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1.
Pediatr Blood Cancer ; : e28177, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31925926

RESUMO

BACKGROUND: Hepatitis-associated aplastic anemia (AA) is a rare syndrome combining acute hepatitis of variable severity and AA. Hepatitis may be severe enough to require urgent liver transplantation (LT). Herein, we describe clinical presentation and management of a cohort of pediatric patients diagnosed with AA after undergoing LT for nonviral hepatitis. METHODS: To describe this rare clinical situation, we performed a national survey and identified nine children treated for AA following LT during the last 10 years in France. RESULTS: All patients were treated first for hepatic failure with urgent LT. AA was diagnosed with a median delay of 34 days [21-200] from the diagnosis of hepatitis. Seven children were treated with antithymocyte globulin/cyclosporine, one with CSA alone and one received bone marrow transplantation. At the last visit (median follow-up: 4 years), outcomes were excellent: all patients were alive and in hematological remission (complete remission: 7; partial remission: 2). Immunosuppressive therapy was pursued in all patients due to the liver transplant. No unusual toxicities were reported. CONCLUSION: AA after LT is considered a therapeutic challenge. Nevertheless, hematological outcome is good using a standard immunosuppressive approach.

2.
Virulence ; 11(1): 14-22, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885324

RESUMO

Prevention of mother-to-child transmission with antiretrovirals is extraordinarily effective. When medically well followed, a mother living with human immunodeficiency virus can now expect to avoid transmitting the virus to her child. Despite the immense difficulties inherent in the global implementation of this treatment, the virtual disappearance of pediatric AIDS can be considered in the long term.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31843562

RESUMO

Congenital erythropoietic porphyria (CEP) is a rare disease characterized by erosive photosensitivity and chronic hemolysis due to a defect of the enzyme uroporphyrinogen-III-synthase (UROS). To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the devastating early and severe form of the disease. We describe 6 patients with CEP treated with HSCT (3 of them twice after failure of a first graft) between 1994 and 2016 in our center, including 2 of the very first living patients treated more than 20 years ago. Four patients are doing well at 6 to 25 years post-HSCT, with near-normal biochemical parameters of porphyrin metabolism without the cutaneous or hematologic features of CEP. One patient died within the first year after HSCT from severe graft-versus-host disease (GVHD), and 1 child died of unexplained acute hepatic failure at 1 year after HSCT, despite full donor chimerism. Retrospectively, it appears that all but 1 child had increased transaminase activity with onset from the early postnatal period, which was significantly more marked in the child who died of liver failure. In contrast, liver function values progressively normalized after engraftment in all other children. Liver pathology before HSCT for 3 patients revealed varying degrees of portal, centrilobular, and perisinusoidal fibrosis; clarification of hepatocytes; and cytosolic porphyrin deposits. The liver porphyrin content in biopsy specimens was >60 times the normal values. Despite difficult engraftment, the long-term efficacy of HSCT in CEP appears to be favorable and reinforces its benefits for the severe form of CEP. Hepatic involvement requires careful evaluation before and after HSCT and further investigation into its pathophysiology and care.

5.
Clin Infect Dis ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633158

RESUMO

BACKGROUND: Perinatal treatment with lopinavir boosted by ritonavir (LPV/r) is associated with steroidogenic abnormalities. Long-term effects in infants have not been studied. METHODS: Adrenal-hormone profiles were compared at weeks 6 and 26 between human immunodeficiency virus (HIV)-1-exposed but uninfected infants randomly assigned at 7 days of life to prophylaxis with LPV/r or lamivudine (3TC) to prevent transmission during breastfeeding. LPV/r in vitro effect on steroidogenesis was assessed in H295R cells. RESULTS: At week 6, 159 frozen plasma samples from Burkina Faso and South Africa were assessed (LPV/r group: n = 92; 3TC group: n = 67) and at week 26, 95 samples from Burkina Faso (LPV/r group: n = 47; 3TC group: n = 48). At week 6, LPV/r-treated infants had a higher median dehydroepiandrosterone (DHEA) level than infants from the 3TC arm: 3.91 versus 1.48 ng/mL (P < .001). Higher DHEA levels (>5 ng/mL) at week 6 were associated with higher 17-OH-pregnenolone (7.78 vs 3.71 ng/mL, P = .0004) and lower testosterone (0.05 vs 1.34 ng/mL, P = .009) levels in LPV/r-exposed children. There was a significant correlation between the DHEA and LPV/r AUC levels (ρ = 0.40, P = .019) and Ctrough (ρ = 0.40, P = .017). At week 26, DHEA levels remained higher in the LPV/r arm: 0.45 versus 0.13 ng/mL (P = .002). Lopinavir, but not ritonavir, inhibited CYP17A1 and CYP21A2 activity in H295R cells. CONCLUSIONS: Lopinavir was associated with dose-dependent adrenal dysfunction in infants. The impact of long-term exposure and potential clinical consequences require evaluation.Giving lopinavir to infants during their first year of life induces early, asymptomatic adrenal disruption compatible with the combined inhibition of CYP 21 and CYP 17 enzymes. The impact of prolonged treatment on the adrenal glands may require further attention.

6.
Eur Respir J ; 54(5)2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31649064

RESUMO

INTRODUCTION: Pulmonary hypertension is a rare but important cause of mortality after haematopoietic stem cell transplantation (HSCT) in children. This complication is poorly characterised in the literature. We report here a series of children who developed pulmonary hypertension after HSCT. METHODS: Between January 2008 and December 2015, we retrospectively analysed 366 children who underwent HSCT (age range 0.5-252 months; median 20.3 months). During the post-HSCT course, echocardiography scans motivated by respiratory symptoms identified 31 patients with elevated tricuspid regurgitation velocity (>2.8 m·s-1), confirmed when possible by right heart catheterisation (RHC). RESULTS: 22 patients had confirmed pulmonary hypertension with mean±sd pulmonary arterial pressure 40.1±10 mmHg (range 28-62 mmHg) and pulmonary vascular resistance 17.3±9.2 Wood Units (range 8-42 Wood Units). Among the 13 responders at reactivity test, only one patient responded to calcium channel blockers. Seven patients (32%) died. 15 pulmonary hypertension patients were alive after a mean±sd follow-up of 6.5±2.3 years (range 2-10 years). All survivors could be weaned off pulmonary hypertension treatment after a median follow-up of 5 months (range 3-16). The delay between clinical symptoms and initiation of pulmonary hypertension therapy was significantly longer in patients who subsequently died (mean±sd 33.5±23 days; median 30 days) than in survivors (mean±sd 7±3 days) (p<0.001). CONCLUSION: Pulmonary hypertension is a severe complication of HSCT with an underestimated incidence and high mortality. Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.

7.
J Clin Immunol ; 39(7): 702-712, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

8.
Pediatrics ; 144(3)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31455612

RESUMO

BACKGROUND: Diagnosis of tuberculosis should be improved in children infected with HIV to reduce mortality. We developed prediction scores to guide antituberculosis treatment decision in HIV-infected children with suspected tuberculosis. METHODS: HIV-infected children with suspected tuberculosis enrolled in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS 12229 PAANTHER 01 Study), underwent clinical assessment, chest radiography, Quantiferon Gold In-Tube (QFT), abdominal ultrasonography, and sample collection for microbiology, including Xpert MTB/RIF (Xpert). We developed 4 tuberculosis diagnostic models using logistic regression: (1) all predictors included, (2) QFT excluded, (3) ultrasonography excluded, and (4) QFT and ultrasonography excluded. We internally validated the models using resampling. We built a score on the basis of the model with the best area under the receiver operating characteristic curve and parsimony. RESULTS: A total of 438 children were enrolled in the study; 251 (57.3%) had tuberculosis, including 55 (12.6%) with culture- or Xpert-confirmed tuberculosis. The final 4 models included Xpert, fever lasting >2 weeks, unremitting cough, hemoptysis and weight loss in the past 4 weeks, contact with a patient with smear-positive tuberculosis, tachycardia, miliary tuberculosis, alveolar opacities, and lymph nodes on the chest radiograph, together with abdominal lymph nodes on the ultrasound and QFT results. The areas under the receiver operating characteristic curves were 0.866, 0.861, 0.850, and 0.846, for models 1, 2, 3, and 4, respectively. The score developed on model 2 had a sensitivity of 88.6% and a specificity of 61.2% for a tuberculosis diagnosis. CONCLUSIONS: Our score had a good diagnostic performance. Used in an algorithm, it should enable prompt treatment decision in children with suspected tuberculosis and a high mortality risk, thus contributing to significant public health benefits.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções por HIV/complicações , Tuberculose/complicações , Tuberculose/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Abdome/diagnóstico por imagem , Antituberculosos/uso terapêutico , Técnicas Bacteriológicas , Criança , Pré-Escolar , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Microscopia , Radiografia , Receptores de Interferon/análise , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tuberculose/tratamento farmacológico , Ultrassonografia
9.
Lancet HIV ; 6(5): e307-e314, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30814028

RESUMO

BACKGROUND: The tolerance of antiretroviral drugs in infants must be carefully evaluated. In previous studies of children with HIV type 1 (HIV-1) less weight gain was observed in children given lopinavir-ritonavir-based combinations than those given nevirapine. We aimed to compare the effects of lopinavir-ritonavir and lamivudine on growth in HIV-exposed uninfected infants included in the ANRS 12174 trial. METHODS: ANRS 12174 was a multicentre, randomised, controlled trial of infant prophylaxis to prevent HIV-1 transmission by breastfeeding done at four antenatal clinics in Burkina Faso, South Africa, Uganda, and Zambia. HIV-exposed uninfected infants born to asymptomatic mothers not eligible for antiretroviral therapy (CD4 count >350 cells per µL) were randomly assigned (1:1) to receive lopinavir-ritonavir or lamivudine 7 days after birth, with stratification by country. In a prespecified secondary analysis, we assessed the effect of lopinavir-ritonavir and lamivudine on the growth of these infants from day 7 until cessation of breastfeeding (maximum treatment time 12 months) in the modified intention-to-treat population, which included all children correctly enrolled with at least one follow-up anthropometric measurement. We compared the growth of infants, defined as children's WHO-defined length-for-age Z score (LAZ), weight-for-length Z score (WAZ), and weight-for-age Z score (WLZ). We used linear mixed effect and ß spline-regression models to compare growth between the treatment groups. The trial is registered with ClinicalTrials.gov, number NCT00640263. FINDINGS: 1273 HIV-exposed uninfected infants and their mothers were enrolled between Nov 16, 2009, and May 7, 2013, of whom 1266 (99%) infants were included in the modified intention-to-treat analysis (630 assigned to lopinavir-ritonavir, 636 assigned to lamivudine). Baseline characteristics of the infants and mothers were similar across the two treatment groups. No differences in least-squares (LS) mean LAZ were identified between the treatment groups at any timepoint. LS mean WLZ was significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·22 [95% CI -0·34 to -0·09], p=0·0006) and 50 weeks (-0·25 [-0·47 to -0·04], p=0·02). LS mean WAZ was also significantly lower in the lopinavir-ritonavir group than the lamivudine group at 26 weeks (difference -0·18 [95% CI -0·30 to -0·05], p=0·01) and 50 weeks (-0·24 [-0·45 to -0·05], p=0·02). Linear mixed models showed that lopinavir-ritonavir was associated with decreases in WLZ and WAZ over time (p<0·0001 and p=0·002), whereas spline regression models indicated that these reductions occurred early and remained constant thereafter (p<0·0001 with a knot at 44 days for WLZ; p=0·02 with a knot at 118 days for WAZ). The difference in LS mean WLZ at 50 weeks between the treatment groups was higher among girls than boys (difference -0·29 [95% CI -0·58 to 0·01], p=0·05 for girls; -0·22 [-0·53 to 0·09], p=0·18 for boys). INTERPRETATION: Less weight gain was observed in infants given lopinavir-ritonavir than those given lamivudine, which is indicative of a persistent effect that could have long-term deleterious effects. This finding merits attention considering the recommendations for early and lifelong treatment of infants with HIV. FUNDING: French National Agency for Research on AIDS and Viral Hepatitis, the Total Foundation, the European Developing Countries Clinical Trials Partnership, and the Research Council of Norway.

10.
Biol Blood Marrow Transplant ; 25(7): 1363-1373, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30876929

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n = 22) or osteopetrosis (n = 5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (n = 21) or a rescue procedure after graft failure (n = 6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.

11.
Hum Gene Ther ; 30(6): 753-761, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30700149

RESUMO

Seventy-five percent of patients with beta thalassemia (ß-thalassemia) do not have human leukocyte antigen-matched siblings and until recently had no access to a curative treatment. Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a monocentric retrospective study and cost-efficacy analysis, this study compared the two-year outcomes and costs of patients with ß-thalassemia treated by gene therapy and hematopoietic stem-cell transplantation (HSCT). Grade III and grade IV complications, hospitalizations, and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. A total of seven patients with ß-thalassemia treated between 2009 and 2016 were included, of whom four received gene therapy. Patients treated by gene therapy were older and had fewer complications and hospital admissions. Infectious complications were three times more frequent for patients treated with HSCT than for gene therapy. Average costs were €608,086 for patients treated by gene therapy and €215,571 for HSCT. The total cost of the vector was 48% of the total cost of gene therapy. Gene therapy as a curative alternative for patients lacking human leukocyte antigen-matched donors was costlier but resulted in fewer complications than HSCT.

12.
J Acquir Immune Defic Syndr ; 81(1): 83-94, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30702449

RESUMO

BACKGROUND: High rates of liver enzyme elevation (LEE) in women receiving antiretroviral treatment (ART) during pregnancy have been reported, but causes remain unclear. We estimated the prevalence and risk factors of LEE in a national prospective multicenter cohort. METHODS: We studied 5748 pregnant women living with HIV enrolled in the French Perinatal Cohort 2005-2014, treated with ART, with no active hepatitis B or C coinfection. Adjusted hazard ratio (aHR) was estimated using Cox models with ART as time-dependent variable, separately for women on ART at conception and those initiating ART during pregnancy. RESULTS: LEE (grade ≥ 1) was observed in 16.7%, grade 3-4 in 2%. Among women with LEE, 6.7% had pre-eclampsia, 9.8% intrahepatic cholestasis of pregnancy, and 1.4% other identified medical causes. Most LEEs (82.2%) were unexplained. In women with unexplained LEE, LEE was the reason for hospitalization in 51 (6%) women, cesarean section in 13 (2%), induction of labor in 3 (0.4%), and change in ART regimen in 49 (6%) women. Unexplained LEE was associated with higher risk of preterm births, P < 0.001. Among women on ART at conception, the risk of unexplained LEE was lower with NNRTI-based regimens than with PI-based regimens: aHR = 0.5 (0.3-0.7), with no difference among the PI drugs. Most women initiating ART during pregnancy were on a PI-based regimen (89%). Among them, LEE was less frequent for women on nelfinavir vs. lopinavir/r [aHR = 0.4 (0.2-0.8)]. CONCLUSIONS: Rates of LEE among pregnant women living with HIV are high and impact obstetrical care management. The possible role of PIs needs further investigation.


Assuntos
Alanina Transaminase/sangue , Fármacos Anti-HIV/efeitos adversos , Aspartato Aminotransferases/sangue , Infecções por HIV/complicações , Fígado/enzimologia , Complicações Infecciosas na Gravidez/enzimologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , França , Infecções por HIV/tratamento farmacológico , Humanos , Fígado/efeitos dos fármacos , Gravidez , Adulto Jovem
14.
Clin Infect Dis ; 68(10): 1750-1753, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30689814

RESUMO

We enrolled 427 human immunodeficiency virus-infected children (median age, 7.3 years), 59.2% severely immunodeficient, with suspected tuberculosis in Southeast Asian and African settings. Nontuberculous mycobacteria were isolated in 46 children (10.8%); 45.7% of isolates were Mycobacterium avium complex. Southeast Asian origin, age 5-9 years, and severe immunodeficiency were independently associated with nontuberculous mycobacteria isolation. CLINICAL TRIALS REGISTRATION: NCT01331811.

15.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

17.
Nat Genet ; 51(1): 196, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429576

RESUMO

In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

19.
Biol Blood Marrow Transplant ; 25(3): 538-548, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30292747

RESUMO

Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients. This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.


Assuntos
Adrenoleucodistrofia/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/mortalidade , Estudos de Casos e Controles , Criança , Progressão da Doença , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tempo para o Tratamento , Adulto Jovem
20.
J Allergy Clin Immunol ; 143(1): 325-334.e2, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906526

RESUMO

BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation. OBJECTIVE: We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies. METHODS: We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes. RESULTS: The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. CONCLUSION: Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.


Assuntos
Síndromes de Imunodeficiência , Receptores de Antígenos de Linfócitos T alfa-beta , Recombinação V(D)J/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Estudos Retrospectivos
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