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1.
Pediatr Transplant ; 24(1): e13599, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31617270

RESUMO

Children receiving HCT loose protective immunity to vaccines received pre-HCT. Therefore, revaccination post-HCT is of major importance. In Denmark, a vaccination schedule with fewer doses post-HCT has been used, including two doses for diphtheria, tetanus, polio, measles, mumps, and rubella, and one dose only for Haemophilus influenzae type B. The background for this was the presumption that post-HCT immunization constituted booster vaccination of donor immunity. Our objective was to evaluate the proportion of children protected after the scheduled vaccination programme. A nationwide retrospective cohort study of all children who have received an HCT in Denmark during 1994-2012. Antibody levels were analysed in blood samples drawn before and after vaccination, and the probability of achieving protection after the scheduled immunization programme was estimated. A total of 198 children were included. The protection post-immunization was as follows: diphtheria 75.3%, tetanus 89.1%, polio 97.7%, and Haemophilus influenzae type B 94.8%. For diphtheria and tetanus, the probability of achieving protection increased to 93.8% and 97.3%, respectively, after a third dose. For measles, mumps, and rubella, the probability of achieving protection was 89.4%, 80.9%, and 94.2%, respectively. In conclusion, our findings support a more extensive vaccination schedule including three doses for diphtheria and tetanus which are in line with current international guidelines.

2.
Bone Marrow Transplant ; 55(1): 207-214, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31527820

RESUMO

Hemorrhagic cystitis (HC) is a debilitating complication following allogenic hematopoietic cell transplantation (HCT). HLA disparity and T-cell depletion have been implicated as risk factors for HC. However, reports on the incidence and risk factors for HC in ex vivo T-cell depleted haploidentical HCT (haploHCT) in children are lacking. We studied 96 haploHCT procedures performed in 83 children between 2002 and 2017. Sixty-three patients were diagnosed with a malignant disease and 20 with nonmalignant disease. All but three patients with SCID underwent myelotoxic and/or lymphotoxic conditioning therapy. Grafts were CD3+ (36.5%) or TcRαß+ (63.5%) depleted to prevent graft versus host disease (GvHD). Fourteen patients (14.6%) were diagnosed with HC; 12 (12.5%) had clinically significant stage II-IV HC. All patients with HC had BK viruria and/or viremia. Increasing age and chemotherapeutic treatment prior to conditioning were identified as risk factors for HC. Immune recovery did not significantly differ between patients with and without HC. Thus, we report a low incidence of HC in pediatric haploHCT using ex vivo T-cell depletion. The combination of a reduced toxicity conditioning regimen, and typically absent pharmaceutical post-HCT GvHD prophylaxis in our patients might have contributed to the decreased the risk of HC, despite HLA disparity.

3.
Int J Cancer ; 146(3): 819-828, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980681

RESUMO

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Doenças do Sistema Nervoso/epidemiologia , Neoplasias do Sistema Nervoso/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Neoplasias do Sistema Nervoso/mortalidade , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Países Escandinavos e Nórdicos/epidemiologia , Adulto Jovem
4.
J Cancer Res Clin Oncol ; 145(12): 3125-3135, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587105

RESUMO

PURPOSE: Solid organ (SOT) and allogeneic haematopoietic stem cell (HSCT) transplant recipients have elevated risks of de novo or secondary cancer. We explored risk factors hereof. METHODS: Among SOT and HSCT between January 2004 and December 2014, standardised incidence ratio (SIR) of de novo/secondary cancer compared with the Danish population was determined and risk factors were identified using Poisson regression. RESULTS: During a median of 3.4 (IQR 1.3-6.4) and 2.6 (0.8-5.4) person-years (PY) after SOT and HSCT, a total of 212/1656 (13%) and 75/992 (8%) persons developed cancer; SIR 3.61 (3.0-4.3) and 2.2 (1.6-3.0), resp.). SIR correlated with younger age and was highest for skin and haematological cancers for both types of transplantation. Within the cohort, cancer was associated with older age (adjusted incidence rate ratio > 50 vs ≤ 19 years, among SOT and HSCT: 9.4 (3.4-25.7) and 25.4 (5.1-126.0), resp.) and current elevated C-reactive protein (CRP) (≥ 10 vs < 10 mg/L: 2.5 (1.8-3.4) and 2.3 (1.4-3.9), resp.), but neither with prior cancer nor type of immunosuppressants. CONCLUSION: Rates of de novo or secondary cancers are elevated in both SOT and HSCT compared with the general population and mainly for skin and haematological cancers. Among transplant recipients, older age and current elevated CRP are risk factors.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Segunda Neoplasia Primária/etiologia , Neoplasias/etiologia , Transplante de Órgãos/efeitos adversos , Adulto , Estudos de Coortes , Feminino , Humanos , Imunossupressores/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transplantados , Adulto Jovem
5.
Pediatr Transplant ; 23(7): e13549, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31313439

RESUMO

Analysis of chimerism in blood post-HCT using STR-PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ-PCR chimerism is 10- to 100-fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9-41.4; P < .0001] and 7.6 [95% CI: 2.2-26.9; P < .01], respectively). The first IMC was detected at a median of 208 days prior to relapse. The 5-year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3-74.4) and 41.0% (14.2-66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC > 0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90 days post-HCT and subsequent relapse by either classification of IMC and AUC for RQ-PCR chimerism was 54.2% (95 CI 27.7- 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ-PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.

6.
Pediatr Pulmonol ; 54(7): 1029-1038, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31004401

RESUMO

BACKGROUND: Pulmonary chronic graft-vs-host disease (cGvHD) after hematopoietic stem cell transplantation (HSCT) is characterized by impairment of the small airways. Assessment of lung clearance index (LCI) gained from multiple breath washout (MBW) is more sensitive than spirometry in detection of small airways disease. The aim of this study was to describe the development of LCI during the first year after pediatric HSCT and how LCI relates to other pulmonary function parameters and cGvHD. METHODS: This prospective, longitudinal study included 28 pediatric HSCT-recipients. Spirometry, Sulfur hexafluoride MBW and diffusion capacity of the lungs were performed before and at 3, 6, 9, and 12 months after HSCT. Respiratory symptoms and signs of cGvHD were recorded at each visit. RESULTS: Before HSCT, 47.8% had abnormal LCI and 12.5% had abnormal forced expiratory volume in 1 second (FEV1 ). Patients with persisting respiratory symptoms 12 months post-HSCT had higher median LCI (factor 5.7, P = 0.0018) and lower FEV1 z-scores (-1.5, P = 0.033) post-HSCT compared to patients free of respiratory symptoms. Overall, post-HSCT LCI values were 3.49 times higher and FEV1 was 2.31 z-scores lower in eight patients with cGvHD in any organ system compared with patients without cGvHD (P = 0.0089 and P < 0.0001). LCI values during the first 3 months were not predictive of pulmonary cGvHD. CONCLUSION: LCI is a sensitive marker for cGvHD and high LCI values were associated with persisting respiratory symptoms after 1 year. Further evaluation of MBW in early detection of HSCT-related pulmonary complications require larger patient cohorts and closer follow-up during the first months after HSCT.

7.
Pediatr Transplant ; 23(4): e13416, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30973668

RESUMO

Graft-versus-host disease (GVHD) is a main cause of morbidity and mortality following hematopoietic stem cell transplantation. The cumulative incidence of acute and chronic GVHD (aGVHD, cGVHD) reaches 30%-50% and 20% in pediatric populations, respectively. Prednisolone and/or calcineurin inhibitors (CNI) are first-line treatments, but no superior second-line treatment has yet been established. Several treatments have been suggested, among others extracorporeal photopheresis (ECP). Technical advances have made treatment of pediatric patients possible; however, only few reports on the feasibility of ECP in children have been published. We retrospectively studied the feasibility, safety, and efficacy of ECP in 15 children with steroid-dependent/refractory acute or chronic GVHD, who initiated ECP treatment between April 2014 and January 2018. Only few and mild side effects directly related to the ECP procedure were registered, even in patients with low body weight. The most frequent cause of shortened or canceled ECP treatment was difficulties with vascular accesses, which were more rarely seen using central venous catheters with larger lumens and made of stiffer material. Nine patients had grade II-III aGVHD. Six of these experienced a response to ECP at day 28, while eight of nine had responded at the last ECP treatment. Six patients had cGVHD when ECP was initiated, and of these, four had a partial response at last ECP treatment. We found ECP to be a feasible and safe treatment, and particularly, children with aGVHD appeared to respond well to ECP.

8.
Biol Blood Marrow Transplant ; 25(7): 1432-1440, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910606

RESUMO

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged by cytotoxic effects of the conditioning regimen, resulting in tissue damage, systemic inflammation, and increased metabolic demands for amino acids to regenerate damaged tissues, reconstitute hematopoietic cells, and establish antioxidant defenses. To date, few studies have addressed the role of plasma amino acid (PAA) levels during transplantation, and it remains unknown if amino acid deficiency can aggravate treatment-related morbidity. We determined plasma levels of the 23 human amino acids in 80 HSCT recipients (age 1.1 to 55.4 years) before conditioning and on days +7 and +21 post-transplant along with C-reactive protein (CRP) and IL-6 levels on day +7. Significant changes were observed in plasma concentrations of several human amino acids during HSCT. On day +7, numerous amino acids were inversely correlated with both CRP and IL-6, including glutamic acid, serine, alanine, glutamine, arginine, cysteine, glycine, histidine, lysine, tryptophan, threonine, taurine, proline, and methionine (r = -.22 to -.66; all P < .05). Patients who developed sinusoidal obstruction syndrome (SOS) had significantly lower mean total PAA levels compared with patients without SOS (2013 ng/L [95% confidence interval (CI), 1709 to 2318 ng/L] versus 2706 ng/L [95% CI, 2261 to 3150 ng/L]; P = .006), along with lower individual levels of glutamic acid, serine, arginine, glycine, lysine, valine, tryptophan, threonine, and proline on day +7 (all P < .05). Patients with severe acute graft-versus-host disease had a lower mean total PAA level (1922 ng/L [95% CI, 1738 to 2106 ng/L] versus 2649 ng/L [95% CI, 2244 to 3055 ng/L]; P = .014) and lower levels of serine, glutamine, cysteine, glycine, lysine, and threonine on day +7 (all P < .05). These results indicate a relationship between low concentrations of certain amino acids and the risk of treatment-related complications.

9.
Br J Haematol ; 184(6): 982-993, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30680711

RESUMO

The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10-3 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10-3 . After a median follow-up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5-47·7) for MRD-positive versus 5·1% (95% CI: 1·3-19·2), P = 0·02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6-51·0, P = 0·012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85·6% (95% CI: 75·4-97·2) and 67·4% (95% CI: 50·2-90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.

10.
Bone Marrow Transplant ; 54(9): 1406-1418, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30683907

RESUMO

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the proposed pediatric EBMT criteria along with the Baltimore and modified Seattle criteria in a population-based cohort. Eighty-seven children (1.1-17.3 years) undergoing myeloablative HSCT from 2010 to 2017 were consecutively included at the Danish National Transplantation Center. In total, 39 (44.8%) patients fulfilled the EBMT criteria and 30 patients (35%) fulfilled the criteria for severe or very severe SOS. Nine (10.3%) patients fulfilled the modified Seattle criteria while none met the Baltimore criteria. Patients fulfilling the EBMT criteria for SOS had longer primary admission (31 days (23-183) vs. 27 days (17-61), p = 0.001), were treated more intensively with diuretics within the first 3 months (29 days (0-90) vs. 3.5 days (0-90), p < 0.0001), and had a longer time to stable platelet counts >50 × 109/L (32 days (16-183) vs. 23 days (14-101), p < 0.0001). Two patients, fulfilling neither Baltimore nor Seattle criteria, but selectively fulfilling EBMT criteria, died of treatment-related acute inflammatory complications within 1 year post-HSCT. In conclusion, application of the pediatric EBMT diagnostic and severity criteria may be helpful in identifying patients at increased risk of severe treatment-related complications and mortality, although with a risk of over-diagnosing SOS.

11.
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.

12.
Medicine (Baltimore) ; 97(29): e11564, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30024557

RESUMO

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.


Assuntos
Causas de Morte , Transplantados/estatística & dados numéricos , Transplante/mortalidade , Adulto , Idoso , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros
13.
J Cancer Res Clin Oncol ; 144(8): 1569-1580, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29804164

RESUMO

PURPOSE: Emerging EBV DNAemia in plasma is considered an early sign of post-transplant lymphoproliferative disorder (PTLD). The aim of this study was to quantify the extent of benefit from screening for EBV DNAemia to detect emerging PTLD among solid organ (SOT) or hematopoietic stem cell transplant recipients (HSCT). METHODS: We used receiver operating characteristic (ROC) curves for assessing ability of models to predict PTLD. Among 2642 recipients transplanted between January 2004 and December 2014, 79 (3%) developed PTLD. RESULTS: EBV DNAemia was observed in 331/1784 recipients (18.6%, 95% CI 16.8-20.4) with measured EBV DNA. The area under the curve (AUC) of the ROC of EBV DNAemia to identify persons with subsequent PTLD was 72% (95% CI, 64-79%) among SOT and 59% (51-68%) among HSCT. Including clinical predictors such as age, gender, transplant year and type, high-risk EBV serostatus, and routine biochemistry in addition to EBV DNAemia increased AUC to 83% (75-90%) among SOT and 84% (79-89%) among HSCT. Among HSCT, including additional factors such as T-cell-depleting treatment, acute graft vs. host disease and donor match increased AUC to 85% (78-91%). CONCLUSIONS: We constructed a model to better predict PTLD compared to EBV DNA screening alone which could have clinical implications.


Assuntos
DNA Viral/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/genética , Transtornos Linfoproliferativos/virologia , Transplante de Órgãos/efeitos adversos , Adolescente , Adulto , Estudos de Coortes , DNA Viral/genética , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Herpesvirus Humano 4/isolamento & purificação , Humanos , Incidência , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/métodos , Transplante de Órgãos/estatística & dados numéricos , Estudos Retrospectivos , Adulto Jovem
14.
Bone Marrow Transplant ; 53(7): 844-851, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29391524

RESUMO

Several immunosuppressive drugs have been proposed for second-line treatment of steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation. However, the studies on these drugs are small, retrospective, uncontrolled and use different endpoints. Therefore, it remains unknown which treatment is superior. We retrospectively evaluated 68 consecutive patients treated with infliximab for aGvHD. We adhered to recently proposed guidelines for aGvHD trials and thus evaluated response on day 7 and 28. Furthermore, we assessed the composite endpoint 6 months freedom from treatment failure (6MFTF). The majority of patients had grade III-IV aGvHD. We found that 41 patients (60%) responded on day 7 and 31 patients (46%) on day 28. Twenty-four patients (35%) achieved 6MFTF. The main reasons for failure within 6 months were death (n = 31) or additional immunosuppression (n = 16). By six and 24 months, 44 and 34% of the patients were alive respectively. Patients with response to infliximab on day 7 and 28 had significantly higher overall survival (OS) probability than non-responders. We show that response on day 7 and 28 identifies high and low risk groups. Patients who fail to respond should be identified early and offered alternative therapy.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Infliximab/uso terapêutico , Doença Aguda , Adulto , Idoso , Fármacos Dermatológicos/farmacologia , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Infliximab/farmacologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
15.
Front Immunol ; 9: 109, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29456530

RESUMO

The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for de novo T cell generation in thymus and peripheral T cell homeostasis. In this study, we investigated the impact of the single nucleotide polymorphism rs6897932 in the IL-7 receptor α-chain (IL-7Rα) which has previously been associated with several autoimmune diseases. We included 460 patients undergoing allogeneic HSCT after a myeloablative conditioning. Patients had a median age of 26.3 years (0.3-67.0 years), and 372 (80.9%) underwent HSCT for malignant diseases. Donors were matched sibling donors (n = 147), matched unrelated donors (n = 244) or mismatched unrelated donors (n = 69), and the stem cell source were either bone marrow (n = 329) or peripheral blood (n = 131). DNA from donors was genotyped for the IL-7Rα single nucleotide polymorphism (SNP) rs6897932 using an allele-specific primer extension assay (CC: n = 252, CT: n = 178, TT: n = 30). The donor T allele was associated with a higher risk of grades III-IV aGVHD (HR = 2.0, 95% CI = 1.1-3.8, P = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1-3.6, P = 0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR = 2.4, 95% CI = 1.2-4.3, P = 0.0068). Numbers of T cells were significantly higher on day +60 in patients receiving a rs6897932 TT graft (CD3+: 109% increase, P = 0.0096; CD4+: 64% increase, P = 0.038; CD8+: 133% increase, P = 0.011). Donor heterozygosity for the T allele was associated with inferior overall survival (HR = 1.7, 95% CI = 1.2-2.3, P = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3-4.0, P = 0.0047), but was not associated with the risk of relapse (P = 0.35). In conclusion, the IL-7Rα rs6897932 genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality following HSCT. These findings indicate that IL-7Rα SNP typing of donors may optimize donor selection and facilitate individualization of treatment in order to limit treatment-related complications.


Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Receptores de Interleucina-7/genética , Doadores de Tecidos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Polimorfismo de Nucleotídeo Único , Transplante Homólogo , Adulto Jovem
16.
Immunobiology ; 223(2): 220-226, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29033080

RESUMO

Successful reconstitution of T lymphocytes after allogeneic haematopoietic stem cell transplantation (HSCT) is needed to establish the graft-versus-leukaemia effect and an effective anti-microbial defense, but the ratio between functionally different T-cell subsets needs to be balanced to avoid graft-versus-host disease (GVHD). IL-7 is essential for T-cell generation in the thymus and peripheral T-cell homeostasis. High IL-7 levels have been associated with impaired T-cell reconstitution, increased risk of acute GVHD and treatment-related mortality, but the underlying cellular mechanisms behind these associations have not been investigated previously. We hypothesized that increased levels of IL-7 post-transplant alters the balance between immune-regulatory T cell subsets during the post-transplant lymphocyte recovery towards a more pro-inflammatory profile. We quantified Th17 cells, Tc17 cells and Tregs in 29 children following HSCT. Th17 cell and Treg counts rose significantly from day +90 to +180 post-HSCT, and prior acute GVHD was associated with significant changes in the concentration of Tregs (9.4×106/L vs. 1.3×106/L, P=0.0052) and the Th17/Treg ratio (1.5 vs. 4.2, P=0.025). The plasma level of IL-7 at day +90 correlated inversely with Th17 cell counts (rs=-0.65, P=0.0002) and the proportion of Tc17 cells (rs=0.64, P=0.0005) at day +90, but not with Tregs. Furthermore, high IL-7 levels at day +7 were predictive of a less naïve T-cell phenotype at day +90. These findings add further evidence that IL-7 is a key regulatory factor that may tune the balance between functionally different T-cell subsets following HSCT.


Assuntos
Autorrenovação Celular , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Interleucina-7/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Timo/imunologia , Doença Aguda , Diferenciação Celular , Criança , Feminino , Homeostase , Humanos , Interleucina-7/imunologia , Masculino , Transplante Homólogo
17.
J Allergy Clin Immunol ; 141(1): 322-328.e10, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28392333

RESUMO

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.


Assuntos
Quebras de DNA de Cadeia Dupla , Distúrbios no Reparo do DNA/genética , Distúrbios no Reparo do DNA/terapia , Reparo do DNA , Transplante de Células-Tronco Hematopoéticas , Adolescente , Alelos , Criança , Pré-Escolar , Distúrbios no Reparo do DNA/diagnóstico , Distúrbios no Reparo do DNA/mortalidade , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mutação , Prognóstico , Resultado do Tratamento , Viroses , Adulto Jovem
18.
Int J Cancer ; 142(4): 702-708, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29023764

RESUMO

Information on late onset liver complications after childhood cancer is scarce. To ensure an appropriate follow-up of childhood cancer survivors and reducing late liver complications, the need for comprehensive and accurate information is presented. We evaluate the risk of liver diseases in a large childhood cancer survivor cohort. We included all 1-year survivors of childhood cancer treated in the five Nordic countries. A Cox proportional hazards model was used to estimate hospitalisation rate (hazard) ratios (HRs) for each liver outcome according to type of cancer. We used the risk among survivors of central nervous system tumour as internal reference. With a median follow-up time of 10 years, 659 (2%) survivors had been hospitalised at least once for a liver disease. The risk for hospitalisation for any liver disease was high after hepatic tumour (HR = 6.9) and leukaemia (HR = 1.7). The Danish sub-cohort of leukaemia treated with haematopoietic stem cell transplantation had a substantially higher risk for hospitalisation for all liver diseases combined (HR = 3.8). Viral hepatitis accounted for 286 of 659 hospitalisations corresponding to 43% of all survivors hospitalised for liver disease. The 20-year cumulative risk of viral hepatitis was 1.8% for survivors diagnosed with cancer before 1990 but only 0.3% for those diagnosed after 1990. The risk of liver disease was low but significantly increased among survivors of hepatic tumours and leukaemia. Further studies with focus on the different treatment modalities are needed to further strengthen the prevention of treatment-induced late liver complications.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Hepatopatias/epidemiologia , Neoplasias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Leucemia/epidemiologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Países Escandinavos e Nórdicos/epidemiologia , Adulto Jovem
19.
J Immunotoxicol ; 14(1): 188-195, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28805477

RESUMO

Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.


Assuntos
Toxoide Diftérico/imunologia , Fluorcarbonetos/toxicidade , Toxoide Tetânico/imunologia , Anticorpos/sangue , Aleitamento Materno , Pré-Escolar , Estudos de Coortes , Exposição Ambiental/efeitos adversos , Feminino , Fluorcarbonetos/sangue , Fluorcarbonetos/imunologia , Humanos , Imunidade Humoral , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Vacinação
20.
Environ Health Perspect ; 125(7): 077018, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28749778

RESUMO

BACKGROUND: Postnatal exposure to perfluorinated alkylate substances (PFASs) is associated with lower serum concentrations of specific antibodies against certain childhood vaccines at 7 y. OBJECTIVES: We prospectively followed a Faroese birth cohort to determine these associations at 13 y. METHODS: In 516 subjects (79% of eligible cohort members) who were 13 years old, serum concentrations of PFASs and of antibodies against diphtheria and tetanus were measured and were compared with data from the previous examination at 7 y. Multiple regression analyses and structural equation models were applied to determine the association between postnatal PFAS exposures and antibody concentrations. RESULTS: Serum concentrations of PFASs and antibodies generally declined from 7 y to 13 y. However, 68 subjects had visited the emergency room and had likely received a vaccination booster, and a total of 202 children showed higher vaccine antibody concentrations at 13 y than at 7 y. Therefore, separate analyses were conducted after exclusion of these two subgroups. Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure. Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10­30% for the five PFASs. Few associations were observed for anti-tetanus concentrations. CONCLUSIONS: These results are in accord with previous findings of PFAS immunotoxicity at current exposure levels. https://doi.org/10.1289/EHP275.


Assuntos
Anticorpos Antibacterianos/sangue , Toxoide Diftérico/imunologia , Exposição Ambiental , Poluentes Ambientais/sangue , Fluorcarbonetos/sangue , Ácidos Sulfônicos/sangue , Toxoide Tetânico/imunologia , Adolescente , Criança , Dinamarca , Toxoide Diftérico/administração & dosagem , Monitoramento Ambiental , Feminino , Humanos , Masculino , Estudos Prospectivos , Toxoide Tetânico/administração & dosagem
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