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1.
Artigo em Inglês | MEDLINE | ID: mdl-32006723

RESUMO

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis, which is mostly administered to neonates in regions where tuberculosis (TB) is endemic. Adverse reactions following BCG vaccination are rare, however immunocompromised individuals and in particular patients with primary immunodeficiencies (PIDs) are prone to develop vaccine-derived complications. OBJECTIVE: We aimed to systematically review demographic, clinical, immunologic and genetic data of PIDs that present with BCG vaccine complications. Moreover, we performed a meta-analysis aiming to determine the BCG-vaccine complications rate for PID patients. METHODS: We conducted electronic searches on Embase, Web of Science, PubMed and Scopus (1966 to September 2018) introducing terms related to PIDs, BCG vaccination, and BCG vaccine complications. Studies with human subjects with confirmed PID, BCG vaccination history and vaccine-associated complications (VAC) were included. RESULTS: A total of 46 PIDs associated with BCG-VAC were identified. Severe combined immunodeficiency was the most common (466 cases) and also showed the highest BCG-related mortality. Most BCG infection cases in PID patients were reported from Iran (n=219, 18.8%). The overall frequency of BCG-VAC in the included 1691 PID cases was 41.5% (95% CI: 29.9, 53.2; I2=98.3%), based on the results of the random effect method used in this meta-analysis. Patients with Mendelian susceptibility to mycobacterial diseases had the highest frequency of BCG-VAC with a pooled frequency of 90.6% (95% CI: 79.7, 1.0; I2=81.1%). CONCLUSIONS: Several PID entities are susceptible to BCG-VAC. Systemic neonatal PID screening programs may help to prevent a substantial amount of BCG vaccination complications.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32007567

RESUMO

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by recurrent upper and lower respiratory tract infections and some non-infectious clinical complications. OBJECTIVE: The current study aimed to provide a detailed evaluation of respiratory presentations and complications in a cohort of Iranian patients with CVID. METHODS: The present retrospective cohort study was conducted on 245 CVID patients who were recorded at the Iranian primary immunodeficiency disorders registry network. Respiratory manifestations were evaluated by reviewing clinical hospital records, immunologic findings, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans. RESULTS: The majority of patients (n=208, 85.2%) had experienced at least one episode of acute respiratory manifestation and pneumonia was observed in 31.6 % (n=77) of cases as a first disease manifestation. During the follow-up pneumonia, sinusitis and otitis media were documented in 166 (68.6%), 125 (51.2%) and 103 (42.6%) cases, respectively. Abnormal PFT measurements were documented in 53.8 % of patients. Among these patients, 21.5% showed restrictive changes, whereas 18.4% of patients showed an obstructive pattern. Bronchiectasis was the most frequent radiological finding confirmed in 27.2 % of patients. Patients with bronchiectasis were older at the time of immunodeficiency diagnosis ( p <0.001) and had longer diagnosis delay ( p <0.001) when compared to patients without bronchiectasis. CONCLUSION: This study highlights the importance of monitoring the respiratory tract system even in asymptomatic patients. PFT and CT scans are the most commonly used techniques aiming to identify these patients early aiming to reduce the rate of long-term respiratory complications.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32058651

RESUMO

BACKGROUND: Congenital agammaglobulinemia is the first primary immunodeficiency disorder characterized by a defect in B lymphocytes development, and subsequently decreased immunoglobulin levels. These patients are prone to suffer from recurrent infections mostly involving the respiratory tract. In this study, we aimed to describe in detail respiratory tract complications as the most prominent clinical feature among agammaglobulinemic patients. METHODS: A total number of 115 patients were included. Demographic, clinical and genetic data were collected from the patients' medical records. Among the available patients, pulmonary function tests (PFTs) and/or high-resolution computed tomography (HRCT) were performed. RESULTS: Respiratory tract complications (85.2%) especially pneumonia (62.6%) were the most prominent clinical features in our cohort. Among patients with abnormal PFT results (N=19), a mixed respiratory pattern was observed in 36.8%. HRCT was carried out in 29 patients; Bhalla scoring-based evaluation of these patients indicated excellent (44.8%), followed by good (34.5%) and mild (20.7%) results. Bronchiectasis was found in 13 patients undergoing HRCT (44.8%). We found significant inverse correlations between the Bhalla score and incidence rate of pneumonia, as well as the presence of bronchiectasis. Patients with abnormal PFT results had statistically significant higher bronchiectasis frequency and lower Bhalla scores compared to those with normal results. Forty-one patients were deceased and here respiratory failure was the most common cause of death (45.5%). CONCLUSION: High prevalence of respiratory tract infections among agammaglobulinemic patients and subsequent progression to permanent lung damage highlights the importance of implementing respiratory evaluation as part of routine follow-up program of agammaglobulinemic patients. Physicians should be aware of this and regularly monitor the respiratory function of these patients to allow for timely diagnosis and treatment initiation aiming to improve patients' prognosis and quality of life.

4.
Pediatr Infect Dis J ; 39(2): 114-120, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31725552

RESUMO

BACKGROUND: Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia. MATERIAL AND METHODS: All first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients' demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality. RESULTS: One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. Of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8-2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed. CONCLUSIONS: This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.

5.
Front Immunol ; 10: 2589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781101

RESUMO

Monogenic forms of vasculitis are rare but increasingly recognized. Furthermore, genetic immunodeficiency is increasingly associated with inflammatory immune dysregulatory features, including vasculitis. This case report describes a child of non-consanguineous parents who presented with chronic digital vasculitis early in life, is of short stature, has facial dysmorphia, immunodeficiency (low serum IgA, high serum IgM), recurrent bacterial infections, lymphoproliferation, absence of detectable serum C1q, and low classical complement pathway activity. We identified a previously reported de novo heterozygous pathogenic splice mutation in PIK3R1 (c.1425 + 1G > A), resulting in the skipping of exon 11 of the p85α subunit of phosphatidylinositol 3-kinase and causing activated PI3Kδ syndrome type II (APDS2). This explained the phenotype, with the exception of digital vasculitis and C1q deficiency, which have never been described in association with APDS2. No mutations were identified in C1QA, B, or C, their promoter regions, or in any other complement component. Functional studies indicated normal monocytic C1q production and release, suggesting that the observed C1q deficiency was caused by peripheral consumption of C1q. Since C1q deficiency has never been associated with APDS2, we assessed C1q levels in two unrelated patients with genetically confirmed APDS2 and confirmed C1q deficiency in those two cases as well. This observation suggests C1q deficiency to be an inherent but previously unrecognized feature of APDS2. We speculate that the consumption of C1q is driven by increased apoptotic bodies derived from immune cellular senescence, combined with elevated IgM production (both inherent features of APDS2). Secondary C1q deficiency in APDS2 may further contribute to immunodeficiency and could also be associated with inflammatory immune dysregulatory phenotypes, such as the digital vasculitis observed in our case.

6.
Front Immunol ; 10: 1433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354696

RESUMO

Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14+ monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14+ monocytes and CD3+ T cells were higher than in healthy donors. There was a strong and positive correlation between CD14+ STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient's CD14+ monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31111319

RESUMO

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.

8.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 37(2): 112-116, feb. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-181151

RESUMO

Introduction: Development of secondary haemophagocytic lymphohistiocytosis (sHLH) in the context of typhoid fever (TF) is a very rare but serious complication. Methods: Description of the first pediatric case of typhoid fever acquired in a non-endemic area complicated by sHLH. A systematic literature review of sHLH in the context of TF was performed with extraction of epidemiological, clinical and laboratory data. Results: The literature search revealed 17 articles (22 patients). Fifteen patients were eligible for data analysis (53.4% children). All patients had fever and pancytopenia. Transaminases and LDH were frequently elevated (46.6%). Salmonella typhi was detected mainly by blood culture (64.3%). All the patients received antibiotics whereas immunomodulation (dexamethasone) was used in two cases. Conclusions: A high suspicion index for this condition is needed even in non-endemic areas. The addition of immunmodulation to standard antimicrobial therapy should be considered in selected cases


Introducción: El síndrome hemofagocítico (HLH) secundario en el contexto de fiebre tifoidea es una complicación rara pero seria. Métodos: Descripción del primer caso pediátrico de fiebre tifoidea adquirida en área no endémica complicada con síndrome hemofagocítico y revisión sistemática de la literatura de casos de HLH secundarios a fiebre tifoidea. Descripción de datos epidemiológicos, clínicos y de laboratorio, diagnóstico y manejo. Resultados: La búsqueda bibliográfica reveló 17 artículos (22 pacientes). Quince pacientes eran elegibles para el análisis (53,4% niños). La fiebre y la pancitopenia estaban siempre presentes, y las transaminasas y la LDH estaban frecuentemente elevados (46,6%). La detección de S. typhi se realizó mediante hemocultivo, principalmente (64,3%). Todos los pacientes reportados recibieron antibióticos; la dexametasona fue usada como tratamiento inmunomodulador en 2 de los casos. Conclusiones: Mantener alto el grado de sospecha de esta condición es necesario, incluso en áreas no endémicas, ya que el uso de tratamiento inmunomodulador junto al tratamiento antimicrobiano puede ser determinante para una evolución clínica favorable


Assuntos
Humanos , Masculino , Criança , Adolescente , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Febre Tifoide/complicações , Febre Tifoide/epidemiologia , Dor Abdominal/etiologia , Distribuição por Idade , Ásia/epidemiologia , Ceftriaxona/uso terapêutico , Países Desenvolvidos , Diagnóstico Diferencial , Doenças Endêmicas , Febre/etiologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Metilprednisolona/uso terapêutico
9.
Enferm Infecc Microbiol Clin ; 37(2): 112-116, 2019 02.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29887216

RESUMO

INTRODUCTION: Development of secondary haemophagocytic lymphohistiocytosis (sHLH) in the context of typhoid fever (TF) is a very rare but serious complication. METHODS: Description of the first pediatric case of typhoid fever acquired in a non-endemic area complicated by sHLH. A systematic literature review of sHLH in the context of TF was performed with extraction of epidemiological, clinical and laboratory data. RESULTS: The literature search revealed 17 articles (22 patients). Fifteen patients were eligible for data analysis (53.4% children). All patients had fever and pancytopenia. Transaminases and LDH were frequently elevated (46.6%). Salmonella typhi was detected mainly by blood culture (64.3%). All the patients received antibiotics whereas immunomodulation (dexamethasone) was used in two cases. CONCLUSIONS: A high suspicion index for this condition is needed even in non-endemic areas. The addition of immunmodulation to standard antimicrobial therapy should be considered in selected cases.


Assuntos
Linfo-Histiocitose Hemofagocítica/etiologia , Febre Tifoide/complicações , Abscesso Abdominal/diagnóstico , Dor Abdominal/etiologia , Distribuição por Idade , Apendicite/diagnóstico , Ásia/epidemiologia , Ceftriaxona/uso terapêutico , Criança , Países Desenvolvidos , Diagnóstico Diferencial , Doenças Endêmicas , Febre/etiologia , Hepatomegalia/etiologia , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Masculino , Metilprednisolona/uso terapêutico , Oriente Médio/epidemiologia , Distribuição por Sexo , Espanha/epidemiologia , Esplenomegalia/etiologia , Febre Tifoide/diagnóstico , Febre Tifoide/tratamento farmacológico , Febre Tifoide/epidemiologia
10.
Expert Rev Clin Immunol ; 14(12): 1029-1041, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30280610

RESUMO

INTRODUCTION: The transcription factors signal transducer and activator of transcription (STAT) 1 and STAT3 fulfill fundamental functions in nonimmune and immune cells. The description and follow-up of patients with germline mutations that result in either loss-of-function or gain-of-function have contributed to our understanding of the pathophysiology of these regulators. Depending on the type of mutations, clinical symptoms are complex and can include infection susceptibility, immune dysregulation as well as characteristic nonimmune features. Areas covered: In this review, we provide an overview about mechanistic concepts, clinical manifestations, diagnostic process, and traditional as well as innovative treatment options aiming to help the clinical immunologist to better understand and manage these complex and rare diseases. Clinical and research papers were identified and summarized through PubMed Internet searches, and expert opinions are provided. Expert commentary: The last several years have seen an explosion in the clinical descriptions and pathogenesis knowledge of the diseases caused by GOF and LOF mutations in STAT1 and STAT3. However, harmonization of laboratory testing and follow-up in international cohorts is needed to increase our knowledge about the natural history of these disorders as well as the development of curative or supportive targeted therapies.


Assuntos
Alergia e Imunologia/educação , Doenças do Sistema Imunitário/genética , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Animais , Educação Médica , Predisposição Genética para Doença , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Fatores Imunológicos/uso terapêutico , Fenótipo , Prognóstico , Fatores de Risco , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
12.
J Allergy Clin Immunol ; 142(6): 1932-1946, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.


Assuntos
Antígeno CTLA-4/genética , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Síndromes de Imunodeficiência/diagnóstico por imagem , Síndromes de Imunodeficiência/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Adulto Jovem
13.
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 , Sirolimo/farmacologia , Subpopulações de Linfócitos T/efeitos dos fármacos
14.
Front Immunol ; 9: 543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599784

RESUMO

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.


Assuntos
Síndromes de Imunodeficiência/tratamento farmacológico , Imunossupressores/uso terapêutico , Sistema de Registros , Sirolimo/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Sociedades Médicas , Adulto Jovem
15.
Clin Immunol ; 188: 94-102, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305966

RESUMO

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.


Assuntos
Antígenos CD28/imunologia , Antígeno CTLA-4/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Antígenos CD28/metabolismo , Antígeno CTLA-4/deficiência , Antígeno CTLA-4/genética , Diarreia/genética , Diarreia/imunologia , Diarreia/metabolismo , Saúde da Família , Feminino , Humanos , Enteropatias/genética , Enteropatias/imunologia , Enteropatias/metabolismo , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto , Linhagem , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
16.
Clin Infect Dis ; 65(12): 1992-1999, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29020166

RESUMO

Background: The global crisis of bacterial resistance urges the scientific community to implement intervention programs in healthcare facilities to promote an appropriate use of antibiotics. However, the clinical benefits or the impact on resistance of these interventions has not been definitively proved. Methods: We designed a quasi-experimental intervention study with an interrupted time-series analysis. A multidisciplinary team conducted a multifaceted educational intervention in our tertiary-care hospital over a 5-year period. The main activity of the program consisted of peer-to-peer educational interviews between counselors and prescribers from all departments to reinforce the principles of the proper use of antibiotics. We assessed antibiotic consumption, incidence density of Candida and multidrug-resistant (MDR) bacteria bloodstream infections (BSIs) and their crude death rate per 1000 occupied bed days (OBDs). Results: A quick and intense reduction in antibiotic consumption occurred 6 months after the implementation of the intervention (change in level, -216.8 defined daily doses per 1000 OBDs; 95% confidence interval, -347.5 to -86.1), and was sustained during subsequent years (average reduction, -19,9%). In addition, the increasing trend observed in the preintervention period for the incidence density of candidemia and MDR BSI (+0.018 cases per 1000 OBDs per quarter; 95% confidence interval, -.003 to .039) reverted toward a decreasing trend of -0.130 per quarter (change in slope, -0.029; -.051 to -.008), and so did the mortality rate (change in slope, -0.015; -.021 to -.008). Conclusions: This education-based antimicrobial stewardship program was effective in decreasing the incidence and mortality rate of hospital-acquired candidemia and MDR BSI through sustained reduction in antibiotic use.


Assuntos
Gestão de Antimicrobianos/métodos , Candidemia/sangue , Candidemia/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Candidemia/microbiologia , Candidemia/mortalidade , Infecção Hospitalar/microbiologia , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/tendências , Humanos , Análise de Séries Temporais Interrompida , Mortalidade/tendências , Papel do Médico , Padrões de Prática Médica/estatística & dados numéricos , Padrões de Prática Médica/tendências , Centros de Atenção Terciária
17.
Blood ; 129(11): 1458-1468, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28159733

RESUMO

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here, we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal-blocking compounds, distinguished CTLA-4 from LRBA mutations. Short-term T-cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or -trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene-sequencing approaches.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígeno CTLA-4/genética , Mutação , Antígeno CTLA-4/metabolismo , Linhagem Celular , Imunodeficiência de Variável Comum/genética , Fatores de Transcrição Forkhead/análise , Humanos , Fenômenos do Sistema Imunológico/genética , Ligantes , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
19.
Medicine (Baltimore) ; 95(24): e3842, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27310962

RESUMO

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/µL (uVL, P = 0.069) and 480 to 830/µL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.


Assuntos
Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/genética , RNA Viral/análise , Tenofovir/administração & dosagem , Adolescente , Fármacos Anti-HIV/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/virologia , Humanos , Masculino , Uso Off-Label , Estudos Retrospectivos , Resultado do Tratamento
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