Spectrum of diseases associated with pyoderma gangrenosum and correlation with effectiveness of therapy: New insights on the diagnosis and therapy of comorbid hidradenitis suppurativa.

Pyoderma gangrenosum (PG) has been linked to various underlying systemic diseases; many associations are based on case reports or small case series, including hidradenitis suppurativa. Literature examining systemic therapies according to underlying comorbid condition is limited. The study objective was to investigate comorbid diseases of PG and correlate disease associations with effectiveness of therapeutic interventions. Using Johns Hopkins Medical Institutions medical records, 220 patients had an ICD-9 code of 686.01 for PG between 1 January 2006 and 30 June 2015, of whom 130 patients met rigorous inclusion/exclusion criteria for PG (non-peristomal). The 130 PG patients in our study were 69% female, 58% Caucasian, and 35% African American. Documented comorbid conditions included inflammatory bowel disease (IBD; 35%), rheumatoid arthritis (RA; 12%), hidradenitis suppurativa (HS; 14%), and monoclonal gammopathy (12%). PG patients with HS versus without HS were more likely to be African-American (83% vs. 28%; P < 0.001) and had an earlier mean age of PG onset (38 vs. 48 years; P = 0.02). Strikingly, 53% of female African-American patients with PG onset prior to age 40 had comorbid HS. Comorbid inflammatory bowel disease was observed in 38% of PG patients with RA, 28% of PG patients with HS, and 27% of PG patients with monoclonal gammopathy. Of the 32 patients who received infliximab for active PG, complete ulcer healing was observed in 83% (5/6) of patients with comorbid HS versus 31% (8/26) of patients without HS (Fisher exact P = 0.03). Screening patients for associated systemic disease for multiple related illnesses is essential. Effectiveness of systemic therapy may depend upon the underlying systemic disease; hidradenitis suppurativa may be a specific example.

Clinical interventions for venous leg ulcers: Proposals to improve the quality of clinical leg ulcer research.

The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research.

Biochemical association of metabolic profile and microbiome in chronic pressure ulcer wounds.

Chronic, non-healing wounds contribute significantly to the suffering of patients with co-morbidities in the clinical population with mild to severely compromised immune systems. Normal wound healing proceeds through a well-described process. However, in chronic wounds this process seems to become dysregulated at the transition between resolution of inflammation and re-epithelialization. Bioburden in the form of colonizing bacteria is a major contributor to the delayed headlining in chronic wounds such as pressure ulcers. However how the microbiome influences the wound metabolic landscape is unknown. Here, we have used a Systems Biology approach to determine the biochemical associations between the taxonomic and metabolomic profiles of wounds colonized by bacteria. Pressure ulcer biopsies were harvested from primary chronic wounds and bisected into top and bottom sections prior to analysis of microbiome by pyrosequencing and analysis of metabolome using 1H nuclear magnetic resonance (NMR) spectroscopy. Bacterial taxonomy revealed that wounds were colonized predominantly by three main phyla, but differed significantly at the genus level. While taxonomic profiles demonstrated significant variability between wounds, metabolic profiles shared significant similarity based on the depth of the wound biopsy. Biochemical association between taxonomy and metabolic landscape indicated significant wound-to-wound similarity in metabolite enrichment sets and metabolic pathway impacts, especially with regard to amino acid metabolism. To our knowledge, this is the first demonstration of a statistically robust correlation between bacterial colonization and metabolic landscape within the chronic wound environment.

The importance of a multifaceted approach to characterizing the microbial flora of chronic wounds.

Chronic wounds contain complex polymicrobial communities of sessile organisms that have been underappreciated because of limitations of standard culture techniques. The aim of this work was to combine recently developed next-generation investigative techniques to comprehensively describe the microbial characteristics of chronic wounds. Tissue samples were obtained from 15 patients with chronic wounds presenting to the Johns Hopkins Wound Center. Standard bacteriological cultures demonstrated an average of three common bacterial species in wound samples. By contrast, high-throughput pyrosequencing revealed increased bacterial diversity with an average of 17 genera in each wound. Data from microbial community profiling of chronic wounds were compared with published sequenced analyses of bacteria from normal skin. Increased proportions of anaerobes, Gram-negative rods and Gram-positive cocci were found in chronic wounds. In addition, chronic wounds had significantly lower populations of Propionibacterium compared with normal skin. Using epifluorescence microscopy, wound bacteria were visualized in highly organized thick confluent biofilms or as scattered individual bacterial cells. Fluorescent in situ hybridization allowed for the visualization of Staphylococcus aureus cells in a wound sample. Quorum-sensing molecules were measured by bioassay to evaluate signaling patterns among bacteria in the wounds. A range of autoinducer-2 activities was detected in the wound samples. Collectively, these data provide new insights into the identity, organization, and behavior of bacteria in chronic wounds. Such information may provide important clues to effective future strategies in wound healing.

Hemoglobin A1c predicts healing rate in diabetic wounds.

Lower-extremity wounds are a major complication of diabetes. Hemoglobin A1c (HbA1c) reflects glycemia over 2-3 months and is the standard measure used to monitor glycemia in diabetic patients, but results from studies have not shown a consistent association of HbA1c with wound healing. We hypothesized that elevated HbA1c would be most associated with poor wound healing. To test this hypothesis, we conducted a retrospective cohort study of 183 diabetic individuals treated at the Johns Hopkins Wound Center. Our primary outcome was wound-area healing rate (cm(2) per day). Calibrated tracings of digital images were used to measure wound area. We estimated coefficients for healing rate using a multiple linear regression model controlling for clustering of wounds within individuals and other common clinic variables. The study population was 45% female and 41% African American, with a mean age of 61 years. Mean HbA1c was 8.0%, and there were 2.3 wounds per individual (310 wounds total). Of all measures assessed, only HbA1c was significantly associated with wound-area healing rate. In particular, for each 1.0% point increase in HbA1c, the daily wound-area healing rate decreased by 0.028 cm(2) per day (95% confidence interval: 0.003, 0.0054, P = 0.027). Our results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound-healing rate in diabetic patients.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Macroscale spatial variation in chronic wound microbiota: a cross-sectional study.

Controlling for sample site is considered to be an important aspect of chronic wound microbiological investigations; yet, macroscale spatial variation in wound microbiota has not been well characterized. A total of 31 curette samples were collected at the leading edge, opposing leading edge, and/or center of 13 chronic wounds. Bacterial community composition was characterized using a combination of 16S rRNA gene-based pyrosequencing; heat map display; hierarchical clustering; nonmetric multidimensional scaling; and permutation multivariate analysis of variance. A total of 58 bacterial families and 91 bacterial genera were characterized among the 13 wounds. While substantial macroscale spatial variation was observed among the wounds, bacterial communities at different sites within individual wounds were significantly more similar than those in different wounds (p=0.001). Our results support the prevalent opinion that controlling for sample site may improve the quality of wound microbiota studies; however, the significant similarity in bacterial communities from different sites within individual wounds indicates that studies failing to control for sampling site should not be disregarded based solely on this criterion. A composite sample from multiple sites across the surface of individual wounds may provide the most robust characterization of wound microbiota.

Combat Wound Initiative program.

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

Molecular microbiology: new dimensions for cutaneous biology and wound healing.

The role of bacteria in the pathogenesis of chronic, nonhealing wounds is unclear. All wounds are colonized with bacteria, but differentiating colonizers from invading organisms is difficult, if not impossible, at the present time. Furthermore, robust new molecular genomic techniques have shown that only 1% of bacteria can be grown in culture; anaerobes are especially difficult to identify using standard culture methods. Recent studies utilizing microbial genomic methods have demonstrated that chronic wounds are host to a wide range of microorganisms. New techniques also show that microorganisms are capable of forming highly organized biofilms within the wound that differ dramatically in gene expression and phenotype from bacteria that are typically seen in planktonic conditions. The aim of this review is to present a concise description of infectious agents as defined by new molecular techniques and to summarize what is known about the microbiology of chronic wounds in order to relate them to the pathophysiology and therapy of chronic wounds.

Community analysis of chronic wound bacteria using 16S rRNA gene-based pyrosequencing: impact of diabetes and antibiotics on chronic wound microbiota.

BACKGROUND: Bacterial colonization is hypothesized to play a pathogenic role in the non-healing state of chronic wounds. We characterized wound bacteria from a cohort of chronic wound patients using a 16S rRNA gene-based pyrosequencing approach and assessed the impact of diabetes and antibiotics on chronic wound microbiota. METHODOLOGY/PRINCIPAL FINDINGS: We prospectively enrolled 24 patients at a referral wound center in Baltimore, MD; sampled patients' wounds by curette; cultured samples under aerobic and anaerobic conditions; and pyrosequenced the 16S rRNA V3 hypervariable region. The 16S rRNA gene-based analyses revealed an average of 10 different bacterial families in wounds--approximately 4 times more than estimated by culture-based analyses. Fastidious anaerobic bacteria belonging to the Clostridiales family XI were among the most prevalent bacteria identified exclusively by 16S rRNA gene-based analyses. Community-scale analyses showed that wound microbiota from antibiotic treated patients were significantly different from untreated patients (p = 0.007) and were characterized by increased Pseudomonadaceae abundance. These analyses also revealed that antibiotic use was associated with decreased Streptococcaceae among diabetics and that Streptococcaceae was more abundant among diabetics as compared to non-diabetics. CONCLUSIONS/SIGNIFICANCE: The 16S rRNA gene-based analyses revealed complex bacterial communities including anaerobic bacteria that may play causative roles in the non-healing state of some chronic wounds. Our data suggest that antimicrobial therapy alters community structure--reducing some bacteria while selecting for others.

Treating the chronic wound: A practical approach to the care of nonhealing wounds and wound care dressings.

UNLABELLED: Chronic wounds are a major healthcare problem costing the United States billions of dollars a year. The American Academy of Dermatology has underscored the significance of wound care in dermatological practice. It is critical for all dermatologists to understand the elements of diagnosis and therapy. We emphasize major aspects of diagnosis and present a simple classification of wound dressings with guidelines for usage and relative cost data. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to diagnose common types of chronic wounds, formulate a therapeutic plan, and describe the major classes of topical therapies and dressings for the chronic wound.

Digital imaging of wounds: are measurements reproducible among observers?

Advances in digital imaging and archiving have made the measurement and documentation of wound areas possible over time. To assess the reproducibility and precision of digital image measurements, we used WoundMatrix Web (http://www.woundmatrix.com/) and recruited a group of caregivers from the Johns Hopkins Wound Center to measure the size of wounds on digital images by measuring length and width and tracing the circumference of the same wounds. One set of images was provided by WoundMatrix (WoundMatrix Inc, Chadds Ford, PA) and a second set used our own photographs taken at the Johns Hopkins Wound Center. Our results demonstrate that digital analysis with WoundMatrix Web is reproducible and precise with acceptable variation among readers. This supports the use of digital images of wounds to follow clinical progress as well as analyze the effects of new clinical interventions in clinical trials.

Lipedema, a frequently unrecognized problem.

Lipedema is characterized by symmetric lower extremity enlargement secondary to the deposition of fat. Lipedema is not rare, but it is commonly misdiagnosed as lymphedema. We describe a 20-year-old woman with massive lower extremity enlargement that did not respond to compression therapy. Magnetic resonance imaging of the lower extremities helped to confirm the diagnosis.

Occlusive wound dressings in emergency medicine and acute care.

One of the great misconceptions in wound care is that a wound heals best when permitted to form a dry scab. By contrast, moisture has repeatedly been shown to significantly accelerate wound healing. Emergency physicians and other acute care providers are encouraged to incorporate occlusive moisture-retentive dressings into their regular practice to expedite healing, reduce pain and scarring, improve wound care convenience and patient compliance, and minimize wound contamination and infection.