[Multidisciplinary management of diabetic foot ulcer infection]. / Prise en charge multidisciplinaire de l'infection de l'ulcération plantaire diabétique.

Infection is one of the most common complications of diabetic foot ulceration resulting in lower extremity amputations and early mortality in this population. Several factors influence the course of diabetic foot ulceration infection and in that context, integrated multidisciplinary management is required as soon as possible. In fact, a holistic interdisciplinary approach should be the standard of care. Whether the infection is categorized as mild, moderate or severe, with or without bone infection, the overall individual's characteristics must be addressed, in addition to local wound care, offloading and antibiotic therapy. Some severe infections have potential indications for hospitalization and are considered as surgical emergencies. In some DFU cases, surgical revascularization of the limb is mandatory to treat the infection. However, surgical interventions and amputations, are sometimes inevitable, they are predictors of bad prognosis. Although some adjuvant therapies are effective to promote wound healing, their use is not recommended to treat diabetic foot ulcer infection. Infection management can be divided into three general interventions: proper clinical diagnosis, microbiological and imaging investigations, and treatment. This review is an update on the up-to-date evidences in scientific literature and includes the latest recommendations from the International Working Group on the Diabetic Foot (IWGDF).

Baseline characteristics and outcomes of children with cancer in the English-speaking Caribbean: A multinational retrospective cohort.

BACKGROUND: English-speaking Caribbean (ESC) childhood cancer outcomes are unknown. PROCEDURE: Through the SickKids-Caribbean Initiative (SCI), we established a multicenter childhood cancer database across seven centers in six ESC countries. Data managers entered patient demographics, disease, treatment, and outcome data. Data collection commenced in 2013, with retrospective collection to 2011 and subsequent prospective collection. RESULTS: A total of 367 children were diagnosed between 2011 and 2015 with a median age of 5.7 years (interquartile range 2.9-10.6 years). One hundred thirty (35.4%) patients were diagnosed with leukemia, 30 (8.2%) with lymphoma, and 149 (40.6%) with solid tumors. A relative paucity of children with brain tumors was seen (N = 58, 15.8%). Two-year event-free survival (EFS) for the cohort was 48.5% ± 3.2%; 2-year overall survival (OS) was 55.1% ± 3.1%. Children with acute lymphoblastic leukemia (ALL) and Wilms tumor (WT) experienced better 2-year EFS (62.1% ± 6.4% and 66.7% ± 10.1%), while dismal outcomes were seen in children with acute myeloid leukemia (AML; 22.7 ± 9.6%), rhabdomyosarcoma (21.0% ± 17.0%), and medulloblastoma (21.4% ± 17.8%). Of 108 deaths with known cause, 58 (53.7%) were attributed to disease and 50 (46.3%) to treatment complications. Death within 60 days of diagnosis was relatively common in acute leukemia [13/98 (13.3%) ALL, 8/26 (30.8%) AML]. Despite this, traditional prognosticators adversely impacted outcome in ALL, including higher age, higher white blood cell count, and T-cell lineage. CONCLUSIONS: ESC childhood cancer outcomes are significantly inferior to high-income country outcomes. Based on these data, interventions for improving supportive care and modifying treatment protocols are under way. Continued data collection will allow evaluation of interventions and ensure maximal outcome improvements.

The Jamaican Haemophilia Registry: Describing the burden of disease.

INTRODUCTION: Jamaica has an estimated 200 persons with haemophilia (PWH), who face significant constraints in access to specialized haemophilia care, including access to clotting factor concentrates. AIM: The aim of this paper is to establish the current burden of disease in PWH in Jamaica. METHODS: PWH were enrolled through the University Hospital of the West Indies, Jamaica. The impact of haemophilia was assessed using a comprehensive battery of heath outcome measures that included the following: laboratory, clinical information and validated outcome measures of joint structure and function, activity, and health-related quality of life (HRQoL) to provide a health profile of the Jamaican haemophilia population. RESULTS: In all, 45 PWH were registered (mean age: 29, range: 0.17-69 years), including 13 children (<18 years of age) and 32 adults. In this sample, 41 had haemophilia A (30 severe) and 4 had haemophilia B (3 severe); 10 patients with haemophilia A were inhibitor positive. The results indicate that adults with haemophilia in Jamaica have significant joint damage: mean Haemophilia Joint Health Score (HJHS) = 42.1 (SD = 17.3); moderate activity levels - mean Haemophilia Activities List (HAL) score = 64.8 (SD = 17.8); and low HRQoL scores - mean Haemo-QoL-A score = 62.3 (SD = 19.4). Results for children are also reported but should be interpreted with caution due to the small sample size. CONCLUSIONS: There is a very high burden of disease in PWH in Jamaica. The health profiles reported in this paper are an essential first step in advocating for a multidisciplinary Comprehensive Care Program for assessment and care of PWH in Jamaica.

Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII.

INTRODUCTION: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. AIM: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. METHODS: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. RESULTS: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. CONCLUSION: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

Defining extended half-life rFVIII-A critical review of the evidence.

INTRODUCTION: Recent haemophilia treatment advances include new recombinant FVIII (rFVIII) products with improved pharmacokinetic (PK) properties that aim to reduce the burden of prophylaxis. These treatments are commonly referred to as extended half-life rFVIII products (EHL rFVIII). There is no uniform definition of what constitutes an EHL rFVIII. Such a definition would help physicians, patients and funders understand the properties of standard and EHL rFVIIIs and thus provide clarity when selecting an EHL in clinical settings. AIM: To critically assess the published evidence on new and emerging rFVIII products in order to propose a definition to classify EHL rFVIIIs. METHODS: We systematically searched PubMed, EMBASE and regulatory authorities (FDA/EMA/Health Canada) websites for publications and regulatory submissions describing prospective crossover PK studies evaluating rFVIIIs that demonstrate improved PK parameters in adults and adolescents with severe haemophilia A. RESULTS: Following critical analyses of the published data, we developed a holistic approach to defining rFVIIIs as EHLs, which requires all of the following: (i) using technology designed to extend rFVIII half-life; (ii) lacking bioequivalence with a standard rFVIII comparator-above the FDA/EMA cut-off of 125% for the 90% confidence intervals for area under the curve ratio; and (iii) having an extended half-life ratio measured in a PK comparator crossover study. CONCLUSION: In this systematic review, a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussions surrounding the appropriate use of rFVIII products. At present, only products using PEGylation or Fc fusion half-life extension technology meet the proposed criteria for definition of EHL rFVIII.

Describing the quality of life of boys with haemophilia in China: Results of a multicentre study using the CHO-KLAT.

INTRODUCTION: The treatment of haemophilia varies across countries and across regions within some countries. Similar variation has been observed in health-related quality of life (HR-QoL). Relatively little is known about the HR-QoL of boys with haemophilia in China. AIM: The aim of this study was to describe the HR-QoL of boys with haemophilia in China using the Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT). METHODS: Boys (4-18 years of age) with haemophilia and their parents were enroled in a cross-sectional study. All parents/guardians of study subjects were requested to complete a CHO-KLAT questionnaire during a clinic visit, and report on several other clinical and socioeconomic factors in the past year. Boys who were > 7 years also completed the CHO-KLAT. RESULTS: A total of 269 parents of boys with haemophilia, from 13 hospitals in 12 provinces, were enroled during 2014. The boys ranged from 4.0 to 17.9 years of age; 91% had haemophilia A, most had moderate (52%) or severe (36%) disease, and most were receiving sub-optimal on-demand therapy or low-dose prophylactic therapy. Child self-report CHO-KLAT scores were available for 171 boys ≥7 years of age and ranged from 24.2 to 85.3 with a mean of 57.6 (n = 171). Parent proxy-reported CHO-KLAT scores ranged from 25.0 to 88.7 with a mean of 55.1 (n = 269). CONCLUSION: HR-QoL scores in boys with haemophilia in China were substantially lower than reported from Canadian and European boys with haemophilia. Longer term prospective studies are required to examine the factors impacting the HR-QoL for boys with haemophilia in China.

Measuring activities and participation in persons with haemophilia: A systematic review of commonly used instruments.

INTRODUCTION: Monitoring clinical outcome in persons with haemophilia (PWH) is essential in order to provide optimal treatment for individual patients and compare effectiveness of treatment strategies. Experience with measurement of activities and participation in haemophilia is limited and consensus on preferred tools is lacking. AIM: The aim of this study was to give a comprehensive overview of the measurement properties of a selection of commonly used tools developed to assess activities and participation in PWH. METHODS: Electronic databases were searched for articles that reported on reliability, validity or responsiveness of predetermined measurement tools (5 self-reported and 4 performance based measurement tools). Methodological quality of the studies was assessed according to the COSMIN checklist. Best evidence synthesis was used to summarize evidence on the measurement properties. RESULTS: The search resulted in 3453 unique hits. Forty-two articles were included. The self-reported Haemophilia Acitivity List (HAL), Pediatric HAL (PedHAL) and the performance based Functional Independence Score in Haemophilia (FISH) were studied most extensively. Methodological quality of the studies was limited. Measurement error, cross-cultural validity and responsiveness have been insufficiently evaluated. CONCLUSION: Albeit based on limited evidence, the measurement properties of the PedHAL, HAL and FISH are currently considered most satisfactory. Further research needs to focus on measurement error, responsiveness, interpretability and cross-cultural validity of the self-reported tools and validity of performance based tools which are able to assess limitations in sports and leisure activities.

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein.

INTRODUCTION: Joint arthropathy is the long-term consequence of joint bleeding in people with severe haemophilia. AIM: This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis. METHODS: ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25-65 IU/kg every 3-5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients. RESULTS: Forty-seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A-LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A-LONG baseline (23.4), mean improvement at ASPIRE Year 2 was -4.1 (95% confidence interval [CI], -6.5, -1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A-LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: -2.4, P = .09; prestudy episodic treatment: -7.2, P = .003). Benefits were seen in subjects with target joints (-5.6, P = .005) as well as those with severe arthropathy (-8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (-1.4, P = .008), range of motion (-1.1, P = .03) and strength (-0.8, P = .04). CONCLUSIONS: Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.

Imaging of haemophilic arthropathy in growing joints: pitfalls in ultrasound and MRI.

The purpose of this review was to summarize the current knowledge on the utilization of magnetic resonance imaging (MRI) and ultrasound (US) for assessing arthropathy in children and adolescents with haemophilia and to recognize the limitations of each imaging modality and pitfalls in the diagnosis of soft tissue and osteochondral abnormalities. Awareness of MRI and US limitations and pitfalls in the assessment of joints in persons with haemophilia is essential for accurate diagnosis and optimal management of haemophilic arthropathy.

Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the São Paulo-Toronto Hemophilia Study.

INTRODUCTION: Although the regular replacement of clotting factor concentrates (prophylaxis) has been well established as the standard of care for severe haemophilia, the high cost of factor concentrates has limited access to prophylaxis in countries with under-developed or developing economies. AIMS: We studied the health gap that could be addressed by providing unlimited access to clotting factor concentrates with implementation of long-term prophylaxis initiated from an early age in life. METHODS: We performed a cross-sectional study of a random, representative sample of boys with moderate and severe haemophilia at three haemophilia treatment centres in Sao Paulo, Brazil, and one centre in Toronto, Canada. RESULTS: Canadian subjects were more often treated with prophylaxis, and began treatment at an earlier age. Fewer Canadian subjects had bleeds within the preceding 6 months (19 vs. 34, P = 0.003). Canadian subjects had lower (better) Pettersson radiographic scores (1.5 vs. 6.0, P = 0.0016), lower (better) Hemophilia Joint Health Scores (5.5 vs. 10.5, P = 0.0038), higher (better) Activity Scale for Kids scores (96.6 vs. 92.0, P = 0.033), more time spent in vigorous activity, and higher (better) social participation scores. CONCLUSIONS: Our findings suggest that increasing access to clotting factor concentrates for young boys with severe haemophilia is a global imperative.

Health-related quality of life questionnaires in individuals with haemophilia: a systematic review of their measurement properties.

BACKGROUND: The evaluation of health related quality of life (HRQOL) is essential for a full assessment of the influence of an illness on patients' lives. The aim of this paper is to critically appraise and compare the measurement properties of HRQOL questionnaires studied in haemophilia. METHODS: Bibliographic databases (Embase, Medline, Cinahl and PsycInfo) were searched for articles evaluating measurement properties of HRQOL questionnaires in haemophilia. Articles were excluded that did not report HRQOL measurement properties, or when <50% of the study population had haemophilia. The methodological quality of the selected studies was evaluated using the COSMIN checklist. The measurement properties of the HRQL questionnaires were rated as 'positive', 'indeterminate' or 'negative', accompanied by levels of evidence. RESULTS: The search resulted in 1597 unique hits, of which 22 studies were included. These articles evaluated three questionnaires for children (CHO-KLAT, Haemo-QoL and one unnamed measure) and five for adults (Hemofilia-QoL, Haemophilia Well-Being Index, HAEMO-QoL-A, Haem-A-QoL, and SF-36). The CHO-KLAT was the paediatric measure that showed the strongest measurement properties in high-quality studies. The Haemophilia Well-Being Index and HAEMO-QoL-A performed best among the adult measures. None of the studies reported measurement error and responsiveness. CONCLUSION: Our findings suggest that there is no need for new disease-specific HRQOL questionnaires for haemophilia, but rather that additional research is necessary to document the measurement properties of the currently available questionnaires, specifically focusing on the structural validity, measurement error and responsiveness of these questionnaires.

A systematic review of ultrasound imaging as a tool for evaluating haemophilic arthropathy in children and adults.

The purpose of this study was to semi-quantitatively assess the evidence on the value of ultrasound (US) for assessment of haemophilic arthropathy (HA) in children and adults based on the following questions: (1) Does early diagnosis of pathological findings, using available US techniques, impact the functional status of the joint? (2) Do current available US techniques have the ability to accurately detect pathological changes in target joints in haemophilic patients? (3) Does treatment (prophylaxis) improve US evidence of haemophilic arthropathy in children and adults? (4) Is there any association between various US scoring systems and other clinical/radiological constructs? Of the 6880 citations identified searching databases such as MEDLINE, Embase, CENTRAL and Web of Science, 20 articles investigating either the diagnostic accuracy of US and/or US scanning protocols and scoring systems for assessment of HA met the inclusion criteria for the study. Of these, 14 articles evaluating the diagnostic accuracy of US were assessed by two independent reviewers for reporting quality using the Standards for Reporting of Diagnostic Accuracy (STARD) tool and for methodological quality using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Using STARD, 1/14 studies (7%) was scored as of high reporting quality and 8/14 (57%), of moderate quality. Assessment with QUADAS-2 reported 2/14 (14%) studies as having high methodological quality and 6/14 (43%) as having moderate quality. There is fair evidence (Grade B) to recommend US as an accurate technique for early diagnosis of HA, to demonstrate that US scores correlate with clinical/US constructs and to prove an association between US findings and functional status of the joint. However, there is insufficient evidence (Grade I) to conclude that US-detectable findings in HA are sensitive to changes in therapy.

Target plasma factor levels for personalized treatment in haemophilia: a Delphi consensus statement.

BACKGROUND: Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient-tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients' bleeding phenotype, levels of physical activity and a variety of other variables. METHODS: A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations. RESULTS: Twenty-eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended. CONCLUSIONS: We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia.

A prospective study of health-related quality of life of boys with severe haemophilia A in China: comparing on-demand to prophylaxis treatment.

INTRODUCTION: Treatment for boys with haemophilia in China is rapidly improving; however, comprehensive outcomes have not been examined prospectively. AIM: The aim of this study was to evaluate the effect of short-term full-dose prophylaxis compared to on-demand treatment, on the Health-Related Quality of Life (HR-QoL) of boys with severe haemophilia A (HA) in China. METHODS: Boys with severe HA (FVIII<1%) completed 3 months of on-demand treatment and 3 months of full-dose prophylaxis (25 FVIII IU per kg 3x per week). The primary outcomes were child- and parent-reported Canadian Hemophilia Outcomes - Kids Life Assessment Tool (CHO-KLAT) scores. The number and type of bleeds and Activities Scale for Kids (ASK) scores were also recorded. RESULTS: Analyses included 23 boys between 4 and 15.9 years of age. The number of bleeds decreased by 94% on prophylaxis (P < 0.0001, Wilcoxon Signed-Rank test). The mean child-reported CHO-KLAT scores for boys ≥7 years (n = 20) was 61.4 (±10.9) during on-demand treatment and 61.9 (±11.4) following short-term prophylaxis (P = 0.72, paired t-test). The mean parent-reported CHO-KLAT score during the on-demand phase was 54.4 (±10.5) with an increase of 3.8 points (±8.1; P = 0.04, paired t-test) following prophylaxis. CONCLUSIONS: Child-reported CHO-KLAT scores were lower in boys with severe HA in China than reported in countries with access to full-dose prophylaxis. Boys reported higher HR-QoL scores than their parents. Small improvements in ASK scores were noted following the prophylaxis phase. These changes were only significant in the parent-reported CHO-KLAT scores. Longer term prospective clinical trials are needed in China to determine the impact of prophylaxis on HR-QoL in boys with severe HA.

Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective.

INTRODUCTION: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens. AIMS: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. METHODS: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. RESULTS AND CONCLUSION: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment.