Efficacy of non-pharmacological interventions to reduce pain in children with sickle cell disease: A systematic review.

BACKGROUND: Pain is the clinical hallmark of sickle cell disease (SCD) leading to hospitalization, psychological sequelae and a decreased health-related quality of life. The aim of this systematic literature review is to evaluate the efficacy of non-pharmacological interventions in reducing sickle cell related pain in children with SCD. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a comprehensive literature search up until October 2022 was performed to identify studies that investigated the efficacy of non-pharmacological interventions on (1) pain frequency and/or intensity, and (2) analgesic and health service use in children with SCD until the age of 21. Both randomized controlled trials (RCTs) and quasi-experimental designed (QED) studies were considered for inclusion. RESULTS: Ten articles (five RCTs and five QED studies) with 422 participants were included. They investigated cognitive behavioural therapy (CBT) (n = 5), biofeedback (n = 2), massage (n = 1), virtual reality (n = 1) and yoga (n = 1). The majority of the interventions were psychological (n = 7) and were performed in the outpatient clinic (n = 6). CBT and biofeedback significantly reduced frequency and/or intensity of SCD-related pain in outpatient settings, while virtual reality and yoga significantly reduced pain in inpatient settings. Biofeedback also significantly reduced analgesic use. None of the included articles reported reduced health service use. CONCLUSION: Non-pharmacological interventions may be effective in reducing pain in paediatric patients with SCD. However, due to the heterogeneity of the included studies a quantitative analysis could not be performed. Awaiting further supporting evidence, healthcare providers should consider implementing these interventions as valuable part of a comprehensive pain management strategy plan.

Measurement of post-transfusion red blood cell survival kinetics in sickle cell disease and ß-Thalassemia: A biotin label approach.

BACKGROUND: Red blood cell (RBC) transfusions are an important treatment modality for patients with sickle cell disease (SCD) and ß-thalassemia. A subgroup of these patients relies on a chronic RBC transfusion regimen. Little is known about RBC survival (RCS) of the transfused allogeneic RBCs. In this study, we aimed to study the RCS kinetics of transfused RBCs in SCD and ß-thalassemia and to investigate factors that determine RCS. METHODS AND MATERIALS: We performed a prospective cohort study on fourteen adults with SCD and ß-thalassemia disease receiving a chronic transfusion regimen. RCS and the influence of donor and patient characteristics on RCS were assessed by simultaneous transfusion of two allogeneic RBCs using RBC biotinylation. Phenotyping of well-known RBC markers over time was performed using flow cytometry. RESULTS: RCS of the two transfused RBC units was similar in most patients. Although intra-individual variation was small, inter-individual variation in RCS kinetics was observed. Most patients demonstrated a non-linear trend in RCS that was different from the observed linear RCS kinetics in healthy volunteers. After an initial slight increase in the proportion of biotinylated RBCs during the first 24 h, a rapid decrease within the first 10-12 days was followed by a slower clearance rate. CONCLUSION: These are the first data to demonstrate that patient-related factors largely determine post-transfusion RCS behavior of donor RBC in SCD and ß-thalassemia, while donor factors exert a negligible effect. Further assessment and modeling of RCS kinetics and its determinants in SCD and ß-thalassemia patients may ultimately improve transfusion therapy.

Extended phenotyping does not preclude the occurrence of delayed haemolytic transfusion reactions in sickle cell disease.

Delayed haemolytic transfusion reaction (DHTR) is a potentially life-threatening complication of red blood cell (RBC) transfusions in sickle cell disease (SCD) and is classically induced by reactivation of previously formed antibodies. Improved antigenic matching has reduced alloimmunization and may reduce DHTR risk. We conducted a retrospective cohort study to investigate the incidence rate of DHTR in SCD patients receiving extended matched units (ABO/RhDCcEe/K/Fya /Jkb /S). Occasional transfusion episodes (OTE) between 2011 and 2020 were reviewed for occurrence of DHTR symptoms using four screening criteria: decreased Hb, increased lactate dehydrogenase (LDH), pain, and dark urine. We included 205 patients who received a cumulative number of 580 transfusion episodes of 1866 RBC units. During follow-up, 10 DHTR events were observed. The incidence rate of DHTR was 13·8/1000 OTEs [95% confidence interval (CI): 7·37-22·2], with a cumulative incidence of 15·2% (95% CI: 8·4-24·0%) after 25 patients having received RBC units. One DHTR event was fatal (10%). Symptoms were misdiagnosed in four DHTR events (40%) as other acute SCD complications. Despite a lower incidence rate compared to most other studies, the incidence rate of DHTR in SCD remains high, in spite of extended matching of donor RBCs. Increased awareness of DHTR is of utmost importance to facilitate early diagnosis and, consequently, improve outcome.

Fluid overload due to intravenous fluid therapy for vaso-occlusive crisis in sickle cell disease: incidence and risk factors.

Intravenous fluid therapy (IV-FT) is routinely used in the treatment of vaso-occlusive crises (VOCs), as dehydration possibly promotes and sustains erythrocyte sickling. Patients with sickle cell disease (SCD) are at risk of developing diastolic dysfunction and fluid overload due to IV-FT. However, data on the adverse effects of IV-FT for VOC is sparse. We aimed to evaluate the incidence and risk factors of fluid overload due to IV-FT in patients with SCD. Consecutive hospitalisations for VOC treated with IV-FT between September 2016 and September 2018 were retrospectively analysed. The median (interquartile range) age was 25·0 (18·3-33·8) years and 65% had a severe genotype (HbSS/HbSß0 -thal). Fluid overload occurred in 21% of 100 patients. Hospital stay was longer in patients with fluid overload (6·0 vs. 4·0 days, P = 0·037). A positive history of fluid overload (P = 0·017), lactate dehydrogenase level (P = 0·011), and top-up transfusion during admission (P = 0·005) were independently associated with fluid overload occurrence. IV-FT was not reduced in 86% of patients despite a previous history of fluid overload. Fluid overload is frequently encountered during IV-FT for VOC. IV-FT is often not adjusted despite a positive history of fluid overload or when top-up transfusion is indicated, emphasising the need for more awareness of this complication and a personalised approach.

Identification of genetic biomarkers for alloimmunization in sickle cell disease.

Most sickle cell disease (SCD) patients rely on blood transfusion as their main treatment strategy. However, frequent blood transfusion poses the risk of alloimmunization. On average, 30% of SCD patients will alloimmunize while other patient groups form antibodies less frequently. Identification of genetic markers may help to predict which patients are at risk to form alloantibodies. The aim of this study was to evaluate whether genetic variations in the Toll-like receptor pathway or in genes previously associated with antibody-mediated conditions are associated with red blood cell (RBC) alloimmunization in a cohort of SCD patients. In this case-control study, cases had a documented history of alloimmunization while controls had received ≥20 RBC units without alloantibody formation. We used a customized single nucleotide polymorphism (SNP) panel to genotype 690 SNPs in 275 (130 controls, 145 cases) patients. Frequencies were compared using multiple logistic regression analysis. In our primary analysis, no SNPs were found to be significantly associated with alloimmunization after correction for multiple testing. However, in a secondary analysis with a less stringent threshold for significance we found 19 moderately associated SNPs. Among others, SNPs in TLR1/TANK and MALT1 were associated with a higher alloimmunization risk, while SNPs in STAM/IFNAR1 and STAT4 conferred a lower alloimmunization risk.

Do Children and Adolescents With Inflammatory Bowel Disease Complete Clinical Disease Indices Similar to Physicians?

OBJECTIVES: The degree to which children and adolescents with inflammatory bowel disease (IBD) complete clinical disease activity indices in accordance with their physician is indefinite. Therefore, we investigated the agreement between patient- and physician-based clinical indices in children and adolescents with a previous diagnosis of IBD. METHODS: In this cross-sectional study, IBD patients (8-18 years) were included prospectively. Patients completed a patient-based short Pediatric Crohn's Disease Activity Index (shPCDAI) for Crohn disease or the Pediatric Ulcerative Colitis Activity Index (PUCAI) for ulcerative or indeterminate colitis. Physicians completed the original physician-based shPCDAI or PUCAI. Agreement was calculated with linear weighted kappa. RESULTS: In total, 154 pairs of clinical indices were collected: 89 pairs of shPCDAI's (median age at assessment 15.6 years, 61% men) and 55 pairs of PUCAI's (median age at assessment 14.0 years, 44% men). The shPCDAI disease activity category only fairly agreed between patient- and physician-based indices (kappa: 0.40 [95% confidence interval 0.24-0.55], P < 0.001), with perfect agreement in 58% of pairs. In the majority of disagreement (81%), patients scored in a higher shPCDAI disease activity category. The PUCAI disease activity category substantially agreed between patient- and physician-based indices (kappa: 0.64 [95% confidence interval 0.45-0.83], P < 0.001), with perfect agreement in 78% of pairs. In the majority of disagreement (75%), patients scored in a higher PUCAI disease activity category. CONCLUSIONS: Patient- and physician-based shPCDAI and PUCAI do not always agree, particularly the shPCDAI, and therefore, should not be interpreted equivalently in management and research on children and adolescents with IBD.

Isolated cortical vein thrombosis: systematic review of case reports and case series.

BACKGROUND AND PURPOSE: Isolated cortical vein thrombosis is a distinct subtype of cerebral venous and sinus thrombosis. Because of the rarity of isolated cortical vein thrombosis, limited knowledge on its clinical and radiological manifestations is available. METHODS: We performed a systematic review of published data. Isolated cortical vein thrombosis had to have been diagnosed by MRI, conventional angiography, computed tomography venography, autopsy, or surgery. Cases with concurrent thrombosis of a cerebral sinus were excluded. RESULTS: Of 175 potentially relevant studies, 47 were included in the analysis, with a total of 116 patients. All studies were case reports and case series. Mean age was 41 years and 68% were women. The most common symptoms were headache (71%), seizures (58%), and focal neurological deficits (62%). Papilledema was not reported in any patient, and increased cerebrospinal fluid pressure was reported only in 2. Infection (19%), pregnancy or puerperium (35% of women), and oral contraceptive use (21% of women) were the most common risk factors. Most cases (73%) were diagnosed with MRI, but conventional angiography was also performed in 47%. A total of 81% had a parenchymal brain lesion and 80% were treated with anticoagulation. In-hospital mortality was 6%. CONCLUSIONS: Signs of increased intracranial pressure seem to be less common in isolated cortical vein thrombosis compared with cerebral venous and sinus thrombosis. MRI and in some cases conventional angiography are the most frequently used diagnostic modalities and anticoagulation is the most widely used therapy.