Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.

4.
Ann Am Thorac Soc ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33413026

RESUMO

RATIONALE: Much is known about the acute infective process of SARS-CoV-2, the causative virus of the COVID-19 pandemic. The marked inflammatory response and coagulopathic state in acute SARS-CoV-2 may promote pulmonary fibrosis. However, little is known of the incidence and seriousness of post-COVID pulmonary pathology. OBJECTIVES: We describe respiratory recovery and self-reported health following infection at time of outpatient attendance. METHODS: Infection severity was graded into three groups: (i) not requiring admission, (ii) requiring hospital admission, and (iii) requiring ICU care. Participants underwent chest radiography and six-minute-walk test (6MWT). Fatigue and subjective return to health were assessed and levels of C-reactive protein (CRP), interleukin-6, soluble CD25 and D-dimer were measured. The association between initial illness and abnormal chest x-ray, 6MWT distance and perception of maximal exertion was investigated. RESULTS: 487 patients were offered an outpatient appointment, of which 153 (31%) attended for assessment at a median of 75 days after diagnosis. 74 (48%) had required hospital admission during acute infection. Persistently abnormal chest x-rays were seen in 4%. The median 6MWT distance covered was 460m. Reduced distance covered was associated with frailty and length of inpatient stay. 95 (62%) felt that they had not returned to full health, while 47% met the case definition for fatigue. Ongoing ill-health and fatigue were associated with increased perception of exertion. None of the measures of persistent respiratory disease were associated with initial disease severity. CONCLUSIONS: This study highlights the rates of objective respiratory disease and subjective respiratory symptoms following COVID-19 and the complex multifactorial nature of post-COVID ill-health.

5.
J Clin Immunol ; 41(1): 194-204, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33403466

RESUMO

Influenza is a potential cause of severe disease in the immunocompromised. Patients with hypogammaglobulinemia, in spite of adequate replacement therapy, are at risk of significant morbidity and adverse outcomes. A seasonal vaccine is the primary prophylactic countermeasure to limit disease. The aim of this study was to evaluate the attitude, knowledge, and influenza vaccine uptake among Irish patients receiving immunoglobulin replacement therapy (IgRT), as well as uptake in co-habitants. Fifty-seven percent of patients receiving IgRT at a regional immunology referral center completed a questionnaire evaluation. Seventy-six percent of IgRT patients received the influenza vaccine for the 2019 season. Ninety-eight percent recognized that influenza could be prevented with vaccination, and 81% deemed it a safe treatment. Ninety-three percent correctly identified that having a chronic medical condition, independent of age, was an indication for vaccination. Despite excellent compliance and knowledge, many were not aware that vaccination was recommended for co-habitants, and only 24% had full vaccine coverage at home. Those who received advice regarding vaccination of household members had higher rates of uptake at home. This study demonstrates awareness and adherence to seasonal influenza vaccine recommendations among patients receiving IgRT. Over three quarters felt adequately informed, the majority stating physicians as their information source. We identified an easily modifiable knowledge gap regarding vaccination of household members. This data reveals a need to emphasize the importance of vaccination for close contacts of at-risk patients, to maintain optimal immunity and health outcome.

6.
Allergy ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284457

RESUMO

INTRODUCTION: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. AIM: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. MATERIALS AND METHODS: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. RESULTS: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. CONCLUSIONS: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation.

7.
PLoS One ; 15(11): e0240784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33166287

RESUMO

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.


Assuntos
Infecções por Coronavirus/patologia , Fadiga/etiologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Fadiga/epidemiologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Prevalência , Índice de Gravidade de Doença
8.
Schizophr Res ; 222: 455-461, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32499165

RESUMO

INTRODUCTION: N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria. METHODS: Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited. RESULTS: 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis. CONCLUSIONS: NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis.

10.
J Med Internet Res ; 22(5): e16763, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32401220

RESUMO

BACKGROUND: Internet search engines are increasingly being utilized as the first port of call for medical information by the public. The prevalence of allergies in developed countries has risen steadily over time. There exists significant variability in the quality of health-related information available on the web. Inaccurately diagnosed and mismanaged allergic disease has major downstream effects on patients, general practitioners, and regional allergy services. OBJECTIVE: This study aimed to verify whether Ireland has a relatively high rate of web-based allergy-related searches, to establish the proportion of medically accurate web pages encountered by the public, and to compare current search results localized to Dublin, Ireland with urban centers elsewhere. METHODS: Google Trends was used to evaluate regional interest of allergy-related search terms over a 10-year period using terms "allergy," "allergy test," "food allergy," and "food intolerance." These terms were then inputted into Google search, localizing them to cities in Ireland, the United Kingdom, and the United States. Output for each search was reviewed by two independent clinicians and deemed rational or nonevidence based, as per current best practice guidelines. Searches localized to Dublin were initially completed in 2015 and repeated in 2019 to assess for changes in the quality of search results over time. RESULTS: Ireland has a persistently high demand for web-based information relating to allergy and ranks first worldwide for "allergy test," second for "food allergy" and "food intolerance," and seventh for "allergy" over the specified 10-year timeframe. Results for each of the four subsearches in Dublin (2015) showed that over 60% of websites promoted nonevidence-based diagnostics. A marginal improvement in scientifically robust information was seen in 2019, but results for "allergy test" and "food intolerance" continued to promote alternative testing 57% (8/14) of the time. This strongly contrasted with results localized to Southampton and Rochester, where academic and hospital-affiliated web pages predominantly featured. Government-funded Department of Health websites did not feature in the top five results for Dublin searches "allergy testing," "food allergy," or "food intolerance" in either 2015 or 2019. CONCLUSIONS: The Irish public demonstrates a keen interest in seeking allergy-related information on the web. The proportion of evidence-based websites encountered by the Irish public is considerably lower than that encountered by patients in other urban centers. Factors contributing to this are the lack of a specialist register for allergy in Ireland, inadequate funding for allergy centers currently in operation, and insufficient promotion by the health service of their web-based health database, which contains useful patient-oriented information on allergy. Increased funding of clinical allergology services will more meaningfully impact the health of patients if there is a parallel investment by the health service in information and communication technology consultancy to amplify their presence on the web.


Assuntos
Hipersensibilidade/epidemiologia , Internet/instrumentação , Ferramenta de Busca , Humanos , Irlanda/epidemiologia
11.
Br J Haematol ; 189(6): 1044-1049, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32330308

RESUMO

Although the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung-centric coagulopathy may play an important role. Elevated D-dimer levels which correlated inversely with overall survival were recently reported in Chinese cohort studies. Critically however, ethnicity has major effects on thrombotic risk, with a 3-4-fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African-Americans. In this study, we investigated COVID19 coagulopathy in Caucasian patients. Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity. Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC). In rare COVID19 cases where DIC does develop, it tends to be restricted to late-stage disease. Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary-specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC. Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality.


Assuntos
Betacoronavirus , Transtornos da Coagulação Sanguínea/etiologia , Infecções por Coronavirus/complicações , Grupo com Ancestrais do Continente Europeu , Pneumonia Viral/complicações , Transtornos da Coagulação Sanguínea/etnologia , Transtornos da Coagulação Sanguínea/patologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/etnologia , Coagulação Intravascular Disseminada/prevenção & controle , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Pulmão/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/sangue , Pneumonia/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/etnologia , Trombose/prevenção & controle
12.
J Neurol ; 267(5): 1348-1352, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31960135

RESUMO

Discordant elevations of cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) ribonucleic acid (RNA) in chronically treated patients known as 'CSF escape' may present as acute encephalitis. Infectious encephalitis caused by herpes simplex virus (HSV) and other neurotropic viruses have been identified as potential triggers of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Autoantibody-mediated encephalitis has been infrequently reported in HIV infected patients and may mimic HIV encephalitis. We report two adults infected with HIV presenting with encephalopathy and seizures. Case 1 had a monophasic encephalopathy with detection of NMDAR antibodies in the context of HIV CSF escape. There was a clinical response to immunotherapy and anti-retroviral therapy adjustment. Case 2 initially presented in non-convulsive status epilepticus associated with HIV CSF escape. He responded to treatment with anti-epileptic drugs and anti-retroviral therapy alteration, but had two further neurological relapses. NMDAR antibodies were detected during the relapses and a clinical response was observed following treatment with immunotherapy. Clinicians should consider autoimmune encephalitis in HIV infected patients presenting with encephalopathy and seizures, particularly in cases with concomitant HIV CSF escape.

13.
Ir J Med Sci ; 188(3): 815-819, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30661174

RESUMO

BACKGROUND: Food-dependent exercise-induced anaphylaxis (FDEIA) is a life-threatening disorder in which the signs and symptoms of anaphylaxis occur if physical exertion occurs within a few hours of exposure to a food. AIMS: The aim of this study was to characterise patients diagnosed with FDEIA and related disorders. METHODS: A retrospective review of electronic clinical data from 2001 to 2016 was carried out. Fifty-seven cases were identified and analysed to establish clinical features, triggering factors and sensitisation patterns. RESULTS: The number of patients per annum diagnosed with FDEIA or related reactions increased from 1 in 2001 to 18 patients in 2016. Sixty-nine percent reported systemic symptoms consistent with anaphylaxis, and 31% had skin manifestations only. In 33% of cases, the level of triggering exercise was mild. Forty-four percent of patients were sensitised to the omega-5-gliadin fraction of wheat. CONCLUSIONS: FDEIA is an increasingly recognised serious allergic disease. The clinical diagnosis is supported by targeted sensitisation testing and molecular-based allergy diagnostics. These tools allow implementation of effective dietary and lifestyle modifications that mitigate against future serious reactions. Given the limited access to physicians with specialist allergy training in Ireland, increased awareness of this condition amongst sports medicine specialists and general physicians is required.


Assuntos
Anafilaxia/diagnóstico , Exercício Físico/fisiologia , Hipersensibilidade Alimentar/diagnóstico , Adolescente , Adulto , Anafilaxia/patologia , Feminino , Hipersensibilidade Alimentar/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
14.
J Allergy Clin Immunol ; 143(4): 1482-1495, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Guanilato Ciclase/genética , Guanilato Ciclase/imunologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Adulto , Feminino , Humanos , Masculino , Mutação , Fenótipo
15.
Immunol Cell Biol ; 96(10): 1060-1071, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29790605

RESUMO

Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.


Assuntos
Antígenos CD57/metabolismo , Diferenciação Celular , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Encurtamento do Telômero , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Citocinas/metabolismo , Humanos , Imunofenotipagem , Contagem de Linfócitos , Doenças da Imunodeficiência Primária , Sirolimo/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos
17.
J Allergy Clin Immunol ; 139(2): 597-606.e4, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27555459

RESUMO

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Transtornos Linfoproliferativos/genética , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Animais , Antibioticoprofilaxia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Estudos de Coortes , Inibidores Enzimáticos/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/mortalidade , Infecções por Herpesviridae/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Cooperação Internacional , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/terapia , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva , Infecções Respiratórias/mortalidade , Infecções Respiratórias/terapia , Inquéritos e Questionários , Análise de Sobrevida , Adulto Jovem
18.
Clin Immunol ; 176: 23-30, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28011187

RESUMO

Common variable immunodeficiency (CVID) is a primary immunoglobulin deficiency characterized by recurrent infections and complications, including autoimmunity, enteropathy, polyclonal lymphocytic infiltration or lymphoid malignancy. Innate T cells can support B cell maturation and antibody production. We investigated the numbers, phenotypes and functions of circulating B cell, γδ T cell, invariant natural killer T (iNKT) cell and mucosal-associated invariant T (MAIT) cell subsets in 23 CVID patients and 27 healthy controls. Switched-memory B cells and plasmablasts were depleted in CVID patients (p<0.0001). γδ T cells were found at normal numbers, but iNKT and MAIT cells were depleted (p<0.0001 and p<0.002). MAIT cells were especially low in patients with complicated CVID (p<0.05). MAIT cells from patients appeared more activated and more frequently produced interleukin-17A, interleukin-22 and tumor necrosis factor-α than MAIT cells from healthy subjects in vitro. Thus, MAIT cell depletion and activation may contribute to immunodeficiency and complications associated with CVID.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
19.
Artigo em Inglês | MEDLINE | ID: mdl-27544398

RESUMO

Circumorificial plasmacytosis is a rare plasma cell proliferative disorder of the orificial mucous membranes. The etiology is unknown, and there are no reported effective treatments to date. We report three cases of idiopathic circumorificial plasmacytosis with varying clinical presentations and responses to treatment, including a first reported case of resolution with adalimumab therapy.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Mucosa Bucal/patologia , Mucosite/diagnóstico , Mucosite/tratamento farmacológico , Plasmócitos/patologia , Idoso , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Clin J Am Soc Nephrol ; 11(8): 1392-9, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27401523

RESUMO

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.


Assuntos
Doença Antimembrana Basal Glomerular/epidemiologia , Falência Renal Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Antimembrana Basal Glomerular/etiologia , Doença Antimembrana Basal Glomerular/mortalidade , Análise por Conglomerados , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Incidência , Irlanda/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Análise Espaço-Temporal , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...