Hearing loss is frequently seen in mucopolysaccharidoses (MPS) patients. Although hematopoietic cell transplantation (HCT) increases overall survival, disease progression is observed in certain ...tissues. This study describes the course of hearing loss (HL) over time in transplanted MPS patients. Transplanted MPS patients between 2003 and 2018 were included and received yearly audiological evaluation, including auditory brainstem response (ABR) or pure tone audiometry (PTA). Twenty‐eight MPS‐1 and four MPS‐6 patients were analyzed with a median follow‐up of 5 years (range 11 months–16 years). Air conduction threshold improved significantly over time (P < .001) with a PTA 1‐year post‐HCT of 50 ± 0.7 dB to 23 ± 11 dB 13 years post‐HCT. Bone conduction threshold worsened with a PTA 1 year post‐HCT of 10 ± 7 dB to 18 ± 9 dB 13 years post‐HCT (P = .34). The degree of HL varied from mainly mild‐severe early after HCT to normal‐mild at longer follow‐up. The type of HL consisted of mainly conductive in the first years post‐HCT in contrast to mainly sensorineural at longer follow‐up. MRIs of the cerebellopontine angle did not show abnormalities. HL is still seen in patients with MPS despite HCT and consists of a conductive type early after HCT in contrast to a sensorineural type at longer follow‐up in the majority of cases. Yearly follow‐up of HL is necessary to timely intervene, as hearing is important in the speech and language development of children and their academic achievements.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
There is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to ...identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures.
The discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.
sPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p ≤ 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants.
The biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.
Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression ...for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; P = .006), well-matched (≤1 HLA mismatch) CB units (71% vs 54%; P = .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively; P = .003). For patients with PS≤60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS >80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.
•A 6-year overall survival of 61% was observed in leukodystrophy patients after cord blood transplantation.•Mismatched cord blood donors, symptomatic disease, and lower PS before cord blood transplantation were predictors of lower survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
The CLN3 disease spectrum ranges from a childhood‐onset neurodegenerative disorder to a retina‐only disease. Given the lack of metabolic disease severity markers, it may be difficult to ...provide adequate counseling, particularly when novel genetic variants are identified. In this study, we assessed whether lymphocyte vacuolization, a well‐known yet poorly explored characteristic of CLN3 disease, could serve as a measure of disease severity.
Methods
Peripheral blood obtained from healthy controls and CLN3 disease patients was used to assess lymphocyte vacuolization by (a) calculating the degree of vacuolization using light microscopy and (b) quantifying expression of lysosomal‐associated membrane protein 1 (LAMP‐1), using flow cytometry in lymphocyte subsets as well as a qualitative analysis using electron microscopy and ImageStream analysis.
Results
Quantifying lymphocyte vacuolization allowed to differentiate between CLN3 disease phenotypes (P = .0001). On immunofluorescence, classical CLN3 disease lymphocytes exhibited abundant vacuole‐shaped LAMP‐1 expression, suggesting the use of LAMP‐1 as a proxy for lymphocyte vacuolization. Using flow cytometry in lymphocyte subsets, quantifying intracellular LAMP‐1 expression additionally allowed to differentiate between infection and storage and to differentiate between CLN3 phenotypes even more in‐depth revealing that intracellular LAMP‐1 expression was most pronounced in T‐cells of classical‐protracted CLN3 disease while it was most pronounced in B‐cells of “retina‐only” CLN3 disease.
Conclusion
Lymphocyte vacuolization serves as a proxy for CLN3 disease severity. Quantifying vacuolization may help interpretation of novel genetic variants and provide an individualized readout for upcoming therapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the ...course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in “hard-to-treat” tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these “hard-to-reach” tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mucopolysaccharidoses (MPS) are devastating inherited diseases treated with hematopoietic cell transplantation (HCT). However, disease progression, especially skeletal, still occurs in all patients. ...Secondary inflammation has been hypothesized to be a cause. To investigate whether systemic inflammation is present in untreated patients and to evaluate the effect of HCT on systemic inflammation, dried blood spots (n = 66) of patients with MPS (n = 33) treated with HCT between 2003 and 2019 were included. Time points consisted of pre-HCT and, for patients with MPS type I (MPS I), also at 1, 3, and 10 years of follow-up. Ninety-two markers of the OLINK inflammation panel were measured and compared with those of age-matched control subjects (n = 31) by using principal component analysis and Wilcoxon rank sum tests with correction. Median age at transplantation was 1.3 years (range, 0.2-4.8 years), and median time of pre-HCT sample to transplantation was 0.1 year. Normal leukocyte enzyme activity levels were achieved in 93% of patients post-HCT. Pretransplant samples showed clear separation of patients and control subjects. Markers that differentiated pre-HCT between control subjects and patients were mainly pro-inflammatory (50%) or related to bone homeostasis and extracellular matrix degradation (33%). After 10 years' follow-up, only 5 markers (receptor activator of nuclear factor kappa-Β ligand, osteoprotegerin, axis inhibition protein 1 AXIN1, stem cell factor, and Fms-related tyrosine kinase 3 ligand) remained significantly increased, with a large fold change difference between patients with MPS I and control subjects. In conclusion, systemic inflammation is present in untreated MPS patients and is reduced upon treatment with HCT. Markers related to bone homeostasis remain elevated up to 10 years after HCT and possibly reflect the ongoing skeletal disease, making them potential biomarkers for the evaluation of new therapies.
•Systemic inflammation is present both before and after HCT in patients with MPS.•Ten years after HCT, bone homeostasis– related markers remain highly elevated in MPS I patients and possibly reflect ongoing skeletal disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Purpose The aim of this study was to review literature exploring the emotional consequences of delirium and delusional memories in intensive care unit patients. Methods A systematic review ...was performed using PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and PsychINFO. Results Fourteen articles were eligible for this review. Five of them assessed delirium during intensive care unit admission, and the remainder assessed delusional memories during or after admission. No association was found for delirium and adverse emotional outcome. Data regarding delusional memories and emotional outcome were heterogenic. Some studies presented worse scores on posttraumatic stress disorder screening tools in patients with delusional memories, whereas other studies found better scores in patients with delirium or delusional memories. Conclusions Based on current literature, no relationship could be shown for delirium and emotional outcome. Regarding delusional memories and adverse emotional outcome, results were in contradiction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, ...although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of care was evaluated by the Measure of Processes of Care questionnaire. Sixty-three HS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, −2.4 range, −3.5 to −1.6; median global functioning z score, −3.2 range, −4.8 to −1.8). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 range, −0.7 to 0.8). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.
•Functional health of transplanted HS patients was significantly diminished. Patients with higher enzyme levels showed favorable results.•Psychosocial health appeared unaffected compared with healthy peers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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