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.

Impact of hospitalization for vaso-occlusive crisis on health-related quality of life in children with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) that impair the health-related quality of life (HRQoL). The aim of this study is to evaluate the impact of hospitalization for VOCs on HRQoL in children with SCD over time. METHODS: In this longitudinal cohort study, children aged 8-18 years diagnosed with SCD at the Amsterdam UMC were included between 2012 and 2021. HRQoL was annually measured as part of standard care using the Pediatric Quality of Life Inventory. The impact of hospitalization for VOC on HRQoL was evaluated using linear mixed models 3, 6, 9, and 12 months after hospitalization. The effect of frequency of hospitalization for VOC on HRQoL was evaluated over the last 12 months. RESULTS: In total, 94 children with SCD were included with a median age of 11.8 years (interquartile range [IQR]: 9-14). Thirty-seven patients (39%) had been hospitalized for a VOC. Hospitalization for VOC led to a decrease of 3.2-4.8 points in total HRQoL compared to patients without hospitalization, most pronounced 3 months after hospitalization. Recurrent admission for VOC in the last 12 months was associated with a decrease of 2.3 points in total HRQoL (p = .04). The most affected subscale was physical functioning. CONCLUSION: The adverse effects of hospitalization for VOC in children with SCD persist up to 12 months after hospitalization. After hospitalization for VOC, extra attention and support for its negative impact on HRQoL are recommended. This study also underlines the importance of systematically measuring HRQoL, allowing clinicians to intervene accordingly.

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.

Product type and the risk of inhibitor development in nonsevere haemophilia A patients: a case-control study.

Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case-control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case-control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2-40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0·96, 95% confidence interval (CI) 0·36-2·52) or for specific types of FVIII concentrates.

Emerging Issues in Diagnosis, Biology, and Inhibitor Risk in Mild Hemophilia A.

Mild hemophilia A (MHA) is an X-linked bleeding disorder defined by factor VIII (FVIII) levels between 5 and 40 U/dL. Diagnosis occurs later in life compared with severe or moderate disease. Although bleeding episodes are especially posttraumatic, their unexpected occurrence may be potentially life threatening if diagnosis is missed or delayed. Desmopressin is the treatment of choice for MHA since it is cheap and safe, but a significant proportion of cases do not attain FVIII postinfusion greater than 50 U/dL, which is considered a safe level for major surgery. Thus, replacement therapy may be needed and is usually successful in MHA, but recent data indicate that this can be associated with the occurrence of inhibitors against FVIII, as for severe hemophilia A. However, in contrast to severe or moderate hemophilia A, patients with MHA have a lifelong risk of inhibitor formation. Inhibitors may change the clinical phenotype dramatically, as the inhibitor frequently cross-reacts with the patient's endogenous FVIII, reducing the endogenous FVIII plasma levels below 1 U/dL. Specific F8 missense mutations predispose to inhibitor development. Inhibitors are frequently provoked by intensive treatment with therapeutic FVIII concentrates (more than 5 consecutive exposure days). Bleeding in inhibitor patients may be treated with desmopressin, high doses of FVIII concentrate or FVIII bypassing agents. Many inhibitors disappear over time when no FVIII concentrate is administered. However, this does not imply that a patient is tolerant and an anamnestic reaction may occur when treatment with FVIII concentrate is again necessary. To eradicate, an inhibitor different strategies may be used: watchful waiting, immunosuppression, or immune tolerance induction regimen.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Inhibitor incidence after intensive FVIII replacement for surgery in mild and moderate haemophilia A: a prospective national study in the Netherlands.

Inhibitor development is currently the most severe complication in mild/moderate haemophilia A patients, causing increased bleeding tendency, hospitalization and mortality. It has been suggested that receiving high doses of factor VIII (FVIII) concentrates for surgical procedures is an important risk factor for inhibitor development in these patients. The current multicentre study aimed to determine prospectively the incidence of inhibitor development after intensive FVIII replacement therapy for surgical procedures in patients with mild/moderate haemophilia A. All consecutive patients with mild/moderate haemophilia A were included when they required at least 10 000 iu of FVIII concentrates (or 250 iu/kg) for 5 or more days for a surgical procedure. Potential clinical risk factors for inhibitor development and results of inhibitor tests were collected. Forty-six patients with a median age of 54 years (interquartile range, 40-59 years) were included in the study. F8 genotyping revealed 20 different missense mutations. Patients received either recombinant (65%) or plasma-derived FVIII concentrates (35%) by intermittent bolus injections (41%) or continuous infusion (57%). Two patients developed a low titre inhibitor post-operatively. The incidence of inhibitor development following intensive treatment for surgery in this unselected prospective cohort of mild/moderate haemophilia A patients was 4% (95% confidence interval, 0·5-14·8).

Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study.

Background: Severe multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA). Methods: We conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach. Results: In 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF. Conclusion: We conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study.

BACKGROUND: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). OBJECTIVES: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. PATIENTS/METHODS: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. RESULTS: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. CONCLUSIONS: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

The factor VIII treatment history of non-severe hemophilia A.

BACKGROUND: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. OBJECTIVE: To assess the FVIII treatment history in patients with non-severe hemophilia A. METHODS: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). RESULTS: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. CONCLUSION: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur.

The incidence and treatment of bleeding episodes in non-severe haemophilia A patients with inhibitors.

The development of an inhibitory antibody in non-severe haemophilia A patients may aggravate the bleeding phenotype considerably. Effective treatment of bleeding episodes may be challenging, with ensuing severe complications. At present, evidence is scarce for optimal treatment of bleeding episodes in this patient group. The aim of this study was to describe the incidence and the treatment of bleeding episodes in inhibitor patients in a population-based unselected cohort of non-severe haemophilia A patients with clinically relevant inhibitors. Data were available for 100 of the 107 non-severe haemophilia A patients (factor VIII (FVIII) baseline, 2-40 IU/dl) from 29 centres in Europe and one centre in Australia who had developed a clinically relevant inhibitor between 1980 and 2011. The majority (89 %) of the patients were treated during the inhibitor period for bleeding episodes or a surgical intervention: 66 % needed treatment for bleeding episodes, at a median annual bleeding rate (ABR) of 1.1 (interquartile range (IQR) 0.1-2.5) and a median total of 2 (IQR 1-6) bleeding episodes. Compared to the median ABR before inhibitor development of 0.095 bleeds per year (IQR 0.02-0.42), the increase in ABR is more than a 10-fold. More than 90 % of the bleeding episodes were treated with only one type of product, most frequently (51 %) FVIII concentrates. This study provides the incidence of bleeding episodes and treatment choices in non-severe haemophilia A patients with inhibitors. The 10-fold increase to a median ABR of 1.1 episodes per year emphasizes the impact of inhibitor development for non-severe haemophilia A patients.

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies.

In nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2-40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15-60; median peak titre 7 BU/ml, IQR 2-30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3-4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.