RESUMO
PURPOSE: Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time. METHODS: 31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control. RESULTS: Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR+ NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LIN-DNAMbright and LIN-CD16+ inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease. CONCLUSION: Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since "Complicated" CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.
Assuntos
Imunodeficiência de Variável Comum , Infecções por Citomegalovirus , Citomegalovirus , Herpesvirus Humano 4 , Replicação Viral , Humanos , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/complicações , Masculino , Feminino , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Adulto , Pessoa de Meia-Idade , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 4/imunologia , Estudos Retrospectivos , Células Matadoras Naturais/imunologia , Adulto Jovem , Viremia/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Imunofenotipagem , Idoso , AdolescenteRESUMO
The first case of the new coronavirus, COVID-19, was reported in China on 17 November 2019. By the end of March 2020, the rapid global spread of infection affected over 1 million people. Italy is one of the countries most impacted, with over 100,000 positive cases identified. The first detected cases were reported on 21 February 2020 in two Italian towns: Vo' Euganeo in the Province of Padua, Veneto region, and Codogno, in the Province of Lodi, Lombardy. In the next weeks the epidemic spread quickly across the country but mainly in the north of Italy. The two regions: Veneto and Lombardy, implemented different strategies to control the viral spread. In Veneto, health personnel tested both symptomatic and asymptomatic subjects, while in Lombardy only symptomatic cases were investigated. We analyzed the evolution of the epidemic in these regions and showed that testing both symptomatic and asymptomatic cases is a more effective strategy to mitigate the epidemic impact. We strongly recommend that decision-makers: ensure early isolation of symptomatic patients and rapid identification of their contacts; maximize testing rapidly, especially among people with multiple daily contacts with infected populations, high exposure to the public in essential services; rapidly increase diagnostic capacity by mobilizing trained personnel capable of performing rRT-PCR on respiratory samples; equip the population with protective masks.
Assuntos
Controle de Doenças Transmissíveis/organização & administração , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Humanos , Itália/epidemiologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , SARS-CoV-2RESUMO
INTRODUCTION: TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, and may be administered off-label to treat disseminated granuloma annulare systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. AREAS COVERED: infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents. EXPERT OPINION: IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity state or clinical remission, decrease drug survival, increase the need for doctors to prescribe a higher drug dosage and, finally, favor the occurrence of adverse events. Concomitant administration of DMARDs such as methotrexate or leflunomide prevents the development of neutralizing Abs against infliximab and adalimumab.
Assuntos
Adalimumab/imunologia , Antirreumáticos/imunologia , Infliximab/imunologia , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Anticorpos Monoclonais/imunologia , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Hipersensibilidade Tardia/imunologia , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Receptores do Fator de Necrose Tumoral/antagonistas & inibidoresRESUMO
INTRODUCTION: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases. AREAS COVERED: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events. EXPERT OPINION: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitor treatment. Finally, patients who are at high risk of herpes zoster (HZ) reactivation would benefit from a second vaccination in adulthood when receiving TNF-α inhibitors.
Assuntos
Fatores Imunológicos/efeitos adversos , Infecções/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Infecções/epidemiologia , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Fatores de RiscoRESUMO
Peptide540-548, peptide611-626, peptide672-686 and peptide766-780, which are derived from human telomerase, constitute the immunogenic component of the GX301 cancer vaccine. The relative immunogenicity of these peptides is unknown, thus it is unsure whether their combined use offers real advantages over single peptide stimulation. Hence, this study compared the number of specific immune responses and responders to each peptide, as well as to their mixture (meaning the co-presence of the 4 peptides in the same culture well), achieved after ex vivo stimulation of PBMC from 21, HLA-A2+ (n.11) or HLA-A2- (n.10), healthy donors. The study was performed on freshly collected PBMC (T0) and on PBMC stimulated for 10 d with single peptides or their mixture (T1). Peptide-specific immune responses were analyzed by Elispot and cytokine intracellular staining by flow cytometry. The results showed that each peptide induced specific immune responses in some subjects, with different panels of responders among the peptides. Moreover, the numbers of responses and responders to the single peptides or their mixture were comparable. Importantly, the overall number of responders to the 4 peptides was higher than to each single peptide, or to their mixture, both at T0 and T1. These data demonstrate the immunogenicity of each of the 4 GX301 telomerase peptides. Moreover, they show the advantage of multi-peptide over single peptide stimulation, providing a clear support to their combined administration in vaccination protocols. However, the data pose a warning against peptide administration as a mixture due to possible interference phenomena during antigen presentation processes.
Assuntos
Vacinas Anticâncer/imunologia , Peptídeos/imunologia , Telomerase/imunologia , Adulto , Linhagem Celular Tumoral , Feminino , Genes MHC Classe I/imunologia , Antígeno HLA-A2/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI.
Assuntos
Artrite Reativa/imunologia , Doenças Autoimunes/microbiologia , Diabetes Insípido Neurogênico/microbiologia , Infecções por Ureaplasma/imunologia , Ureaplasma urealyticum , Artrite Reativa/microbiologia , Autoanticorpos , Doenças Autoimunes/etiologia , Diabetes Insípido Neurogênico/etiologia , Diabetes Insípido Neurogênico/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Neurofisinas/imunologia , Precursores de Proteínas/imunologia , Infecções por Ureaplasma/complicações , Vasopressinas/imunologiaRESUMO
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases. Serum levels of TNF-α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF-α inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc.
Assuntos
Antirreumáticos/uso terapêutico , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/biossíntese , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite/etiologia , Artrite/prevenção & controle , Certolizumab Pegol , Avaliação de Medicamentos , Quimioterapia Combinada , Endotélio Vascular/fisiopatologia , Etanercepte , Previsões , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Fragmentos Fab das Imunoglobulinas/farmacologia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Imunoglobulina G/efeitos adversos , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/farmacologia , Infliximab , Tuberculose Latente/complicações , Tuberculose Latente/fisiopatologia , Infecções Oportunistas/etiologia , Infecções Oportunistas/prevenção & controle , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , Receptores do Fator de Necrose Tumoral/uso terapêutico , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
INTRODUCTION: During the last decade, many new biological immune modulators have entered the market as new therapeutic principles. Biologics, including TNF-α inhibitors, are the new frontier in the treatment of immune-mediated or inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ankylosing spondylitis, systemic sclerosis, disseminated granuloma annulare, psoriasis and/or psoriatic arthritis. TNF-α inhibitors have demonstrated efficacy and are well tolerated in large, randomized, controlled clinical trials. However, a substantial proportion of patients do not respond to these agents and potential adverse drug reactions may be associated with its use. AREAS COVERED: Pharmacogenetics has the potential of increasing drug efficiency by identifying genetic factors responsible for lack of response or toxicities to TNF-α inhibitors. In this review, we analyze the influence of several polymorphisms upon the efficacy and safety of TNF-α inhibitors. EXPERT OPINION: Several polymorphisms have been proven to influence the response to etanercept. Among them, single nucleotide polymorphisms (SNPs) -308 G/G, -857 C/T, +489 GG and GA, HLA-DRB1-encoding SE (allele *0404 and allele *0101) favor the response to etanercept, whereas SNP -308 A/A and TNFR1A AA decrease the response. Large clinical studies are needed to confirm the relevance of these associations in order to tailor treatment and to decrease unnecessary toxicity.
Assuntos
Anti-Inflamatórios/uso terapêutico , Imunoglobulina G/uso terapêutico , Farmacogenética , Polimorfismo de Nucleotídeo Único , Receptores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Animais , Etanercepte , Humanos , Seleção de Pacientes , Fenótipo , Medicina de PrecisãoRESUMO
INTRODUCTION: TNF-α inhibitors have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying antirheumatic drugs in the treatment of chronic inflammatory immune-mediated diseases. Etanercept is a fusion protein that acts as a 'decoy receptor' for TNF-α. AREAS COVERED: This paper evaluates the efficacy and safety of etanercept in patients with chronic inflammatory immune-mediated diseases. EXPERT OPINION: Etanercept was first approved for the treatment of rheumatoid arthritis (RA) and subsequently of chronic plaque psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile RA. Etanercept as other TNF-α inhibitors, particularly infliximab, may be administered off-label to treat other chronic inflammatory immune-mediated diseases such as systemic sclerosis, Behcet disease, systemic lupus erythematosus, polymyositis, dermatomyositis and mixed connective tissue disease. Early etanercept treatment prevents joint damage and helps to avoid long-term disability in arthritis. Etanercept administered at a dose of 50 mg once weekly is effective in inducing an earlier remission of RA, and etanercept 50 mg twice weekly may favor a more rapid improvement of psoriasis and psoriatic arthritis. Etanercept and adalimumab may exert beneficial effects on lipid profile and improve endothelial dysfunction. Appropriate screening tests for latent tuberculosis, hepatitis B virus and hepatitis C virus should be performed before starting etanercept. TNF-α inhibitors including etanercept are contraindicated in patients with demyelinating diseases.
Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Antirreumáticos/farmacologia , Doença Crônica , Etanercepte , Humanos , Imunoglobulina G/farmacologia , Imunossupressores/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI.