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1.
J Clin Immunol ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863244

RESUMO

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections, inflammation, and autoimmunity with an impact on health-related quality of life (HRQoL). Few data are available for children, whereas no study has been conducted in adults. Here, we investigated HRQoL and emotional functioning of 19 children and 28 adults enrolled in Italian registry for CGD. PEDsQL and SDQ were used for children and their caregivers, and adults completed the SF-12 questionnaire. Mean scores were compared with norms and with patients affected by chronic diseases. Comparisons were made for CGD patients who underwent or not hematopoietic stem cell transplantation (HSCT). When compared with norms, CGD children exhibited higher difficulties in social/school areas, peer relationship, and conduct/emotional problems (< 5 years of age), as scored by proxies. Differently, CGD adults reported higher difficulties both in mental and physical area than norms. Only for children, clinical status had a damaging effect on psychosocial and school dimensions, whereas age had a negative impact on social areas. No significant difference was observed between patients treated or not with HSCT. When compared with patients affected by chronic diseases, CGD children and adults both displayed fewer physical disabilities. Differently, in mental scale adults scored lower than those with rheumatology diseases and had similar impairment in comparison with patients with diabetes mellitus and cancer. This study emphasized the impact of CGD on HRQoL since infancy and its decline in adulthood, with emotional difficulties occurring early. HRQoL impairment should be considered in clinical picture of CGD and pro-actively assessed and managed by clinicians.

2.
Front Pediatr ; 7: 232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275905

RESUMO

Background and aims: Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses. Methods: We report the incidence of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia. Results: Out of 690 patients, 25 patients (3.6%) developed 33 tumors. Of the 25 affected patients, 8 patients suffered from common variable immunodeficiency (CVID), 5 from combined immunodeficiency (CID), 3 from Ataxia-telangectasia (AT), 2 from Hermanksy-Pudlak type 2 (HSP2), 2 from gammaglobulinemia X-linked (XLA), 2 from Wiskott-Aldrich syndrome (WAS), 2 from Hyper IgE syndrome (HIES), 1 from severe combined immunodeficiency (SCID). The age at diagnosis ranged from 1 to 52 years, with a median age of 19.6 years. The time between the diagnosis of PID and onset of tumor was short, often <1 year between diagnosis and the appearance of cancer in the case of CID. Moreover, in two cases of CID, the diagnosis of cancer was made before the diagnosis of PID, so cancer was the onset clinical manifestation. Hematological malignancies were prevalent (22/33, 66.7%) with a minority of solid tumors (11/33, 33.33%). In particular Non-Hodgkin lymphomas were the most frequent (16/33, 48.48%). In total 13 patients survived (52%) and tumor was the main cause of death (7 cases). Two patients underwent BMT once the disease was in remission. Conclusions: Therefore, the correct management of tumors that arise in patients with primitive immunodeficiency still represents a challenge in the pediatric field. For this reason now it is mandatory to collect in a unique international registry the cases of malignancies in PID that could lead to a better understanding of the etiopathogenesis and of the biological and clinical characteristics of these tumors, with the aim of defining adequate preventive measures and guaranteeing an early diagnosis which also creating a shared and specific therapeutic strategy, with the prospect of obtaining a better prognosis for these patients.

3.
J Clin Immunol ; 39(5): 470-475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129864

RESUMO

PURPOSE: Selective IgA deficiency (SIgAD) is the most common humoral primary immunodeficiency. Long-term follow-up data in large cohort of pediatric patients are scarce. METHODS: We report on a single-center cohort of 184 pediatric patients affected with selective IgA deficiency and describe the characteristics at diagnosis and during follow-up. RESULTS: Respiratory infections were the most common clinical finding leading to the initial diagnosis (62%). Positive family history for antibody deficiencies (selective IgA deficiency, common variable immunodeficiency) led to SIgAD diagnosis in 16% of cases. During follow-up, while the incidence of respiratory infections was not particularly high, gastrointestinal symptoms were reported in 27% of patients. Allergic manifestations were found in 23% at diagnosis and an additional 16% of patients during follow-up, leading to a prevalence of atopy of 39% among SIgAD patients. Autoimmune manifestations, excluding celiac disease, were found in 9% of affected patients during follow-up. Celiac disease was found in a high prevalence (14%). Increase of serum IgA levels to partial deficiency (9%) and normal serum levels for age (4%) was observed during follow-up. A small percentage of patients (2%) progressed to common variable immunodeficiency (CVID). CONCLUSIONS: In conclusion, this is the first study to describe a large single-center pediatric cohort of patients affected with SIgAD, revealing that overall most patients do well with regard to infections. Many develop CD, at a rate much higher than the general population. A few normalize their IgA levels. A few progress to CVID. Thus, careful follow-up is suggested to diagnose and treat potential complications earlier for avoiding potential morbidities.

4.
J Allergy Clin Immunol Pract ; 7(7): 2369-2376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30922987

RESUMO

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. OBJECTIVE: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. METHODS: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. RESULTS: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. CONCLUSIONS: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

5.
J Allergy Clin Immunol ; 144(2): 584-593.e7, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30910492

RESUMO

BACKGROUND: Lacking protective antibodies, patients with primary antibody deficiencies (PADs) experience frequent respiratory tract infections, leading to chronic pulmonary damage. Macrolide prophylaxis has proved effective in patients with chronic respiratory diseases. OBJECTIVE: We aimed to test the efficacy and safety of orally administered low-dose azithromycin prophylaxis in patients with PADs. METHODS: We designed a 3-year, double-blind, placebo-controlled, randomized clinical trial to test whether oral azithromycin (250 mg administered once daily 3 times a week for 2 years) would reduce respiratory exacerbations in patients with PADs and chronic infection-related pulmonary diseases. The primary end point was the number of annual respiratory exacerbations. Secondary end points included time to first exacerbation, additional antibiotic courses, number of hospitalizations, and safety. RESULTS: Eighty-nine patients received azithromycin (n = 44) or placebo (n = 45). The number of exacerbations was 3.6 (95% CI, 2.5-4.7) per patient-year in the azithromycin arm and 5.2 (95% CI, 4.1-6.4) per patient-year in the placebo arm (P = .02). In the azithromycin group the hazard risk for having an acute exacerbation was 0.5 (95% CI, 0.3-0.9; P = .03), and the hazard risk for hospitalization was 0.5 (95% CI, 0.2-1.1; P = .04). The rate of additional antibiotic treatment per patient-year was 2.3 (95% CI, 2.1-3.4) in the intervention group and 3.6 (95% CI, 2.9-4.3) in the placebo group (P = .004). Haemophilus influenzae and Streptococcus pneumoniae were the prevalent isolates, and they were not susceptible to macrolides in 25% of patients of both arms. Azithromycin's safety profile was comparable with that of placebo. CONCLUSION: The study reached the main outcome centered on the reduction of exacerbation episodes per patient-year, with a consequent reduction in additional courses of antibiotics and risk of hospitalization.

8.
J Allergy Clin Immunol Pract ; 7(5): 1568-1577, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30716504

RESUMO

BACKGROUND: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. OBJECTIVE: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. METHODS: Data were collected from an international cohort of 18 patients with CXCR4 mutations. RESULTS: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. CONCLUSIONS: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.

9.
J Clin Immunol ; 39(1): 45-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30547383

RESUMO

Studies of chest computed tomography (CT) in patients with primary antibody deficiency syndromes (ADS) suggest a broad range of bronchial pathology. However, there are as yet no multicentre studies to assess the variety of bronchial pathology in this patient group. One of the underlying reasons is the lack of a consensus methodology, a prerequisite to jointly document chest CT findings. We aimed to establish an international platform for the evaluation of bronchial pathology as assessed by chest CT and to describe the range of bronchial pathologies in patients with antibody deficiency. Ffteen immunodeficiency centres from 9 countries evaluated chest CT scans of patients with ADS using a predefined list of potential findings including an extent score for bronchiectasis. Data of 282 patients with ADS were collected. Patients with common variable immunodeficiency disorders (CVID) comprised the largest subgroup (232 patients, 82.3%). Eighty percent of CVID patients had radiological evidence of bronchial pathology including bronchiectasis in 61%, bronchial wall thickening in 44% and mucus plugging in 29%. Bronchiectasis was detected in 44% of CVID patients aged less than 20 years. Cough was a better predictor for bronchiectasis than spirometry values. Delay of diagnosis as well as duration of disease correlated positively with presence of bronchiectasis. The use of consensus diagnostic criteria and a pre-defined list of bronchial pathologies allows for comparison of chest CT data in multicentre studies. Our data suggest a high prevalence of bronchial pathology in CVID due to late diagnosis or duration of disease.


Assuntos
Brônquios/patologia , Síndromes de Imunodeficiência/patologia , Parede Torácica/patologia , Adolescente , Adulto , Idoso , Bronquiectasia/patologia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/patologia , Feminino , Humanos , Lactente , Masculino , Espirometria/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
10.
Front Immunol ; 9: 1761, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131802

RESUMO

Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA, or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency. These findings offer useful insight for human Tfh biology, with potential implications for understanding the molecular basis of HIGM syndrome caused by mutations in CD40.


Assuntos
Antígenos CD40/deficiência , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Antígenos CD40/genética , Ligante de CD40/genética , Pré-Escolar , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/genética , Imunofenotipagem , Ativação Linfocitária , Masculino , Mutação , Adulto Jovem
12.
Clin Immunol ; 188: 12-19, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29223406

RESUMO

Chronic Granulomatous Disease (CGD) is caused by the failure of the phagocytes to kill pathogens. We carried out a retrospective analysis of cellular, molecular and clinical features of 14 young patients (mean age at the onset of symptoms and diagnosis: 10 and 25months, respectively), 7 with autosomal recessive and 7 X-linked form, referred to the Children's Hospital of Brescia between 1999 and 2016. Two new mutations were found, one localized in the CYBB and one in the NCF1 genes. Twelve patients were followed in our institution; the average length of their follow-up after diagnosis was 66months in X-linked patients and 126months in autosomal recessive inheritance. The overall survival was 67%, 40% in X-linked and 86% in autosomal recessive form. Eight patients were treated with HSCT. We did not find a clear correlation between the clinical symptoms and the type of mutation, but the fine characterization of the patients was mandatory for therapeutic option, genetic counseling and prenatal diagnosis.


Assuntos
Doença Granulomatosa Crônica/genética , Mutação , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Adolescente , Infecções Bacterianas/diagnóstico , Pré-Escolar , Feminino , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/terapia , Humanos , Lactente , Padrões de Herança , Estimativa de Kaplan-Meier , Linfadenite/diagnóstico , Masculino , Pneumonia/diagnóstico , Estudos Retrospectivos
14.
Mol Cell Biochem ; 438(1-2): 153-166, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28744812

RESUMO

Ataxia telangiectasia (AT) is a rare incurable genetic disease caused by biallelic mutations in the Ataxia telangiectasia-mutated gene. Intra-erythrocyte infusion of dexamethasone improves clinical outcomes in AT patients; however, the molecular mechanisms that lead to this improvement remain unknown. Hence, to gain a better understanding of these mechanisms, we assessed the effects of glucocorticoid administration on gene expression in the blood of AT patients. Whole blood was obtained from nine children enrolled in a phase two clinical trial, who were being treated with dexamethasone (AT Dexa), from six untreated AT patients (AT) and from six healthy volunteers (WT). CodeLink Whole Genome Bioarrays were used to assess transcript expression. The reliability of the differentially expressed genes (DEGs) was verified by qRT-PCR analysis. The enriched Gene Ontology (GO) terms and the pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG) of DEGs obtained by group comparisons were achieved using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Functional network analyses were computed by Reactome FI. The likely involved transcription factors were revealed by iRegulon. Among the identified DEGs influenced by the pathology and restored by dexamethasone, we detected 522 upregulated probes coding for known proteins, while 22 probes were downregulated, as they were in healthy subjects. These results provide useful information and represent a first step towards gaining a better understanding of the underlying mechanisms of the effects of dexamethasone on AT patients.


Assuntos
Ataxia Telangiectasia/sangue , Ataxia Telangiectasia/tratamento farmacológico , Dexametasona/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Adolescente , Criança , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Neuropediatrics ; 49(1): 26-34, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28992644

RESUMO

AIM: Visual impairment is present in almost all patients with ataxia telangiectasia (AT) and, due to their early onset, constitute an important disabling aspect of the syndrome: the quality of vision is limited by dyspraxia and oculomotor abnormal movements. The purpose of this observational study was to describe visual disorders, notably oculomotor impairment, in a sample of children with AT. METHODS: Fifteen AT patients (mean age 12 years and 4 months) underwent a neurovisual evaluation, particularly focused on oculomotor functions (fixation, smooth pursuit, saccades, and abnormal ocular movements). We compared the visual profile obtained with that described using the International Cooperative Ataxia Rating Scale (ICARS) subscale of oculomotor dysfunction. RESULTS: Refractive errors were seen in eight patients and strabismus in three. Major oculomotor findings were fixation abnormalities (6/15), saccadic impairment (15/15), and abnormal smooth pursuit (14/15). Abnormal ocular movements were seen in 13/15 (saccadic intrusion in 8 and nystagmus in 5). Using ICARS scale, 13/15 children presented gaze-evoked nystagmus, 4/15 a clearly saccadic pursuit, and 11/15 dysmetria of saccades. DISCUSSION: We propose a clinical neurovisual evaluation, which could be integrated with ICARS scores in the study of oculomotor involvement in AT pediatric patients. We strongly recommend the empowerment of visual functions to slow down progressive global disability of these patients.


Assuntos
Ataxia Telangiectasia/complicações , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Adolescente , Criança , Técnicas de Diagnóstico Oftalmológico , Feminino , Humanos , Masculino , Oftalmologia
16.
Orphanet J Rare Dis ; 12(1): 126, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28679388

RESUMO

BACKGROUND: Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1. RESULTS: In the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new "ATMdexa1 variants" originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients' blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment. CONCLUSIONS: For the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/tratamento farmacológico , Ataxia Telangiectasia/metabolismo , Dexametasona/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Adolescente , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biomarcadores , Criança , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Leucócitos Mononucleares/metabolismo , Masculino
17.
Orphanet J Rare Dis ; 12(1): 69, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28399932

RESUMO

BACKGROUND: Ring chromosome 14 syndrome is a rare chromosomal disorder characterized by early onset refractory epilepsy, intellectual disability, autism spectrum disorder and a number of diverse health issues. RESULTS: The aim of this work is to provide recommendations for the diagnosis and management of persons affected by ring chromosome 14 syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years subjects affected by ring chromosome 14 syndrome. The literature search was performed in 2016. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. CONCLUSION: Conventional cytogenetics is the primary tool to identify a ring chromosome. Children with a terminal deletion of chromosome 14q ascertained by molecular karyotyping (CGH/SNP array) should be tested secondarily by conventional cytogenetics for the presence of a ring chromosome. Early diagnosis should be pursued in order to provide medical and social assistance by a multidisciplinary team. Clinical investigations, including neurophysiology for epilepsy, should be performed at the diagnosis and within the follow-up. Following the diagnosis, patients and relatives/caregivers should receive regular care for health and social issues. Epilepsy should be treated from the onset with anticonvulsive therapy. Likewise, feeding difficulties should be treated according to need. Nutritional assessment is recommended for all patients and nutritional support for malnourishment can include gastrostomy feeding in selected cases. Presence of autistic traits should be carefully evaluated. Many patients with ring chromosome 14 syndrome are nonverbal and thus maintaining their ability to communicate is always essential; every effort should be made to preserve their autonomy.


Assuntos
Transtorno do Espectro Autista/genética , Cuidadores , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Citogenética , Humanos , Cromossomos em Anel
18.
Clin Immunol ; 178: 45-55, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28126470

RESUMO

Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.


Assuntos
Agamaglobulinemia/imunologia , Ataxia Telangiectasia/imunologia , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Agamaglobulinemia/complicações , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/mortalidade , Proteínas Mutadas de Ataxia Telangiectasia/genética , Causas de Morte , Criança , Estudos de Coortes , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Deficiência de IgA/complicações , Deficiência de IgA/imunologia , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/etiologia , Neoplasias/genética , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
19.
J Allergy Clin Immunol ; 140(2): 553-564.e4, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28069426

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of signal transducer and activator of transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease. This condition is characterized by fungal and bacterial infections caused by impaired generation of TH17 cells; meanwhile, some patients with chronic mucocutaneous candidiasis disease might also have viral or intracellular pathogen infections. OBJECTIVE: We sought to investigate the effect of STAT1 GOF mutations on the functioning of natural killer (NK) cells. METHODS: Because STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in 8 patients with STAT1 GOF mutations. RESULTS: Functional analysis of NK cells shows a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF mutations. Moreover, NK cells from these patients display lower production of IFN-γ in response to IL-15 and reduced proliferation after stimulation with IL-2 or IL-15, suggesting that STAT5 signaling is affected. In addition, signaling studies demonstrate that the increased phosphorylation of STAT1 in response to IFN-α is associated with detectable activation of STAT1 and increased STAT1 binding to the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) promoter in response to IL-15, whereas STAT5 phosphorylation and DNA binding to IL-2 receptor α (IL2RA) are reduced or not affected in response to the same cytokine. CONCLUSION: These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.


Assuntos
Candidíase Mucocutânea Crônica/genética , Células Matadoras Naturais/imunologia , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Candidíase Mucocutânea Crônica/imunologia , Criança , Citocinas/farmacologia , Feminino , Expressão Gênica , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fosforilação , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/metabolismo
20.
J Clin Immunol ; 37(1): 36-41, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27766541

RESUMO

PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD.


Assuntos
Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/diagnóstico por imagem , Pneumopatias Fúngicas/diagnóstico por imagem , Pneumopatias Fúngicas/etiologia , Tomografia Computadorizada por Raios X/métodos , Biomarcadores , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Pneumopatias Fúngicas/terapia , Masculino , Estudos Retrospectivos , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/patologia
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