Epidermolysis Bullosa and Chronic Wounds: A Model for ... · DIME: debridement, infection/inflammation control, and moisture balance before the edge effect for advanced therapies

Epidermolysis Bullosa and Chronic Wounds:A Model for Wound Bed Preparation ofFragile Skin

C M E1 AMA PRACategory 1 Credit TM

ANCC3.3 Contact Hours

Elena Pope, MD, MSc, FRCPC & Head Section of Dermatology & The Hospital for Sick Children & Toronto, Ontario, CanadaIrene Lara-Corrales, MD, FRCPC (Derm) & Assistant Professor of Pediatrics & University of Toronto & Toronto, Ontario,Canada & Pediatric Dermatologist & Interdisciplinary Clinic, The Hospital for Sick Children & Toronto, Ontario, CanadaJemima E. Mellerio, BSc, MD, FRCP & Consultant Dermatologist and Lead for the Adult Epidermolysis Bullosa Service &St John’s Institute of Dermatology, Guy’s & St. Thomas’ NHS Foundation Trust, and Great Ormond Street Hospital for ChildrenNHS Foundation Trust & London, United KingdomAnnaE.Martinez,MBBS,MRCP,MRCPCH &Consultant Pediatrician andClinical Lead for thePediatric Epidermolysis BullosaService & Great Ormond Street Hospital & London, United KingdomCathryn Sibbald, RPh, BScPhm, ACPR & MD Candidate 2013 & University of Toronto & Toronto, Ontario, CanadaR. Gary Sibbald, BSc, MD, MEd, FRCPC (Med) (Derm), FACP, FAAD, MAPWCA, for the EB International ConsensusPanel & Professor of Public Health and Medicine & University of Toronto & Toronto, Ontario, Canada & Director & InternationalInterprofessional Wound Care Course & Masters of Science in Community Health (Prevention & Wound Care) & Dalla LanaSchool of Public Health & University of Toronto & Past President & World Union of Wound Healing Societies & Clinical Editor &Advances in Skin & Wound Care & Ambler, Pennsylvania

Acknowledgments: This article is dedicated to all persons suffering from epidermolysis bullosa in an attempt to improve their quality of life. The authors thank the late Alex Melkic andDeanna Molinaro from whom we have learned so much and Molnlycke for their unrestrictive educational grant support.

Dr Pope has disclosed that her institution received an unrestricted educational grant from Molnlycke Health Care to host the EB International Consensus Panel. Dr Lara-Corrales hasdisclosed that The Hospital for Sick Children is a recipient of grant/research funding from the Canadian Dermatology Foundation Society of Pediatric Dermatology. Dr Mellerio, Dr Martinez,and Dr C. Sibbald have disclosed that they have no financial relationships related to this article. Dr R.G. Sibbald has disclosed that he is a board member of Coloplast, Covidien, J & J(Systagenix), Molnlycke, Registered Nurses’ Association of Ontario, Hollister; and was a board member of 3M, BSN Medical, Gaymar, KCI, and Healthpoint Biotherapeutics; he was amember of the speaker’s bureau for 3M, BSN Medical, Gaymar, KCI, Coloplast, Covidien, J & J (Systagenix), and Molnlycke; is a member of the speaker’s bureau for Galderma; was arecipient of grant/research funding from 3M, BSN Medical, Canadian International Development Agency, Coloplast, Covidien, Government of Ontario, KCI, J & J (Systagenix), Molnlycke,and the Registered Nurses’ Association of Ontario; and is a recipient of grant/research funding from Exciton, J & J (Systagenix), Hollister, and Healthpoint Biotherapeutics.

All staff and planners, including spouses/partners (if any), in any position to control the content of this CME activity have disclosed that they have no financial relationships with, or financialinterests in, any commercial companies pertaining to this educational activity.

Lippincott CME Institute has identified and resolved all conflicts of interest concerning this educational activity.

To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed answer form, answering at least 13 of the 18 questions correctly.

This continuing educational activity will expire for physicians on April 30, 2014.

PURPOSE:

To enhance the learner’s competence with information about a wound bed preparation model of fragile skin for

patients with epidermolysis bullosa (EB).

TARGET AUDIENCE:

This continuing education activity is intended for physicians and nurses with an interest in skin and wound care.

APRIL 2013

ADVANCES IN SKIN & WOUND CARE & APRIL 2013177WWW.WOUNDCAREJOURNAL.COM

Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

WWW.WOUNDCAREJOURNAL.COM

OBJECTIVES:

After participating in this educational activity, the participant should be better able to:

1. Differentiate between the types and subtypes of EB.

2. Apply EB assessment and treatment strategies to patient care scenarios.

ABSTRACT

Epidermolysis bullosa (EB) is a group of inherited diseases with4 subtypes. This disorder is amodel for fragile skin,with some affectedindividuals having chronic, difficult-to-heal wounds. The care ofwounds in people with EB can be guided by the Wound BedPreparation paradigm. The treatment of chronic EB wounds is outlinedwith a quick reference guide of 12 consensus recommendationscreated by a panel of 11 experts. These recommendations werereviewed by a computer-facilitated modified Delphi process where15 external reviewers (68.8% of whom reported having 11 or moreyears’ experience with EB care). Inclusion of recommendations wascontingent on 80% agreement from reviewers.KEYWORDS: epidermolysis bullosa (EB), skin diseases, EB simplex,junctional EB, dystrophic EB, Kindler syndrome

ADV SKIN WOUND CARE 2013;26:177-88; quiz 189-90.

INTRODUCTIONEpidermolysis bullosa (EB) is a rare group of genetic blistering

skin diseases with skin fragility leading to bulla formation.1 There

is a wide spectrum of severity in EB: the mildest form is localized

EB simplex, where blistering predominantly affects the feet and

hands, but other forms, notably recessive dystrophic EB (RDEB)

and junctional EB, are characterized by more extensive skin and

mucosal involvement, systemic complications, disfigurement,

and often severely limited life expectancy. It is persons with these

more severe forms of EB who have a tendency to develop lifelong

chronic wounds and infections. In 2012, a best practice con-

sensus was created examining the issue of wound bed prep-

aration (WBP) that was literally ‘‘born on the back’’ of Alex, a

person with RDEB.2 This WBP knowledge can be applied not

only to all patients with EB, but also as a model for fragile skin

and chronic ulcers (Figure 1).

The consensus project united EB experts with wound healers

(basic scientists, physicians, and nurse clinicians) with a pioneer

in bone marrow transplantation (Table 1). The aim was to facil-

itate knowledge of the 4 different subtypes of EB so that affected

individuals are recognized early and receive appropriate symp-

tomatic treatment, including optimal local wound care to pre-

vent life-threatening infections and failure to thrive. Another

objective was to increase awareness of complications such as car-

diomyopathy and squamous cell carcinomas (persistent inflam-

mation leads to malignant transformation) that may rarely occur

even in childhood. By reading this continuing education article, cli-

nicians will be better able to identify and treat EB and its subtypes.

Attempts to optimize wound care in EB patients began many

years ago. In January 1997, Canada was the first country in the world

to approve an artificial skin substitute grown in vitro (Graftskin

[Apligraf; Organogenesis, Canton, Massachusetts]: a bovine type

1 collagen with human fibroblasts and an epidermal cell layer). In

February 1997, Alex (Figure 1) had 2 pieces of Graftskin placed on

the upper part of his extensive back ulceration (covering 50% of

his back for 3 years). One week after application, the skin sub-

stitutes (with fluid release slits to maintain contact) under the silver

and foam dressing were intact. In contrast, the other skin substi-

tute piece without the bacterial balancing silver was destroyed

by the local collagenase, partly produced by the Pseudomonas or-

ganisms. Subsequent applications of both Vicryl skin substitute

populated with human fibroblasts (Dermagraft; Shire Regen-

erative Medicine, San Diego, California) and Graftskin resulted

in complete wound healing of Alex’s back. These results were

subsequently reproduced on wounds of other EB patients.3,4

Although Alex has since died as a result of infection and car-

diomyopathy, his contribution to the better understanding of

local wound care has shaped what clinicians know today.

The authors have published a model for WBP.5–7 This model

includes treating the whole patient, patient-centered concerns,

and local wound care. In EB patients, ideal treatment of the cause

involves replacing type VII collagen for RDEB patients through

bone marrow transplants or other gene-modifying therapies.8

Treating the cause also includes optimizing other cofactors in-

volved in healing, including nutrition (such as supplements and

early insertion of feeding tubes) and the correction of anemia.

The components of local wound care are as follows: DIM before

DIME: debridement, infection/inflammation control, and moisture

balance before the edge effect for advanced therapies (eg, skin

substitutes for stalled but healable wounds). Trauma and pain

associated with local wound care have been improved with

local silicone mesh products, soft silicone foam coatings, and

silicone tape.

Wagner et al9 published a seminal article in 2010 reporting

on the first 7 patients with RDEB undergoing immunoablative

chemotherapy and allogeneic stem cell transplant. Of the 7 pa-

tients, 1 died of cardiomyopathy before transplantation and a

second patient died of infection and transplant rejection 183 days

after transplantation. All recipients had a reduction in new blister

formation between days 30 and 130 after transplantation. Five of

ADVANCES IN SKIN & WOUND CARE & VOL. 26 NO. 4 178 WWW.WOUNDCAREJOURNAL.COM



the 6 recipients had an increase in type VII collagen expression,

but without formation of normal anchoring fibrils.

There are 2 key concerns surrounding transplantation pro-

cedures. First, the small number of individuals eligible for trans-

plant may develop human leukocyte antigens from the allogeneic

cells in the skin transplant, increasing the potential for rejection of

a bone marrow transplant. Second, older individuals with RDEB

(especially after age 20 years) are very susceptible to aggressive

squamous cell carcinomas, and the immunosuppression associ-

ated with allogeneic stem cell transplantation may increase this.

The authors have currently completed the full circle to apply the

principles of wound bed preparation, specifically for people with

EB, not only to optimize healing but also to prevent infections and

other complications before and after bone marrow transplanta-

tion (Figure 2). In addition, the authors are suggesting strategies

for persons with EB and their circle of care (parents and healthcare

providers) in resource-poor areas where links to EB experts will

help improve diagnosis and treatment.

Epidermolysis bullosa also represents a model for fragile skin

found in older adults, Skin Changes at Life’s End,10 and other

patients suffering from chronic disease or immunosuppression.

Therefore, the principles discussed in this article can be applied

to other patient populations with skin fragility.

METHODSThe process of consensus building with a full discussion of the

dermatological and general medical components of the care

of individuals with EB has been published elsewhere.2 Briefly,

the recommendations were generated by a diverse panel of 11

experts and reviewed by 15 external reviewers (Tables 1 and 2).

Inclusion of recommendations was contingent on 80% agree-

ment from responders.

This article summarizes the EB recommendations with a special

emphasis on the wound healing component as outlined with the

WBP paradigm and utilizes EB as a model for fragile skin.

TREAT THE CAUSE

1. Assess the patient’s ability to heal.

2. Develop an individualized goal of care.Epidermolysis bullosa is caused by mutations in structural proteins

with resultant fragile skin. There are currently 4 main subtypes

Figure 1.

WOUND BED PREPARATION ADAPTED TO THE PERSON WITH EPIDERMOLYSIS BULLOSA




described, based on the specific genetic defect and the level at

which blisters form in the skin in response to trauma (Figure 3).1,11

Epidermolysis Bullosa Simplex: The most common type of

EB simplex is localized EB simplex with skin cleavage within the

basal layer of the epidermis. The blisters are usually on the palms

and soles, aggravated by heat and friction. The inheritance is au-

tosomal dominant with mild disease. Mutations are present in

keratins 5 or 14. A less common but also autosomal dominant

type, Dowling-Meara, features clustered distal blisters with a string

of pearl-like arrangement. Although painful keratoderma is noted

with time, patients tend to be less severe with increasing age.

Junctional EB: Skin and mucosal cleavage occurs at the

lamina lucida level of the basement membrane zone, including

periorificial areas of skin, ocular, tracheolaryngeal, gastrointestinal,

genitourinary, and renal systems. The mode of inheritance is

usually autosomal recessive, with mutations in the genes encoding

collagen XVII, !6"4 integrin, or laminin 332. The Herlitz form

is the most severe (exuberant granulation in the perioral area,

around the nails, and denuded diaper area), with death in most

cases in the first 1 to 2 years of life. The non-Herlitz form is often

severe in infancy, but life expectancy is considerably longer.

Dystrophic EB: This type of EB involves cleavage beneath the

lamina densa, within the dermis at the level of the anchoring fibrils

due to mutations in the type VII collagen gene.l The autosomal

dominant form is the second most common EB type, and pa-

tients present with blisters in areas prone to bumps or knocks

such as the toes, knees, fingers, and elbows. The autosomal reces-

sive form is usually more debilitating, with blisters from birth

and pseudosyndactyly, where toes and fingers become fused. This

form is associated with lifelong chronic wounds and with the de-

velopment of aggressive squamous cell carcinomas in the 30s to

40s. If they reach their mid-50s, 90% of individuals will have had

a squamous cell carcinoma.

Kindler Syndrome: This rare form of EB may result in cleav-

age at any of the 3 levels outlined above. Blisters in early childhood

are gradually replaced by scarring, keratoderma (thickened palms

and soles), poikiloderma (hypopigmentation and hyperpigmen-

tation, telangiectasia, and atrophy), and photosensitivity. It is

caused by mutations in the gene encoding kindlin 1, which is in-

volved in basal layer keratinocyte adhesion at focal contacts.

Genetic EngineeringUntil recently, care of patients with EB has consisted of trying to

minimize trauma-induced blistering of the skin and supportive care

of resulting wounds. However, there are some new and exciting

therapies being proposed to target the cause of the skin fragility

in these patients, including replacement of the abnormal protein

(eg, collagen VII in RDEB) and bone marrow transplantation.

Recent studies have suggested that delivery of allogeneic fi-

broblasts to the skin of patients with RDEB may be beneficial

in improving skin adhesion and increasing type VII collagen

deposition at the dermal-epidermal junction.12 There are promis-

ing data from patients with RDEBtreated with immunomyeloablative

chemotherapy and allogeneic stem cell transplantation, resulting

in improved wound healing, decreased blister formation, and

increased collagen VII deposition at the dermal-epidermal junc-

tion. Although encouraging, further study is needed to deter-

mine long-term safety and efficacy of this modality.9 Until then,

treatment goals are aimed at optimizing wound healing and min-

imizing disability from blistering.

Nutrition and HemoglobinThere are many different ways in which nutrition may be compro-

mised in patients with EB; both poor dietary intake and increased

metabolic demands can impair wound healing.13 Adequate pro-

tein is a prerequisite to good wound healing through its integral

role in the production of granulation tissue, and albumin levels

Table 1.

CONSENSUS PANEL AND EXTERNAL REVIEWERS

Panel Members

Elena Pope, co-chair Pediatrics, Dermatology (Canada)

Irene Lara-Corrales MD, Pediatrics, Dermatology

(Canada)

Jemima Mellerio MD, Dermatology, Adult and

Pediatric EB (United Kingdom)

Anna Martinez MD, Pediatrics, Pediatric EB

(United Kingdom)

Greg Schultz PhD, Scientist (United States)

Rob Burrell PhD, Scientist (Canada)

Laurie Goodman Nurse (Canada)

Patricia Coutts Nurse (Canada)

John Wagner MD, Bone marrow transplant

(United States)

Upton Allen MD, Pediatrics, Infectious Diseases

(Canada)

Gary Sibbald, co-chair Dermatology, Medicine (Canada)

External Reviewers

Edward Barrett (Canada) Andrew Lin (Canada)

Anna Bruckner (United

States)

Anne Lucky (United States)

Maya El Hachem (Italy)

Celia Moss (United Kingdom)

Louise Foret-Lalonde

(Canada)

Dedee Murrell (Australia)

Gerry Kelly-Mancuso

(United States)

Annmarie Ormonde (Italy)

Michelle Lee (Canada)

Francis Pallison (Chile)

Agnes Schwieger (Germany)

Rosemarie Watson (Ireland)

Karen Wiss (United States)




less than 2.0 to 3.0 g/dL can have a negative impact (reference

range, 3.0–5.4 g/dL).14,15 To optimize nutrition, a dietitian should

be consulted to calculate caloric intake and ensure that the diet

includes adequate amounts of protein, zinc, and iron in forms that

are palatable for patients, especially those with fragile mucosal

barriers. Feeding tubes are often required in children with RDEB

and other severe types of EB to improve growth centiles or a very

low body mass index.

Low hemoglobin can affect tissue oxygenation and will also

inhibit healing in people with EB.16 There are several reasons for

increased blood loss and decreased production of red blood cells,

including:

& increased blood loss through blisters and chronic wounds on

the skin and in the gastrointestinal tract

& chronic inflammation leading to decreased production of red

blood cells

& iron deficiency and increased iron utilization

& deficiencies of other vitamins and minerals including vitamin

B12 and folate.

Although there is evidence for targeting hemoglobin levels to

levels greater than 100 g/dL,16 for many individuals with severe

EB and chronic wounds, a hemoglobin of 80 g/dL is a more

realistic recommendation. Attempts to maintain the hemoglobin

at higher levels lead to the potential for iron overload from intra-

venous iron or blood transfusions.

Deep Infection and InflammationChronic wounds with large open areas are often stuck in the

inflammatory stage of the healing process. Proinflammatory metal-

loproteases and elastases can be derived from both the host and

critically colonizing bacteria. Antimicrobials have a known spec-

trum of antibacterial action, but some antimicrobials also have

an anti-inflammatory action that can promote healing both by

decreasing bacterial numbers in the wound but also by de-

creasing inflammation. In young infants, erythromycin is a rea-

sonable agent for anti-inflammatory and antimicrobial effects,

with trimethoprim (TMP)an appropriate alternative after 6 months

of age. Tetracyclines should be reserved for older children after the

emergence of permanent teeth.

Both infection and inflammation can impair wound healing.

All wounds are colonized with bacteria and infection results

when the bacterial load and virulence overcome the ability of the

patient’s immune system to resist invasion. Once infection oc-

curs, treatment takes 2 to 4 weeks.7 Inflammation is present in

many wounds, but can be prolonged and stall healing when deg-

radation of extracellular matrix and growth factors occurs more

rapidly than the collagen matrix synthesis.17 Observational data

have suggested that patients with more severe forms of EB treated

with long-term, low-dose, anti-inflammatory antibacterial treat-

ment, such as erythromycin or TMP, have reduced wound sever-

ity and develop fewer new blisters.18 In a small cohort of children

with EB, TMP was associated with a trend toward a greater reduc-

tion in the total wound surface area compared with placebo.18

PATIENT-CENTERED CONCERNS

3. Address pain and itch along with potentialtreatments.Pain and itch are very common and debilitating symptoms in

EB with significant effects on quality of life.19 Various recommen-

dations have been made to help prevent pain. Skin protection to

avoid trauma includes use of silicone adhesives or foam dressings,

modified sleeping and seating surfaces, and good footwear.

Releasing fluid from blisters, while leaving the roof intact, can

prevent blister expansion.6 Finally, the use of hand cleansers and

clean techniques when changing dressings can avoid potential

translocation of bacteria into areas of compromised skin and

increased risk of superficial critical colonization or deep or sec-

ondary painful infection.

Figure 2.

ADVANCED THERAPIES FOR EB

A, Alex, a person with EB. B, Two pieces of Graftskin applied. C, One piece of Graftskin is covered with a nanocrystalline silver dressing. D, Both pieces have moisture balancing foam

with soft silicone. E, Only piece under silver and foam dressing survives at 1 week.




Table 2.

WOUND CARE RECOMMENDATIONS FOR PERSONS WITH EPIDERMOLYSIS BULLOSA

Main Themes Specific Themes Specific Recommendations

A. Treat the cause Assess the patient’s

ability to heal

Evaluate EB type–specific involvement (simplex, junctional,

dystrophic, Kindler syndrome) and comorbidities

Consider age of the patient

Assess nutrition status: growth centiles, body mass index

Monitor hemoglobin levels

Develop individualized goals

and plan of care

Low hemoglobin consider:

iron supplementation, transfusion(s)

Low albumin: protein supplements, feeding tube

Address other specific subtype involvement

B. Patient-centered

concerns

Address and support

management of patient-centered

concerns to enable healing

Pain:

World Health Organization pain ladder for nociceptive pain

Neuropathic pain: consider tricyclics, gabapentin, pregabalin

Local or topical approaches

Nonpharmacological approaches

Itch (only partly histamine mediated)

Combine nonsedating H1 antihistamine in the morning with sedating

preparations at night

Consider liquid quick onset preparations for breakthrough

Activities of daily living:

Consider rehabilitation consult

Provide education and support

to the patient/parent and their

circle of care to increase treatment

adherencea

Build confidence with patient and their circle of care individuals,

to increase adherence

Develop interprofessional team

Explore the support from established EB centers

Consult:

ebcare network ([email protected])

DebRA programs (http://www.debra.org/international)

C. Local wound care Assess wound(s) location

and characteristics

Location

Target wound or wounds

Longest length x widest width at right angles

MEASURE mnemonic

Gently cleanse wounds with

low-toxicity solutions

Saline, water, or acetic acid (0.5%–1.0%)

Consider baths, whirlpool ± with salt, bleach, other antimicrobials

Debridement Drain blisters with a sterile needle to prevent tracking but leave

roof on blister

Consider nontraumatic conservative debridement of slough

Assess and treat Superficial critical colonization (NERDS) and abnormal inflammation

Deep/surrounding tissue infection (STONEES)/generalized

inflammationcontinues



mailto:[email protected]

http://www.debra.org/international


To help treat pain, it is important to distinguish nociceptive from

neuropathic pain. Nociceptive pain is characteristically described

as gnawing, aching, tender, or throbbing, provoked by stimulus,

and can be treated with a stepwise approach proposed in the

World Health Organization’s pain ladder.20,21 Acetaminophen

is used first, with subsequent addition of nonsteroidal anti-

inflammatory medications (ibuprofen or naproxen) and then

narcotics (morphine, hydromorphone) as needed for optimal

pain control. Neuropathic pain is burning, stinging, shooting, or

stabbing and requires modalities such as tricyclic antidepressants

(amitriptyline, or more selective nortriptyline or desipramine) or

anticonvulsants (gabapentin, pregabalin).

It is important to obtain a good history of the presence and

timing of itch, in order to tailor therapies to target or prevent

triggers. For patients who experience nighttime itch, a sedating

medication such as diphenhydramine may be beneficial. Uncom-

monly, diphenhydramine may produce paradoxical excitement

instead of sedation or leave patients groggy in the morning. In

these cases, hydroxyzine or doxepin may be helpful alternatives.

Hydroxyzine syrup allows for very small doses to be adminis-

tered, and the drowsiness is often less severe by morning, but the

effect in the skin may last for up to 72 hours. For daytime itch,

nonsedating antihistamines, such as cetirizine or loratadine, can

be used; however, a small subset of patients may experience drows-

iness with these products. Refrigeration of topical products used on

the skin can also produce a cooling sensation and minimize itch.

4A. Consider activities of everyday living andrestrictions.Epidermolysis bullosa patients carry a large disease burden with

impacts on all aspects of daily living. It is helpful to involve oc-

cupational and physiotherapists to maximize independence in

activities of daily living, as well as leisure activities. It is also

important to screen for concurrent anxiety or depression with

Table 2.

WOUND CARE RECOMMENDATIONS FOR PERSONS WITH EPIDERMOLYSIS BULLOSA, CONTINUED

Main Themes Specific Themes Specific Recommendations

Select an appropriate dressing/

topical therapy based on the

subtype of EB

Autolytic debridement: alginates, hydrogels

Superficial critical colonization: silver, honey,

polyhexamethylene biguanide

Moisture balance with silicone coatings to prevent trauma, pain

Evaluate the expected rate of

healing or reassess wound goals

of care

Reassess individuals not healing at the expected rate

Low hemoglobin

Low albumin

Infection

Systemic organ compromise

Edge effect: If a wound is stalled

or the edge/other areas appear

atypical, consider a skin biopsy to

rule out squamous cell carcinoma

or other complications prior to

considering active therapeutic

options

Determine if wound is healable but stalled

Consider advanced or active therapies

Skin graftsbLiving skin equivalents (beware of potential HLA sensitization for

future bone marrow transplant and other procedures)

Biological agents

D. Provide organizational

support

Consider a healthcare system

support structure including

specialized nurses,

interprofessional clinics, and a

structured approach to new cases

Each new case needs diagnosis and

typing/subtyping ASAP

Develop healthcare system support for new patients

(existing models)

Individual patients need community virtual interprofessional team

http://www.internationalebforum.org

aFor professionals requiring further support, contact DebRA or other established EB centers.bIf cellular therapy candidate (identify early, especially junctional EB): use filtered blood products; consider the risk of HLA exposure with any cellular products (eg, allogeneic skin grafting);

optimization of the vaccine strategies for potentially immunocompromised individuals.



http://www.internationalebforum.org


appropriate referralswhere indicatedandprovidepsychosocial sup-

port with information about support and patient advocacy groups.

4B. Quality of life is affected by local wound care.The frequency of dressing changes and time involved depends on

the extent of the wounds and the dressings used. Although many

foam dressings can be left in place for up to 7 days, most patients

with severe EB require dressing changes every day to every 1 to

3 days. The amount of exudate from the wound along with odor

or discomfort will often determine the frequency of dressing

changes. If materials stick, dressing changes may be facilitated by

bathtub bathing and soaking. Baths are preferred over showers

that can cause extension of the blisters due to pressure from the

water stream.

The dressing changes take time, and the dressings themselves

can be hugely expensive. Community nurses are sometimes re-

quired to help with dressing changes, which adds a layer of

scheduling inconveniences and system costs above those already

mentioned. The dressing changes are often very painful, and if

so, it is important to recommend that the patient take an anal-

gesic approximately 30 minutes before the anticipated change.

The need for dressing changes and limitations on mobility makes

schooling and employment challenging for many of the more

severe types of EB patients.

Figure 3.

TYPES OF EB PRESENTATION




LOCAL WOUND CARE

5. Document thewoundsand their ability toheal.Documentation of wounds is best achieved by locationVa body

diagram with the wound location and size is often useful. It is

also important to see the entire skin of a person with EB at least

every 6 months. A rotational system should be worked out with

the patient and his/her circle of care, so that at each visit the most

severe wound is examined along with the needed other areas of

the body to complete the every-6-months skin rotation. Any

wound that appears atypical with stalled healing should be

biopsied. This is particularly important for people with RDEB,

where aggressive squamous cell carcinomas are very common and

can develop at a very young age. The current recommendation is

screening surveillance every 6 months from the age of 10 years in

this group of patients. The risk of developing these lesions in-

creases to 90% of individuals who survive over the age of 50 years.22

One framework that can be used for wound assessment is the

modified MEASURE paradigm (measure size, exudate [amount

and characteristics], appearance [base or granulation tissue],

suffering [pain], undermining [depth measured in centimeters],

re-evaluate, and edge).23 This documentation provides a good

assessment of the extent of the wound in its current state, as well

as a good tool for monitoring the healing process. A modified

model tailored to patients with EB is outlined below in more

detail, with the deletion of undermining.

& Size: This is measured with the longest length and the widest

width at right angles to the longest length.

& Exudate: Exudate is derived from the dermis or deeper struc-

tures and consists of varying amounts of serum, blood, or pus. The

most predominant component should be listed first and then the

subsequent component(s). For example, serosanguineous exu-

date has more serum than blood, or all 3 components may be

present such as sero–pustular-sanguineous.

The amount of exudate is then quantitated as none, scant,

mild, moderate, or heavy. For example, when the dressing is

removed, if there is less than 25% of the surface soiled, the

exudate could be categorized as scant; with 25% to 50%, it would

be a mild exudate; 50% to 75%, moderate exudate; and more

than 75% or wound exudate dressing strikethrough (leakage)

would indicate a heavy exudate.

&Appearance: The wound base and the margin should be as-

sessed. The base can have black, yellow, or red-pink tissue. Black

tissue usually indicates necrosis or tissue death. Yellow can be

fibrin in the wound base that may be healthy, and the lattice

framework for pink buds of healthy granulation to appear. This

needs to be distinguished from loose yellow slough that represents

dead surface cells. Healthy granulation tissue is firm and pink. It

needs to fill the wound base to the level of the wound edge for

epithelium to migrate across the surface as quickly as possible.

Unhealthy granulation tissue has a bright red color, is friable, and

bleeds easily. When a dressing is removed, blood may be obvious

on the inner aspects of the dressing, and punctate bleeding points

are seen on the wound surface. This type of granulation is often

associated with critical colonization of the wound surface and

may respond to topical antimicrobial agents. The wound base can

be characterized as having 50% healthy pink granulation and 30%

unhealthy bright red friable granulation, with 20% yellow slough.

Wound edges may be healthy or unhealthy. A healthy wound

edge often has a tapered appearance like a sandy beach and water

interface. This is often surrounded by a rim of new epithelium that

is often purple in color. A stalled or nonhealing chronic wound often

has a cliff-like edge due to stalled epithelial migration. Unhealthy

wound margins may be red, warm, and edematous with infection

spreading into the wound margin or macerated if there is excess

exudate in the wound base that is not managed by the dressing.

& Suffering (Pain): Pain needs to be documented and is best

measured with an 11-point numerical rating scale. The patient is

given direction that 0 is no pain and 10 is like slamming your

finger in a car door, with 5 representing a bee sting, where is your

pain now? The pain can then be characterized as nociceptive or

neuropathic and treated by the criteria in the section above on

patient-centered concerns.20 Young infants may relate best to the

pictures in the Faces Pain Scale. Most individuals can live with a

pain level of 2 to 3 out of 10. Pain levels of 4 or higher should be

treated. Itch can be as troublesome as pain and needs treatment,

despite the less than optimal results from many of these patients

with traditional sedating antihistamines.

Reassessment: Wounds that are not 30% smaller by week 2 to

4 are unlikely to heal by week 12.24 Because many patients with

EB, especially severe cases, have multiple medical problems and

suboptimal hemoglobin and serum albumin levels, maintenance

or nonhealable wounds are common. Healing may not always be

the primary goal; however, it is desirable. Controlling pain and

preventing infection are often the most important elements.

Edge Effect: This is where patients who have had optimal

treatment of the cause and aggravating factors (where possible),

along with patient-centered concerns and local wound care, may

benefit from advanced therapies as outlined in Figure 2.

6. Gently cleanse wounds with low-toxicitysolutions.Once the old dressing has been removed, the area should be

gently cleaned with solutions with low or no toxicity. Options

include saline solution, water, or solutions with low concentra-

tions of acetic acid (white vinegarV5% diluted 1 in 5 or 1 in 10),

benzalkonium chloride, and/or chlorhexidine. Some patients

may not tolerate the vinegar because of burning or stinging, and




the cleansing agent should be rotated in these cases. The gauze

can be saturated with the solution and applied as a soak to hy-

drate the wound surface with the net movement of liquid from

the gauze to the wound surface. Alternately the same material

can be squeezed or wrung out leaving damp gauze to apply to

the wound, resulting in a compress that acts as an astringent

(coagulates protein). The net movement from a compress is from

the wound surface to the gauze and results in removal of surface

debris. With both methods, the cloth should be changed every

30 to 60 seconds to complete the cleansing process. Irrigation is

too harsh for the fragile skin associated with EB.

Dilute acetic acid will lower the pH of the wound surface, and

this is often helpful to remove Pseudomonas or other gram-

negative organisms from the wound surface that thrive in an

alkaline environment. Pseudomonas has a lower virulence than

most gram-positive organisms (eg, Staphylococcus aureus or Strep-

tococcus) and can often be treated topically rather than with systemic

antibiotics, and it is best to consider 2 topical antimicrobials

(such as acetic acid with silver or iodine preparations).

7. Debridement.The inherent skin fragility of patients with EB requires that extra

care be taken in the changing of dressings and local wound care

in order to prevent further skin damage from mechanical fric-

tion or trauma. Bathing or soaking areas before removing old

dressings can minimize pain and avoid tearing off a superficial

blister roof. Bath water can be made antimicrobial by adding

dilute acetic solution (5% white vinegar diluted to 0.25%–1.0%),

or bleach (5–10 mL in 5 L of water) may decrease the bacterial

carriage.25 It is important to rinse off either of these solutions

with clean water after bathing.

If intact blisters are present, they should be punctured with a

sterile needle and gentle pressure applied to remove the contents.

The roof should be left to act as a natural biologic dressing. If crusts

(scabs) have formed over the wound, they should be soaked and

carefully lifted off as the presence of the eschar can impair heal-

ing and create a proinflammatory stimulus.

8. Assess and treat superficial criticalcolonization, deep and surrounding infection,or inflammation.The presence of infection or inflammation should be clinically

assessed and documented. Helpful tools include the mnemonics

NERDS (nonhealing; increased exudate; red, friable tissue;debris,

dead slough; smell) and STONEES (increased size; temperature

[3- F warmer than contralateral skin]; os, exposed/probing to bone;

new areas of breakdown; erythema/edema of surrounding skin;

increased exudate and smell).26

If there are 3 or more NERDS criteria, a topical antimicrobial

agent may be beneficial including topical dressings with silver,

iodine, polyhexamethylene biguanide, honey, or topical surfac-

tants. Care should be taken using silver dressings or topical prod-

ucts in children as systemic absorption occurs. Some of these

dressings may sting and burn on application, and often it is im-

portant to respect patient preference with careful monitoring of

the clinical results. More detail on these choices can be found in

Wound Bed Preparation 20117 or the complete report on the

consensus document.2

For deep infections, treatment will be based on empirical choices

that should have broad-spectrum coverage, and then more specific

anibiotics can be ordered based on the culture and sensitivity results.

9. Moisture balanceVuse silicone foamsinstead of adhesives.The choice of dressing depends on the wound characteristics,

but should be selected with a goal of optimal moisture balance.

In EB patients, silicone foam dressings work well as they allow

large amounts of fluid to be absorbed while providing protective

padding and will not adhere strongly to the skin when removed

preventing pain and trauma on removal.2 Other nonadherent

moisture balance dressings will also be useful with calcium algi-

nates for areas of bleeding or hydrogels/hydrofibers for gentle

moisture balance where fluid donation or fluid lock is required.

Some highly exudative wounds require fluid lock technology with

superabsorbent dressings with diaper-like technology.

10/11. Evaluate stalled but healable chronicwoundsVedge effect: when to use advancedtherapies.Healable wounds should be 30% smaller by week 4 to heal by

week 12. If a wound has not healed at the expected rate, it

may be stalled. Advanced therapies can be considered in these

circumstances and include advanced wound care matrices, a

group of cellular (living cells) or acellular (biologically inert)

products derived from biological (animal, human, or plant),

synthetic, or composite (combined) sources.27 Unfortunately, the

evidence to date for these therapies has resulted from studies of

other chronic wounds and has not been evaluated in wounds on

patients with EB.7 Apligraf and Dermagraft are living skin sub-

stitutes, both supplying a dermal layer with fibroblasts and colla-

gen, which produce matrix proteins. Apligraf also has an epidermal

layer produced from multiplying keratinocytes forming a replicated

architecture of human epidermis. Studies of the use of Apligraf and

Dermagraft in EB have shown promising effects,4 but further eval-

uation needs to be completed to demonstrate cost-effectiveness

in patients with EB to facilitate healthcare system coverage.

12. Healthcare system support.The treatment of EB is complex and requires a host of inter-

professional team members for optimal care (Figure 4).




Over the past decade, EB specialized clinics have opened in

16 countries. Other resources exist in DebRA programs world-

wide (http://www.debra.org/international) or through http://www.

internationalebforum.org/index.php?id=16.

Each new case requires a diagnosis and typing or subtyping

as soon as possible. Healthcare systems need to build support

networks such as the one established in the United Kingdom

that provides ongoing support from knowledgeable practition-

ers. Families need to regroup, and healthcare providers need to

be flexible to build trust and improve patient outcomes.

SUMMARYEpidermolysis bullosa is a highly complex, multisystem disease,

with severe EB types having devastating effects on the quality of

life and life span of affected patients and their families. Wound

care requires an interprofessional coordinated approach that ad-

dresses the patient as a whole. The authors have brought together

experts in the field of EB, the science of wound care, and clinical

wound care practice to provide the best available approaches for

optimal wound care to people with EB. Until a definitive cure be-

comes available, these practice goals are to minimize suffering, im-

prove wound healing, and prepare patients for potential corrective

procedures, thereby improving the lives of affected individuals.&

REFERENCES1. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa

(EB): report of the Third International Consensus Meeting on Diagnosis and Classification

of EB. J Am Acad Dermatol 2008;58:931-50.

2. Pope E, Lara-Corrales I, Mellerio J, et al. A consensus approach to wound care in

epidermolysis bullosa. J Am Acad Dermatol 2012;67:904-17.

3. Fivenson DP, Scherschun L, Choucair M, et al. Graftskin therapy in epidermolysis bullosa.

J Am Acad Dermatol 2003;48:886-92.

Figure 4.

PATIENT, FAMILY & CIRCLE OF CARE

PRACTICE PEARLS

& Epidermolysis bullosa is a rare group of inherited diseaseswith 4 subtypes that serves as a model for a fragile skin.

& Junctional and recessive dystrophic variants of EB develop

chronic wounds.

& The Wound Bed Preparation paradigm can be used as a

guide to the management of EB associated chronic wounds

(including hemoglobin > 80 and albumin > 2.0).

& Pain and itch are often more important to patients thanhealthcare providers (consider soft silicone dressings, ap-

propriate systemic therapy).

& Atypical nonhealing ulcers should be biopsied to rule out

squamous cell carcinoma.

& Gene therapy and skin equivalents along with other active

therapies may have an important future role in the manage-

ment of EB.



http://www.debra.org/international

http://www.internationalebforum.org/index.php?id=16

http://www.internationalebforum.org/index.php?id=16


4. Sibbald RG, Zuker R, Coutts P, Coelho S, Williamson D, Queen D. Using a dermal skin

substitute in the treatment of chronic wounds secondary to recessive dystrophic epidermolysis

bullosa: a case series. Ostomy Wound Manage 2005;51(11):22-46.

5. Sibbald RG, Orsted H, Schultz GS, Coutts P, Keast D; International Wound Bed Preparation

Advisory Board; Canadian Chronic Wound Advisory Board. Preparing the wound bed 2003:

focus on infection and inflammation. Ostomy Wound Manage 2003;49(11):23-51.

6. Kirshen C, Woo K, Ayello EA, Sibbald RG. Debridement: a vital component of wound bed

preparation. Adv Skin Wound Care 2006;19:506-17.

7. Sibbald RG, Goodman L, Woo KY, et al. Special considerations in wound bed preparation

2011: an update. Adv Skin Wound Care 2011;24:415-36.

8. Kiuru M, Itoh M, Cairo MS, Christiano AM. Bone marrow stem cell therapy for recessive

dystrophic epidermolysis bullosa. Dermatol Clin 2010;28:371-82.

9. Wagner JE, Ishida-Yamamoto A, McGrath JA, et al. Bone marrow transplantation for recessive

dystrophic epidermolysis bullosa. N Engl J Med 2010;363:629-39.

10. Sibbald RG, Krasner DL, Lutz J. SCALE: Skin Changes at Life’s End: final consensus statement:

October 1, 2009. Adv Skin Wound Care 2010;23:225-36.

11. Intong LR, Murrell DF. Inherited epidermolysis bullosa: new diagnostic criteria and classi-

fication. Clin Dermatol 2012;30:70-7.

12. Wong T, Gammon L, Liu L, et al. Potential of fibroblast cell therapy for recessive dystrophic

epidermolysis bullosa. J Invest Dermatol 2008;128:2179-89.

13. Mellerio JE, Weiner M, Denyer JE, et al. Medical management of epidermolysis bullosa:

proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile,

2005. Int J Dermatol 2007;46:795-800.

14. Bolitho C, Xaymardan M, Lynch GW, Zoellner H. Vascularity during wound maturation

correlates with fragmentation of serum albumin but not ceruloplasmin, transferrin, or

haptoglobin. Wound Repair Regen 2010;18:211-22.

15. Posthauer ME. The role of nutrition in wound care. Adv Skin Wound Care 2012;25:62-3.

16. Keast DH, Fraser C. Treatment of chronic skin ulcers in individuals with anemia of chronic

disease using recombinant human erythropoietin (EPO): a review of four cases. Ostomy

Wound Manage 2004;50(10):64-70.

17. Trengove NJ, Stacey MC, MacAuley S, et al. Analysis of the acute and chronic wound

environments: the role of proteases and their inhibitors. Wound Repair Regen 1999;

7:442-52.

18. Lara-Corrales I, Parkin PC, Stephens D, et al. The efficacy of trimethoprim in wound heal-

ing of patients with epidermolysis bullosa: a feasibility trial. J Am Acad Dermatol 2012;

66:264-70.

19. van Scheppingen C, Lettinga AT, Duipmans JC, Maathuis CG, Jonkman MF. Main problems

experienced by children with epidermolysis bullosa: a qualitative study with semi-structured

interviews. Acta Derm Venereol 2008;88:143-50.

20. Woo K, Sibbald G, Fogh K, et al. Assessment and management of persistent (chronic)

and total wound pain. Int Wound J 2008;5:205-15.

21. Sarzi-Puttini P, Vellucci R, Zuccaro SM, Cherubino P, Labianca R, Fornasari D. The appropriate

treatment of chronic pain. Clinical Drug Investig 2012;32(Suppl 1):21-33.

22. Fine JD, Johnson LB, Weiner M, Li KP, Suchindran C. Epidermolysis bullosa and the risk of

life-threatening cancers: the National EB Registry experience, 1986-2006. J Am Acad

Dermatol 2009;60:203-11.

23. Keast DH, Bowering CK, Evans AW, Mackean GL, Burrows C, D’Souza L. MEASURE: a proposed

assessment framework for developing best practice recommendations for wound assessment.

Wound Repair Regen 2004;12(3 Suppl):S1-17.

24. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. The accuracy of venous leg ulcer prognostic

models in a wound care system. Wound Repair Regen 2004;12:163-8.

25. Mellerio JE. Infection and colonization in epidermolysis bullosa. Dermatol Clin 2010;28:267-9.

26. Woo KY, Sibbald RG. A cross-sectional validation study of using NERDS and STONEES

to assess bacterial burden. Ostomy Wound Manage 2009;55(8):40-8.

27. Hankin CS, Knispel J, Lopes M, Bronstone A, Maus E. Clinical and cost efficacy of advanced

wound care matrices for venous ulcers. J Manage Care Pharm 2012;18:375-84.

CONTINUING MEDICAL EDUCATION INFORMATION FOR PHYSICIANS

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PROVIDER ACCREDITATION INFORMATION FOR NURSESLippincott Williams & Wilkins, publisher of the Advances in Skin

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Epidermolysis Bullosa and Chronic Wounds: A Model for ... · DIME: debridement, infection/inflammation control, and moisture balance before the edge effect for advanced therapies