The impact of obesity on chronic oedema/lymphoedema of the leg - an international multicenter cross-sectional study (LIMPRINT).

BACKGROUND/OBJECTIVES: Obesity and chronic oedema/lymphoedema are two distinct but related conditions, rarely investigated together. The aim was to study the impact of increased weight on chronic oedema and related factors. SUBJECTS/METHODS: A cross-sectional study, 38 centers, nine countries. Patients with clinically confirmed chronic oedema/lymphoedema of the leg were included. Weight category was estimated as: normal weight (BMI 20-30), class I-II obesity (BMI 30-40), or class III obesity (BMI > 40). Factors were tested for an association with increased weight, using a multivariable model. RESULTS: A total of 7397 patients were included; 43% with normal weight, 36% class I-II obesity and 21% class III obesity. Increased weight was associated with more advanced stages of chronic oedema (ISL stage III; the most advanced form); affecting 14% in normal weight, 18% class I-II obesity and 39% class III obesity (p < 0.001). Ten factors were independently associated with increased weight: diabetes (OR 2.4), secondary lymphoedema (OR 2.7), cellulitis/erysipelas within 12 months (OR 1.2), bilateral lymphoedema (OR 3.6), compression therapy (OR 2.1), increased swelling duration (1-2 years OR 1.3, 2-5 years OR 2.5, 5-10 years OR 3.6, >10 years OR 3.5) decreased mobility (walking with aid OR 1.9, being chair bound OR 1.2) and age (reference<45 years; 45-64 years OR 1.5, 75-84 years OR 0.6, 85+ years OR 0.2). Increased weight was associated with a lower presentation of peripheral arterial disease (OR 0.7) and poorer chronic oedema control (OR 0.8). Patients with obesity had lower function, appearance and more severe symptoms (LYMQOL) and lower quality of life (EuroQol). CONCLUSIONS: Obesity negatively impacts chronic oedema, leading to more advanced stages. Achieving good control of swelling with compression is more difficult in these patients. Increased awareness of chronic oedema/lymphoedema as a complication of obesity is important for early detection and for developing effective strategies to prevent and manage them.

Topical oxygen therapy and singlet oxygen in wound healing: A scoping review.

The aim of this scoping review was to provide an overview of current research into topical oxygen therapies including the under-researched singlet oxygen for wound healing. A scoping review was undertaken using five databases. After duplicates and ineligible studies were excluded, 49 studies were included for a narrative review. Out of the included 49 studies, 45 (91.8%) were published in the past 10 years (2013-2023) with 32 (65.3%) published in the past 5 years (2018-2023). Eight of the studies were systematic reviews and/or meta-analysis and 18 were RCTs. The search identified zero human RCTs on singlet oxygen, but one human cohort study and five studies in animals. There is evidence that topical oxygen therapy may be useful for the treatment of chronic wounds, mainly diabetic foot ulcers. Singlet oxygen has shown potential, but would need further confirmation in controlled human trials, including more research to understand the bio-properties.

Factors associated with cellulitis in lymphoedema of the arm - an international cross-sectional study (LIMPRINT).

BACKGROUND: Lymphoedema is a globally neglected health care problem and a common complication following breast cancer treatment. Lymphoedema is a well-known predisposing factor for cellulitis, but few have investigated the risk factors for cellulitis in this patient cohort on an international level. The aim of this study was to identify the frequency of cellulitis in patients with lymphoedema of the arm, including potential risk factors for cellulitis. METHODS: An international, multi-centre, cross-sectional study including patients with clinically assessed arm lymphoedema. The primary outcome was the incidence of cellulitis located to the arm with lymphoedema within the last 12 months, and its potential associated risk factors. The secondary outcome was life-time prevalence of cellulitis. Adults with clinically-assessed arm lymphoedema/chronic oedema (all causes) and able to give informed consent were included. End-of-life-patients or those judged as not in the patient's best interest were excluded. Both univariable and multivariable analysis were performed. RESULTS: A total of 2160 patients were included from Australia, Denmark, France, Ireland, Italy, Japan, Turkey and United Kingdom. Secondary lymphoedema was present in 98% of the patients; 95% of these were judged as related to cancer or its treatment. The lifetime prevalence of cellulitis was 22% and 1-year incidence 11%. Following multivariable analysis, factors associated with recent cellulitis were longer swelling duration and having poorly controlled lymphoedema. Compared to having lymphoedema less than 1 year, the risk increased with duration: 1-2 years (OR 2.15), 2-5 years (OR 2.86), 5-10 years (OR 3.15). Patients with well-controlled lymphoedema had a 46% lower risk of cellulitis (OR 0.54, 95% CI 0.39-0.73, p < 0.001). More advanced stages of lymphoedema were associated with cellulitis even after adjustment for swelling duration and control of swelling by logistic regression (stage II OR 5.44, stage III OR 9.13, p = 0.002), demonstrated in a subgroup analysis. CONCLUSION: Patients with advanced arm lymphoedema are at particular risk of developing cellulitis. Prevention of lymphoedema progression is crucial. The results lend towards a positive effect of having well-treated lymphoedema on the frequency of cellulitis.

Prevalence and characteristics of pain in patients with lower-extremity ulcers-A cross-sectional study.

The study aimed to investigate the prevalence and characteristics of pain in different ulcer types and to identify factors associated with pain experience in patients with lower-extremity ulcers. A cross-sectional single-centre study was performed, including 130 newly referred outpatients with lower-extremity ulcers. Pain intensity was measured with a visual analog scale (VAS) and pain characteristics with the short form mcgill pain questionnaire-2 (SF-MPQ-2). The mean pain intensity was 29.5 (SD 31.8) at rest and 35.5 (SD 34.1) during movement (0-100 VAS). 61.5% of the patients experienced pain (VAS > 0) at rest and 70.8% during movement. Moderate to severe pain at rest was seen in 39.2% and in 43.8% of patients during movement. The mean total score on SF-MPQ-2 (range 0-220) was 35.9 (SD 32.6). Most of the patients described pain as intermittent (mean 11.8 SD 13.9). Analgesics were prescribed for 78% of the patients. Ulcer type (i.e., arterial, immunological, pressure and venous) and age were associated with pain severity, and women had a significantly lower well-being score than men. Prevalence of pain in patients with lower-extremity ulcers was high across different ulcer aetiologies. Pain intensity and quality must be assessed to obtain adequate pain management.

The Safety and Antimicrobial Properties of Stabilized Hypochlorous Acid in Acetic Acid Buffer for the Treatment of Acute Wounds-a Human Pilot Study and In Vitro Data.

Acute wounds may require cleansing to reduce the risk of infection. Stabilized hypochlorous acid in acetic buffer (HOCl + buffer) is a novel wound irrigation solution with antimicrobial properties. We performed a first-in-man, prospective, open-label pilot study to document preliminary safety and performance in the treatment of acute wounds. The study enrolled 12 subjects scheduled for a split-skin graft transplantation, where the donor site was used as a model of an acute wound. The treatment time was 75 s, given on 6 occasions. A total of 7 adverse events were regarded as related to the treatment; all registered as pain during the procedure for 2 subjects. One subject had a wound infection at the donor site. The mean colony-forming unit (CFU) decreased by 41% after the treatment, and the mean epithelialization was 96% on both days 14 (standard deviation [SD] 8%) and 21 (SD 10%). The study provides preliminary support for the safety, well-tolerance, and efficacy of HOCl + buffer for acute wounds. The pain was frequent although resolved quickly. Excellent wound healing and satisfying antimicrobial properties were observed. A subsequent in vitro biofilm study also indicated good antimicrobial activity against Pseudomonas aeruginosa with a 96% mean reduction of CFU, when used for a treatment duration of 15 min (P < .0001), and a 50% decrease for Staphylococcus aureus (P = .1010). Future larger studies are needed to evaluate the safety and performance of HOCl + buffer in acute wounds, including the promising antimicrobial effect by prolonged treatment on bacterial biofilms.

A simplified method for monitoring cytokines in wound fluid.

Cytokines in wound fluid are used as surrogates for wound healing in clinical research. The current methods used to collect and process wound fluid are noninvasive but not optimal. The aim of this prospective study was to evaluate a method (NovaSwab) by which wound fluid is collected by a surface swab and eluted in a physiological buffer for subsequent cytokine analysis. Wound fluid from 12 patients with leg ulcers was assessed by NovaSwab at the start (Day 0) and at the end of a 23-h collection period of wound fluid retained by foam oblates beneath an occlusive film dressing (Day 1). GM-CSF, IL-1α, IL-1ß, IL-6, IL-8, PDGF-AA, TNF-α and VEGF levels were measured by multiplex and electrochemiluminescence assays. IL-1α (2.4×), IL-1ß (2.0×) and IL-8 (1.8×) levels increased from Day 0 to Day 1 as detected by NovaSwab, indicating local production of these polypeptides in the wounds. On Day 1, the NovaSwab method yielded higher levels of IL-1α (4.0×), IL-1ß (2.7×) and IL-6 (2.7×), and 35% lower levels of VEGF than those in wound fluid accumulated for 23 h in foam oblates (on average, 5 ml of wound fluid). In vitro experiments showed that the investigated cytokines in cell-free wound fluid were recovered in a quantitative manner by the NovaSwab method. We conclude that the method presented here is a promising research tool to study the kinetics of soluble cytokines over the course of wound healing. More studies are needed to determine the interobserver variation and reproducibility of the NovaSwab method.

Cytokines and Venous Leg Ulcer Healing-A Systematic Review.

Venous leg ulcers (VLUs) are the most common type of leg ulcers with a significant socioeconomic burden due to slow healing. Cytokines may be involved in the pathogenesis of VLUs. In this systematic review, our objective was to investigate the association between cytokine levels, including growth factors, with the healing of VLUs. PubMed, Embase, Web of Science and Cochrane Library were searched from their inception to August 2021. We retrieved 28 articles investigating 38 different cytokines in 790 patients. Cytokines were most commonly investigated in wound fluid and less frequently in biopsies and serum. The studies were judged as having a moderate to high risk of bias, and the results were often inconsistent and sometimes conflicting. A meta-analysis was not performed due to clinical and methodological heterogeneities. We found weak evidence for elevated IL-1α, IL-6, IL-8, TNF-α and VEGF levels in non-healing VLUs, an elevation that declined with healing. TGF-ß1 levels tended to increase with VLU healing. Other cytokines warranting further investigations include EGF, FGF-2, GM-CSF, IL-1ß, IL-1Ra and PDGF-AA/PDGF-BB. We conclude that non-healing VLUs may be associated with an elevation of a palette of pro-inflammatory cytokines, possibly reflecting activated innate immunity in these wounds. There is a paucity of reliable longitudinal studies monitoring the dynamic changes in cytokine levels during wound healing.

Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study): the protocol for a Copenhagen IBD Inception Cohort Study.

INTRODUCTION: Inflammatory bowel diseases (IBD), encompassing Crohn's disease and ulcerative colitis, are chronic, inflammatory diseases of the gastrointestinal tract. We have initiated a Danish population-based inception cohort study aiming to investigate the underlying mechanisms for the heterogeneous course of IBD, including need for, and response to, treatment. METHODS AND ANALYSIS: IBD Prognosis Study is a prospective, population-based inception cohort study of unselected, newly diagnosed adult, adolescent and paediatric patients with IBD within the uptake area of Hvidovre University Hospital and Herlev University Hospital, Denmark, which covers approximately 1 050 000 inhabitants (~20% of the Danish population). The diagnosis of IBD will be according to the Porto diagnostic criteria in paediatric and adolescent patients or the Copenhagen diagnostic criteria in adult patients. All patients will be followed prospectively with regular clinical examinations including ileocolonoscopies, MRI of the small intestine, validated patient-reported measures and objective examinations with intestinal ultrasound. In addition, intestinal biopsies from ileocolonoscopies, stool, rectal swabs, saliva samples, swabs of the oral cavity and blood samples will be collected systematically for the analysis of biomarkers, microbiome and genetic profiles. Environmental factors and quality of life will be assessed using questionnaires and, when available, automatic registration of purchase data. The occurrence and course of extraintestinal manifestations will be evaluated by rheumatologists, dermatologists and dentists, and assessed by MR cholangiopancreatography, MR of the spine and sacroiliac joints, ultrasonography of peripheral joints and entheses, clinical oral examination, as well as panoramic radiograph of the jaws. Fibroscans and dual-energy X-ray absorptiometry scans will be performed to monitor occurrence and course of chronic liver diseases, osteopenia and osteoporosis. ETHICS AND DISSEMINATION: This study has been approved by Ethics Committee of the Capital Region of Denmark (approval number: H-20065831). Study results will be disseminated through publication in international scientific journals and presentation at (inter)national conferences.

Effect of Stabilized Hypochlorous Acid on Re-epithelialization and Bacterial Bioburden in Acute Wounds: A Randomized Controlled Trial in Healthy Volunteers.

The aim of this randomized controlled trial was to evaluate the wound-healing effect and antimicrobial properties of a novel stabilized hypochlorous acid solution on acute wounds, using a suction blister wound model. One suction blister was raised and de-roofed on each forearm in 20 healthy volunteers. Stabilized hypochlorous acid/control (sterile 0.9% NaCl) solutions were assigned to either wound by randomization. Wounds were irrigated and treated on days 0, 2 and 4. Re-epithelialization was assessed blindly by digital planimetry, and bacterial growth was assessed as the number of colony-forming units cultured from surface swabs. Hypochlorous acid solution increased the degree of re-epithelialization on day 4 by 14% compared with the control solution (95% confidence interval (CI) 6.8-20%, p = 0.00051) and was not inferior (p < 0.0001) to the control solution on day 10 (0.3%, 95% CI -1.3-1.9%). Median bacterial counts were lower with stabilized hypochlorous acid compared with control and were further reduced after irrigation and treatment of both groups on day 4, but remained lower in the stabilized hypochlorous acid group compared with the control group. This study demonstrates immediate and durable antimicrobial action and a beneficial effect on acute wound healing after irrigation and treatment with a stabilized hypochlorous acid formulation.

[Research trends in wound care].

Advanced wound care strategies are emerging, but more robust clinical data are needed such as identification of precise biomarkers for point-of-care diagnostics and 24/7 data. This will aid in the implementation of effective therapies in relevant patients. Increased knowledge among health care providers, health literacy improvement as well as patient involvement are also important in this process. In this review we focus on current research trends in compression therapy, modulation of inflammation and growth factors, the proteolytic microenvironment and microbiology.

Wounds in chronic leg oedema.

Wounds and chronic oedema are common disorders, but rarely studied together. The objective of this cross-sectional study was to investigate the point-prevalence and risk factors of wounds on the leg, in chronic leg oedema. Forty sites in nine countries were included. Of 7077 patients with chronic leg oedema, 12.70% had wounds. Independent risk factors were: peripheral arterial disease (odds ratio (OR) 4.87, 95% confidence intervals (CI) 3.63-6.52), cellulitis within the past 12 months (OR 2.69, 95% CI 2.25-3.21), secondary lymphoedema (OR 2.64, 95% CI 1.93-3.60), being male (OR 2.08, 95% CI 1.78-2.44), being over 85 years of age (OR 1.80, 95% CI 1.23-2.62), underweight (OR 1.79, 95% CI 1.14-2.79), bed bound (OR 1.79, 95% CI 1.01-3.16), chair bound (OR 1.52, 95% CI 1.18-1.97), diabetes (OR 1.47, 95% CI 1.23-1.77), and walking with aid (OR 1·41, 95% CI 1.17-1.69). 43.22% of those with wounds had clinically defined well-controlled oedema, associated with a significantly lower risk of wounds (OR 0.50, 95% CI 0.42-0.58, P < .001). Hard/fibrotic tissue (OR 1.71, 95% CI 1.19-2.48), and a positive Stemmers sign (OR 1.57, 95% CI 1.05-2.35) were associated with wounds. The study reinforces the importance of measures to control oedema, as controlled swelling was associated with a 50% lower risk of wounds.

Lipoedema.

Lipoedema is an overlooked and often misdiagnosed condition, which mainly affects women. This review summarises the present knowledge of the condition. It is characterised by bilateral and symmetrical accumulation of subcutaneous adipose tissue mainly in the legs. Patients with lipoedema often display tenderness to palpation or spontaneous pain in the adipose tissue. Lipoedema is diagnosed based on the medical history and clinical findings. Treatment includes conservative and surgical options with the aim of relieving symptoms and increasing mobility, but there is a paucity of randomised controlled trials.

Factors Predicting Limb Volume Reduction Using Compression Bandaging Within Decongestive Lymphatic Therapy in Lymphedema: A Multicountry Prospective Study.

Objectives: To identify predictive factors associated with limb volume reduction using different decongestive lymphatic therapy (DLT) systems in patients with lymphoedema, over a period of up to 28 days. Methods: A multicountry (Canada, France, Germany, the United Kingdom) prospective cohort study using (DLT): skin care, exercise, compression bandaging, and manual lymphatic drainage for up to 4 weeks. Reduction in limb volume comparing DLT with (1) standard multilayer bandaging with inelastic material, and with (2) multilayer bandaging with Coban2, together with the identification of factors associated with limb volume changes. Results: Out of 264 patients with upper or lower limb lymphedema, 133 used Coban2 and 131 used standard care. Following DLT, mean limb volume reduction was 941 mL using Coban2 compared with 814 mL using standard care. A difference of 127 mL was found (95% confidence interval -275 to 529 mL, p = 0.53). Of the 176 patients with leg swelling, 166 (94.3%) had a limb volume measurement after 28 days and were included in the risk factor analysis. Of these, 132 (79.5%) were female, with overall mean age of 60.1 years (standard deviation = 14.7), with secondary lymphedema in 102/163 (62.6%). Duration of lymphedema was >10 years in 75/161 (46.6%) and 99/166 (59.7%) were International Society of Lymphology late-stage II/III, indicating longstanding and/or a high frequency of patients with advanced stages of lymphedema. Ninety-one (54.8%) received Coban2 and 75 (45.2%) had standard care. Multivariable factors for a greater leg volume reduction were large initial leg volume (p < 0.001), DLT treatment duration of 4 weeks compared with 2 weeks (p = 0.01), and peripheral arterial disease (p = 0.015). Conclusion: Limb volume changes were found to be similar between groups. Lack of standardization of DLT makes interpretation of effectiveness problematic. There is an urgent need for randomized-controlled trials. Despite this, severe lymphedema with a large limb volume responded well to DLT in this study.

Quality of Life and Costs Within Decongestive Lymphatic Therapy in Patients with Leg Lymphedema: A Multicountry, Open-Label, Prospective Study.

Background: Little is known of the impact in terms of health-related quality of life (HRQoL) and cost-effectiveness with decongestive therapy. Objectives: To examine changes in limb volume, quality of life (QoL), and treatment cost of methods of decongestive lymphatic therapy (DLT). Methods: Patients with chronic edema/lymphedema of the leg were invited to participate in a study of DLT in four countries (United Kingdom, France, Germany, and Canada). In each country two sites were selected. One site used their standard method of DLT in their service, including compression with multilayer bandaging with inelastic material. The other site used a system that included 3M™ Coban 2™ as the bandage treatment alongside other standard components of DLT. Patients were followed for either 2 or 4 weeks depending on the local protocols. At entry, at 2 weeks, and at 4 weeks, patients were assessed by using a health index (EQ-5D), a disease-specific HRQoL tool (LYMQOL) and resource usage was recorded over the treatment period. Results: Of the 165 patients with cost data, 90 were treated with Coban 2 and 75 with standard care compression bandaging. There was good evidence of an improvement in EQ-5D of 0.077 (p < 0.001) in all patients. LYMQOL showed significant improvements (p < 0.001) with lower scores. There were no major differences between the two arms of the study with respect to HRQoL. The number of treatment episodes was higher in those treated with standard care (8.15 vs. 6.37), but the overall treatment cost was higher with Coban 2 (£890.7) compared with standard care (£723.0). Conclusion: QoL improved in the standard care and Coban 2 group bandages, and there was no demonstrable difference between the care systems. Further work is required to examine the role of the individual parts of DLT that provide the greatest benefit to patients and the health systems that support them.

[Pyoderma gangrenosum].

Pyoderma gangrenosum is a diagnostic and therapeutic challenge. A misdiagnosis or delayed diagnosis can lead to increased morbidity and death. A fast workup and initiation of treatment is essential. In this review, we present new diagnostic criteria, which can ease the diagnosis, and we summarise the evidence of different treatment modalities. The evidence points towards local immunosuppressive treatment in mild disease, supplemented by systemic glucorticosteroids, ciclosporin or tumour necrosis factor-alpha inhibitors in severe cases. Other biologics are emerging.

Eruptive Melanocytic Nevi: A Review.

Eruptive melanocytic nevi (EMN) is a phenomenon characterized by the sudden onset of nevi. Our objective was to compile all published reports of EMN to identify possible precipitating factors and to evaluate the clinical appearance and course. We conducted a systematic bibliographic search and selected 93 articles, representing 179 patients with EMN. The suspected causes were skin and other diseases (50%); immunosuppressive agents, chemotherapy or melanotan (41%); and miscellaneous, including idiopathic (9%). The clinical manifestations could largely be divided into two categories: EMN associated with skin diseases were frequently few in number (fewer than ten nevi), large, and localized to the site of previous skin disease, whereas those due to other causes presented most often with multiple small widespread nevi. In general, EMN seem to persist unchanged after their appearance, but development over several years or fading has also been reported. Overall, 16% of the cases had at least one histologically confirmed dysplastic nevus. Five cases of associated melanoma were reported. We conclude that the clinical appearance of EMN may differ according to the suggested triggering factor. Based on the clinical distinction, we propose a new subclassification of EMN: (1) widespread eruptive nevi (WEN), with numerous small nevi, triggered by, for example, drugs and internal diseases, and (2) Köbner-like eruptive nevi, often with big and few nevi, associated with skin diseases and most often localized at the site of previous skin disease/trauma. The nature of the data precluded assessment of risk of malignant transformation.