Patients with sickle cell disease (SCD) experience a considerable physical and psychosocial disease burden. In recent years, the application of allogeneic hematopoietic stem cell transplantation ... Show morePatients with sickle cell disease (SCD) experience a considerable physical and psychosocial disease burden. In recent years, the application of allogeneic hematopoietic stem cell transplantation (HSCT) to treat adults with SCD has increased. A thorough understanding of patients' physical, mental, and social health before and after cure is needed to meet the needs of this growing group of patients. We aimed to explore the perspectives of adult SCD patients on the changes in their experienced health and personal life goals after being cured. A mixed-methods approach was used, comprising a semistructured interview and a set of 9 Patient Reported Outcomes Measurement Information System (PROMIS) measures. Adult SCD patients who underwent HSCT at least 1 year earlier were eligible to participate in the study. Interviews were thematically analyzed using MAXQDA software. PROMIS T scores were compared with reference scores of the general population using SPSS Statistics. Ten patients participated in the study; their median age was 29.5 years (range, 19 to 49 years), and their median time since HSCT was 2.7 years (range, 1.0 to 3.5 years). Themes from the interviews were (1) pain/living pain free, (2) physical wellbeing, (3) mental well-being, (4) perspective/outlook, (5) education/work, (6) family/friends, and (7) activities/participation. Following the PROMIS framework, we described these themes in a narrative synthesis according to health domain and categorized in 4 chronological time phases: before HSCT, first year post-transplantation, current situation, and future expectations. Physical health improved greatly, but transplantation-related toxicity, ongoing pain from avascular osteonecrosis, and fatigue negatively impacted quality of life in some patients. Furthermore, emotional struggles during the post-transplantation period were common, and patients expressed a need for psychological help. Patients reported improvements in social health and the ability to pursue personal life goals. The mean T scores of all PROMIS measures fell within the normal symptom limits compared with reference data of the general population, although, large variations were observed among the participants, matching our qualitative findings. In general, adult SCD patients experienced improved physical, mental, and social health after cure by HSCT and were able to pursue personal life goals. Yet they found themselves confronted with a new and unfamiliar reality that brought different challenges. Pain due to irreversible avascular osteonecrosis continued to have a negative impact. Clinicians should aim to help patients have realistic expectations before transplantation and offer timely psychological care. (c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. Show less
This prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not... Show moreThis prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not associated with mortality. Its place in the current EORTC/MSGERC definitions should be reconsidered.Background Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. Methods In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. Results Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). Conclusions Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
BackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of... Show moreBackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy.MethodsIn a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA.ResultsOf 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83).ConclusionsReal-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
BackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of... Show moreBackgroundInvasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy.MethodsIn a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA.ResultsOf 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83).ConclusionsReal-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample). Show less
Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided... Show moreObjectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ) Show less
Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular... Show moreSilent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular shunting is defined as reduced oxygen offloading due to the rapid transit of blood through the capillaries caused by increased flow and has been suggested as a potential mechanism underlying reduced oxygenation and SCI. We investigated the venous arterial spin labeling signal (VS) in the sagittal sinus as a proxy biomarker of cerebral functional shunting, and its association with hemodynamic imaging and hematological laboratory parameters. We included 28 children and 38 adults with SCD, and ten healthy racematched adult controls. VS, cerebral blood flow (CBF), velocity in the brain feeding arteries, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were measured before and after acetazolamide administration. VS was higher in patients with SCD compared to controls (P<0.01) and was increased after acetazolamide administration in all groups (P<0.01). VS was primarily predicted by CBF (P<0.01), but CBF-corrected VS was also associated with decreased CMRO2 (P<0.01). Additionally, higher disease severity defined by low hemoglobin and increased hemolysis was associated with higher CBF-corrected VS. Finally, CMRO2 was negatively correlated with fetal hemoglobin, and positively correlated with lactate dehydrogenase, which could be explained by changes in oxygen affinity. These findings provide evidence for cerebral functional shunting and encourage future studies investigating the potential link to aberrant capillary exchange in SCD. Show less
Rijneveld, A.W.; Holt, B. van der; Weerdt, O. de; Biemond, B.J.; Loosdrecht, A.A. van de; Wagen, L.E. van der; ... ; Dutch-Belgian HOVON Cooperative Gr 2022
Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and... Show moreClofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients <= 40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004. Show less
Red blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic characteristics may be associated... Show moreRed blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic characteristics may be associated with the risk of RBC alloimmunization and may therefore serve to identify high-risk patients. The aim of this systematic review was to summarize the available evidence on genetic risk factors for RBC alloimmunization. Electronic databases were searched up to April 2020 for studies (Search terms included transfusion, alloimmunization and genetic). A total of 2581 alloimmunized cases and 26,558 controls were derived from 24 studies. The alleles that were most frequently studied and that demonstrated significant associations in a meta-analysis with alloimmunization to the Duffya antigen were HLA-DRB1*04 (Odds Ratio 7.80 (95%CI 4.57-13.33)), HLA-DRB1*15 (OR 3.76 (95%CI 2.14-6.59)), and HLA-DRB1*03 (OR 0.12 (95%CI 0.05-0.29)). Furthermore, significant associations with anti-K formation was found for the alleles HLA-DRB1*10 (OR 2.64 (95%CI 1.41-4.95)), HLA*DRB1*11 (OR 2.11, (95% CI 1.34-3.32)), and HLA-DRB1*13 (OR 1.71 (95%CI 1.26-2.33)). Overall, the available evidence was of moderate to low quality, hampering interpretation of reported results. There is an urgent need for high quality evidence on genetic risk factors for RBC alloimmunization. Show less
In patients with sickle cell disease (SCD), cerebral blood flow (CBF) is elevated to counteract anemia and maintain oxygen supply to the brain. This may exhaust the vasodilating capacity of the... Show moreIn patients with sickle cell disease (SCD), cerebral blood flow (CBF) is elevated to counteract anemia and maintain oxygen supply to the brain. This may exhaust the vasodilating capacity of the vessels, possibly increasing the risk of silent cerebral infarctions (SCI). To further investigate cerebrovascular hemodynamics in SCD patients, we assessed CBF, arterial transit time (ATT), cerebrovascular reactivity of CBF and ATT (CVRCBF and CVRATT) and oxygen delivery in patients with different forms of SCD and matched healthy controls. We analyzed data of 52 patients with severe SCD (HbSS and HbS beta(0)-thal), 20 patients with mild SCD (HbSC and HbS beta(+)-thal) and 10 healthy matched controls (HbAA and HbAS). Time-encoded arterial spin labeling (ASL) scans were performed before and after a vasodilatory challenge using acetazolamide (ACZ). To identify predictors of CBF and ATT after vasodilation, regression analyses were performed. Oxygen delivery was calculated and associated with hemoglobin and fetal hemoglobin (HbF) levels. At baseline, severe SCD patients showed significantly higher CBF and lower ATT compared to both the mild SCD patients and healthy controls. As CBFpostACZ was linearly related to CBFpreACZ, CVRCBF decreased with disease severity. CVRATT was also significantly affected in severe SCD patients compared to mild SCD patients and healthy controls. Considering all groups, women showed higher CBFpostACZ than men (p < 0.01) independent of baseline CBF. Subsequently, post ACZ oxygen delivery was also higher in women (p < 0.05). Baseline, but not post ACZ, GM oxygen delivery increased with HbF levels. Our data showed that baseline CBF and ATT and CVRCBF and CVRATT are most affected in severe SCD patients and to a lesser extent in patients with milder forms of SCD compared to healthy controls. Cerebrovascular vasoreactivity was mainly determined by baseline CBF, sex and HbF levels. The higher vascular reactivity observed in women could be related to their lower SCI prevalence, which remains an area of future work. Beneficial effects of HbF on oxygen delivery reflect changes in oxygen dissociation affinity from hemoglobin and were limited to baseline conditions suggesting that high HbF levels do not protect the brain upon a hemodynamic challenge, despite its positive effect on hemolysis. Show less
Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a... Show moreLenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% +/- 2% standard error and overall survival, 54% = 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML.In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study. Show less
Ossenkoppele, G.J.; Breems, D.A.; Stuessi, G.; Norden, Y. van; Bargetzi, M.; Biemond, B.J.; ... ; Swiss Grp Clinical Canc Res SAKK 2020
More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might... Show moreMore effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n = 222) to receive standard chemotherapy ("3 + 7") with or without lenalidomide at a dose of 20 mg/day 1-21. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without lenalidomide (20 mg/day 1-21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl). Show less
In sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing... Show moreIn sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing physiologic needs. But hyperemia limits cerebrovascular reserve (CVR) and ischemic risk prevails despite elevated CBF. The cerebral metabolic rate of oxygen (CMRO2) directly reflects oxygen supply and consumption and may therefore be more insightful than flow-based CVR measures for ischemic risk in SCD. We hypothesized that adults with SCD have impaired CMRO2 at rest and that a vasodilatory challenge with acetazolamide would improve CMRO2. CMRO2 was calculated from CBF and oxygen extraction fraction (OEF), measured with arterial spin labeling and T-2-prepared tissue relaxation with inversion recovery (T-2-TRIR) MRI. We studied 36 adults with SCD without a clinical history of overt stroke, and nine healthy controls. As expected, CBF was higher in patients with SCD versus controls (mean +/- SD: 74 +/- 16 versus 46 +/- 5 mL/100 g/min, P < .001), resulting in similar oxygen delivery (SCD: 377 +/- 67 versus controls: 368 +/- 42 mu mol O-2/100g/min, P = .69). OEF was lower in patients versus controls (27 +/- 4 versus 35 +/- 4%, P < .001), resulting in lower CMRO2 in patients versus controls (102 +/- 24 versus 127 +/- 20 mu mol O-2/100g/min, P = .002). After acetazolamide, CMRO2 declined further in patients (P < .01) and did not decline significantly in controls (P = .78), indicating that forcing higher CBF worsened oxygen utilization in SCD patients. This lower CMRO2 could reflect variation between healthy and unhealthy vascular beds in terms of dilatory capacity and resistance whereby dysfunctional vessels become more oxygen-deprived, hence increasing the risk of localized ischemia. Show less
Purpose To compare cerebral blood flow (CBF) and cerebrovascular reserve (CVR) quantification from Turbo-QUASAR (quantitative signal targeting with alternating radiofrequency labeling of arterial... Show morePurpose To compare cerebral blood flow (CBF) and cerebrovascular reserve (CVR) quantification from Turbo-QUASAR (quantitative signal targeting with alternating radiofrequency labeling of arterial regions) arterial spin labeling (ASL) and single post-labeling delay pseudo-continuous ASL (PCASL). Methods A model-based method was developed to quantify CBF and arterial transit time (ATT) from Turbo-QUASAR, including a correction for magnetization transfer effects caused by the repeated labeling pulses. Simulations were performed to assess the accuracy of the model-based method. Data from an in vivo experiment conducted on a healthy cohort were retrospectively analyzed to compare the CBF and CVR (induced by acetazolamide) measurement from Turbo-QUASAR and PCASL on the basis of global and regional differences. The quality of the two ASL data sets was examined using the coefficient of variation (CoV). Results The model-based method for Turbo-QUASAR was accurate for CBF estimation (relative error was 8% for signal-to-noise ratio = 5) in simulations if the bolus duration was known. In the in vivo experiment, the mean global CVR estimated by Turbo-QUASAR and PCASL was between 63% and 64% and not significantly different. Although global CBF values of the two ASL techniques were not significantly different, regional CBF differences were found in deep gray matter in both pre- and postacetazolamide conditions. The CoV of Turbo-QUASAR data was significantly higher than PCASL. Conclusion Both ASL techniques were effective for quantifying CBF and CVR, despite the regional differences observed. Although CBF estimated from Turbo-QUASAR demonstrated a higher variability than PCASL, Turbo-QUASAR offers the advantage of being able to measure and control for variation in ATT. Show less
Sickle cell disease is characterized by chronic hemolytic anemia and vascular inflammation, which can diminish the vasodilatory capacity of the small resistance arteries, making them less adept at... Show moreSickle cell disease is characterized by chronic hemolytic anemia and vascular inflammation, which can diminish the vasodilatory capacity of the small resistance arteries, making them less adept at regulating cerebral blood flow. Autoregulation maintains adequate oxygen delivery, but when vasodilation is maximized, the low arterial oxygen content can lead to ischemia and silent cerebral infarcts. We used magnetic resonance imaging of cerebral blood flow to quantify whole-brain cerebrovascular reserve in 36 adult patients with sickle cell disease (mean age, 31.9 +/- 11.3 years) and 11 healthy controls (mean age, 37.4 +/- 15.4 years), and we used high-resolution 3D FLAIR magnetic resonance imaging to determine the prevalence of silent cerebral infarcts. Cerebrovascular reserve was calculated as the percentage change in cerebral blood flow after a hemodynamic challenge with acetazolamide. Co-registered lesion maps were used to demonstrate prevalent locations for silent cerebral infarcts. Cerebral blood flow was elevated in patients with sickle cell disease compared to controls (median [interquartile range]: 82.8 [20.1] vs. 51.3 [4.8] mL/100g/min, P<0.001). Cerebral blood flow was inversely associated with age, hemoglobin, and fetal hemoglobin, and correlated positively with bilirubin, and LDH, indicating that cerebral blood flow may reflect surrogates of hemolytic rate. Cerebrovascular reserve in sickle cell disease was decreased by half compared to controls (34.1 [33.4] vs. 69.5 [32.4] %, P<0.001) and was associated with hemoglobin and erythrocyte count indicating anemia-induced hemodynamic adaptations. In total, 29/36 patients (81%) and 5/11 controls (45%) had silent cerebral infarcts (median volume of 0.34 vs. 0.02 mL, P=0.03). Lesions were preferentially located in the borderzone. In conclusion, patients with sickle cell disease have a globally reduced cerebrovascular reserve as determined by arterial spin labeling with acetazolamide and reflects anemia-induced impaired vascular function in sickle cell disease. Show less
