Nutritional Profile and Topic Management for Wound Healing in Children with Epidermolysis Bullosa: What Is the Evidence? A Systematic Review

Maria Lúcia dos Santos , Ana Cristina Monteiro , Andréa Nascimento , Sívia Barbosa , Artur Delgado , Patrícia Zamberlan ^*

1. Instituto da Criança e do Adolescente do Hospital das Clínicas - Faculty of Medicine/University of Sao Paulo, Butantã, SP, Brazil

* Correspondence: Patrícia Zamberlan

Academic Editor: Amy Anne D. Lassig

Special Issue: Clinical Nutrition: Recent Advances and Remaining Challenges in Aiding Acute Surgical or Traumatic Wound Healing

Received: April 11, 2024 | Accepted: July 09, 2024 | Published: July 17, 2024

Recent Progress in Nutrition 2024, Volume 4, Issue 3, doi:10.21926/rpn.2403010

Recommended citation: dos Santos ML, Monteiro AC, Nascimento A, Barbosa S, Delgado A, Zamberlan P. Nutritional Profile and Topic Management for Wound Healing in Children with Epidermolysis Bullosa: What Is the Evidence? A Systematic Review. Recent Progress in Nutrition 2024; 4(3): 010; doi:10.21926/rpn.2403010.

© 2024 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

Wounds acquired as a result of genetic diseases such as EB are challenging to treat, as the drugs used, whether topical or not, tend to stabilize them momentarily. They often reappear whenever there is a care failure and can occur spontaneously during daily tasks [1].

Epidermolysis bullosa (EB) is a group of rare, inherited skin disorders characterized by extreme fragility of the skin and mucous membranes, leading to blisters and erosions in response to minor mechanical trauma or friction. Mutations in genes responsible for the structural integrity and adhesion of the skin layers cause this condition. Depending on the specific genetic mutations and the proteins involved, EB can be classified into several subtypes, varying in severity and clinical presentation. Despite the passing years and several emerging researches, there is still no cure; topical therapies may help alleviate some symptoms and discomfort, improving patients' quality of life [1,2].

This class of skin disease is comprehensive and can be divided according to the degree of phenotypic manifestations and the level of tissue separation within the cutaneous basement membrane zone [3]. The molecular complexity of these subtypes is compounded by the variability in mutation types (missense, nonsense, insertions, deletions), their locations within the genes, and the resultant effects on protein function. This complexity leads to a wide range of clinical manifestations, from mild blistering to severe, life-threatening conditions, and necessitates tailored approaches to diagnosis, management, and potential therapeutic interventions. The four main types are EBS, JEB, DEB, and EB Kindler, which are differentiated by the level of blister cleavage and subdivided according to the pattern of genetic inheritance, lesion morphology, and involved genetic mutation [1,2,3,4]:

• EBS: This subtype is typically caused by mutations in the KRT5 and KRT14 genes, which encode keratin proteins K5 and K14. These proteins are crucial for the structural stability of the epidermal keratinocytes;
• JEB: This subtype is associated with mutations in genes such as LAMA3, LAMB3, LAMC2, and COL17A1, which encode components of the hemidesmosomes and anchoring filaments, such as laminin-332 and type XVII collagen. These mutations disrupt the adhesion between the epidermis and the dermis, causing blistering at the level of the lamina lucida within the basement membrane zone;
• (DEB): This subtype is caused by mutations in the COL7A1 gene, which encodes type VII collagen, a critical component of anchoring fibrils that secure the epidermis to the dermis. DEB can further be divided into two subtypes: recessive and dominant. Recessive DEB (RDEB) is the most severe type, transmitted when both parents carry the defective gene, and Dominant DEB (DDEB) can be transmitted if only one parent carries the faulty gene, and it typically presents with milder clinical symptoms,
• EB Klinder: This rare subtype involves mutations in the FERMT1 gene, which encodes kindlin-1, a protein essential for cell adhesion, signaling, and cytoskeletal organization.

The most important aspects for children with EB are care-related, including proper wound management and dressing changes. Skin protection measures are also vital to decrease tissue rupture. Children are usually active and engage in constant movement inherent to their age, which results in more skin lesions and thus should be avoided, as friction and shear forces can exacerbate blister formation.

Nutrition plays a vital role in symptom control and proper wound healing, which may be compromised by malnutrition, itching, and pain. A balanced diet rich in proteins, vitamins, and minerals aids in wound healing and improves the immune system's performance. Children with EB have an increased risk of developing infections, anemia, and growth deficits, and therefore, nutrition seems promising in treatment [5]. Personalized nutritional interventions are necessary for patients with EB and monitoring by specialists, given the importance of managing the nutritional alterations and deficiencies the patient faces, thus ensuring well-being and quality of life.

The involvement of various specialists is necessary for maintaining care, as well as close monitoring by a multidisciplinary team including physicians, nutritionists, nurses, psychologists, therapists, pharmacists, and physiotherapists, who should work closely together to ensure that the patient's needs are met and that the care plan is adjusted as necessary. For effective wound management associated with EB, professionals must understand the underlying causes and contributing factors to its development [3,5,6].

Advances in research and treatment options offer hope that children with EB may have a better quality of life, with minimized symptoms and maximized comfort and well-being.

1.1 Review Question

What is the nutritional status of children with EB, and what are the available and effective treatments for wound healing?

1.2 Objectives

• To identify and synthesize the available evidence on wound healing in patients with EB;
• To describe the nutritional profile of children diagnosed with EB.

2. Material and Methods

This systematic review was conducted following the guidelines of the Joanna Briggs Institute and The PRISMA [7,8].

2.1 Eligibility Criteria

2.1.1 Participants

Patients up to 19 years old, with no gender, race, and/or socioeconomic status restrictions, were diagnosed with EB undergoing wound treatment.

2.1.2 Interventions

This review considered studies that used dressings, bandages, and/or ointments with pharmacological or non-pharmacological principles to heal wounds and evaluated the nutritional status, wound area, presence of wound infection, and time to wound healing in patients with EB. The interventions were used independently and/or in combination. All interventions used for wound healing in patients with EB were included.

2.1.3 Comparators

The usual care described in the primary studies, such as saline solution, placebo, and non-adherent gauze, were considered comparators.

2.1.4 Outcomes

This review considered studies that assessed the nutritional status, types of topical wound treatments, time to wound healing, wound area, and presence of wound infection.

2.1.5 Types of Studies

Included were studies with a multicenter randomized clinical trial design, single-center randomized clinical trial design, retrospective observational study, longitudinal study, and cross-sectional study.

2.2 Search Strategy

The search strategy was conducted in three stages to identify published and unpublished studies. The search was limited to 1 January 1984 to 31 January 2024. The same search strategy was used for all databases included in the survey (considering the controlled language of each). These databases included Web of Science, LILACS, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the Brazilian Registry of Clinical Trials. ProQuest and the Brazilian CAPES Thesis Database were searched to identify unpublished studies. The following descriptors were used: Epidermolysis Bullosa, Wound Healing, Nutritional Status, Malnutrition, Nutritional Support, and Children.

2.2.1 Study Selection

The searches identified during the search were uploaded to the reference manager myendnoteweb.com (Clarivate Analytics, PA, USA), and duplicates were removed. Titles and abstracts were screened by two independent reviewers, guided by inclusion and exclusion criteria. Two independent reviewers reviewed full texts. There was no disagreement at this stage, and the search and selection process is described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [7] flow diagram.

2.2.2 Quality Assessment

Two independent reviewers conducted the methodological quality assessment. For studies with a randomized controlled trial design, the Risk of Bias 2 (RoB 2) tool from Cochrane [8] was used, comprising five questions that assess bias related to the randomization process, deviation from planned interventions, missing outcome data, outcome measurement bias, and bias in the selection of reported results. For studies with a quasi-experimental design, the checklist for quasi-experimental studies (non-randomized experimental studies [9]) was utilized, consisting of nine questions that evaluate the clarity of cause and effect relationships, similarity between treatment groups, and variation in outcome measures. The certainty of evidence was assessed using GRADEPro [10].

2.2.3 Data Extraction

Data were extracted from the studies by two independent reviewers using the standardized data extraction tool in Joanna Briggs [11]. The extracted data included specific details about the participants (age, gender, subtype of EB, type of intervention, measured outcomes, country and year of publication, wound size, time to wound healing, and nutritional status). There were no disagreements between the reviewers at this stage. The results of the extraction of the studies were reported in the form of narrative synthesis and tables and odds ratio.

2.2.4 Data Synthesis

The data were combined using the standardized mean difference (SMD) and the random-effects model [12], a meta-analysis approach to standardize and combine the results of studies that assessed the same outcome but measured it differently [13]. For the combination of dichotomous data, the odds ratio (OR) and the fixed-effects model were used in the absence of significant heterogeneity (I² ≤ 50%). In contrast, the random-effects model was chosen despite considerable heterogeneity [14].

Heterogeneity among studies was assessed using the I² test, with statistical significance at p < 0.05. I² values ranging from 0% to 25% indicate low heterogeneity, 25% to 75% moderate heterogeneity, and greater than 75% high heterogeneity.

Studies were included in the meta-analysis if the measured results were sufficiently similar to be combined and contained sufficient data.

The meta-analysis results were presented using forest plots, and the potential publication bias of included studies was assessed using funnel plots. Statistical calculations were performed using Review Manager software version 5.4.1 from Cochrane [15].

The certainty of evidence was assessed using the GRADEPro [10] system, as summarized in Table 1.

Table 1 Recommendation grades for the certainty of evidence from studied outcomes in the review.

Results were presented descriptively in tables and figures for studies not included in the meta-analysis.

3. Results

3.1 Search and Selection of Studies

Through a database search, 1044 articles were identified. After examining titles and abstracts, 994 articles were considered out of this review's scope and were excluded. Further screening was performed by reading the full text, and 16 articles were found to be non-eligible. After a second evaluation, 5 articles were excluded due to: participants over 19 years old (n =2) and articles just about the pharmacodynamic profile of the medicine used in the treatment (n = 4). Finally, 28 articles met the inclusion criteria and were finally considered in the present systematic review.

Figure 1 displays the flowchart for the assessment and eligibility of the studies included in the review.

Figure 1 Flow diagram of studies assessed for eligibility per screening stage. (From Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71. doi: 10.1136/bmj.n71. [7].

3.2 Characteristics of Included Studies

The selected studies for the review are described in Table 2.

Table 2 Characteristics of the studies included in the review.

The 30 articles included in the review examined 994 patients with Epidermolysis Bullosa, with 21 conducted as clinical trials [16,24,25,26,27,28,29,30,31,40,41,42,43,44,45] and seven conducted as observational studies [22,32,34,35,36,37,38]. The majority of them described the disease subtypes as Simplex EB (EBS) [17,18,20,23,25,32,34,36,39,41,42], Junctional EB (JEB) [17,20,21,23,25,29,32,34,35,36,37,41,42], Dystrophic EB (DDEB) [17,18,19,20,21,22,24,25,29,31,32,34,35,37,38,42,45] and Kindler [21,29,31]. Of the studies that contained information on gender, 415 (41.7%) patients were female, and 450 (45.3%) were male.

The central interventions studied in the primary research for wound healing varied from dressings and coverings with collagen [24], cellulose [16], carboxymethylcellulose [16], cotton acetate [17], 1% mupirocin creams [17], 10% birch triterpenes [20,22,25,29], 3% and 6% allantoin [23,25,31], diacerein [26,40,41,44], 1% henna [27], calcitriol [30], fibroblasts [30], hydrocolloid (HCD) [45], tissue-engineered skin [42].

Of the studies included in the review, only 6 assessed the nutritional status [32,34,35,36,37,38], with 5 demonstrating the nutritional condition by subtypes of the disease [32,34,35,37,38]: 6 used anthropometry [32,34,35,36,37,38], 2 analyzed patients' dietary intake and adequacy [37,38], hemoglobin was collected in 4 studies (to assess the presence of anemia) [32,34,35,36], 2 studies had values of albumin [32,35], zinc [32,35], and vitamin D [34,35], 1 study assessed ferritin [32], and 1 assessed vitamin B12 [35].

Figure 2 summarizes the main clinical factors related to alterations in the nutritional status of patients with EB among the selected studies for the review that evaluated the patients' nutritional condition.

Figure 2 Clinical factors related to alterations in the nutritional status of patients with EB among the selected studies for the review. Source: Adapted from Morales-Olvera D, Gris-Calvo JI, García-Romero MT. Nutritional status of pediatric patients with epidermolysis bullosa. A cross-sectional study. Nutr Clín Diet Hosp. 2022; 42: 146-151. [37]

EB is a rare genetic disease without racial or color preference. Figure 3 illustrates the countries of origin of the patients included in this review, demonstrating that EB affects patients worldwide.

Figure 3 Countries of origin of the patients included in the review.

3.3 Quantitative Synthesis

In a combined estimate from four studies [17,20,25,43] measuring the effect of topical treatment for wound healing in EB patients, the outcome favored topical treatment compared to control (SMD -0.82; 95% CI -1.26 – 0.38, N = 482, I² = 71%), as shown in Figure 4. The most effective topical treatments, according to the review, were 6% allantoin cream, 10% birch bark extract in gel, cotton acetate dressing coated with dialkylcarbamoylchloride chloride, biocellulose and carboxymethylcellulose dressing.

Figure 4 The effectiveness of topical treatment in wound healing among patients with EB.

After the combined analysis, a subgroup analysis was conducted to assess the effectiveness of topical treatment in wound healing among patients with EB at 30, 60, and 90-day follow-ups, and the effect of topical treatment on wound and itch control was examined. These results are described in Figure 5.

Figure 5 Effectiveness of topical treatment in wound healing among patients with EB at 30, 60, and 90-day follow-ups, and the effect of topical treatment on wound and itch control.

It is possible to observe differences in wound healing between the subgroups that received the topical treatment compared to the group that did not receive it (control) at 30 and 60 days. The same did not occur at 90 days. There were differences in infection control but not in itching.

After analyzing 5 studies [32,34,35,36,37] that evaluated patients with EB and malnutrition, it was possible to observe that patients with DEB have a 2.5 times higher chance of presenting the condition when compared to patients with JEB, as seen in Figure 6. However, it is essential to remember that the small number of studies in the review makes it impossible to generalize such results. It is known that DEB can be more severe due to the formation of blisters below the dense lamina of the basal layer of the skin, leading to more incredible difficulty in healing, as well as other complications, including malnutrition. Difficulty feeding is also present due to blisters in the oral cavity (mouth), throat, and esophagus, which are sometimes very painful. Pain associated with chewing and swallowing can lead to food refusal and insufficient intake of nutrients.

Figure 6 Prevalence of malnutrition by EB subtype (DEB and JEB).

Additionally, more significant protein loss is associated with insufficient protein intake since the blisters on the skin can result in loss of fluids and proteins, leading to malnutrition. This loss can be significant, leading to protein malnutrition, characterized by inadequate protein intake. Scars resulting from blisters can lead to contractures and limitations in joint movement, affecting the patient's ability to eat correctly. Some patients with EB may require dietary alterations, sometimes making it difficult to ingest nutrients, increasing the risk of undernutrition.

3.4 Risk of Bias Assessment

The Critical Appraisal Tool for Quasi-Experimental Studies [9] checklist was used to evaluate the studies with quasi-experimental design. The result indicated a low risk of bias. Table 3 shows the utilization of the checklist for assessing the experimental studies included in the review and the total score of each study.

Table 3 Evaluation of methodological quality of quasi-experimental studies included in the review.

1. Is it clear in the study what is the ‘cause’ and what is the ‘effect’ (i.e. there is no confusion about which variable comes first)?, 2. Were the participants included in any comparisons similar?, 3. Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?, 4. Was there a control group?, 5. Were there multiple measurements of the outcome both pre and post the intervention/exposure?, 6. Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?, 7. Were the outcomes of participants included in any comparisons measured in the same way?, 8. Were outcomes measured in a reliable way?, 9. Was appropriate statistical analysis used?.

The experimental studies included in the review met the JBI critical appraisal criteria, whose checklist is composed of 9 questions. Positive evaluations were found for 7 out of 9 questions in 5 studies and for 8 questions in 2 studies, denoting a low risk of bias and high methodological rigor. Two questions did not apply to the majority of the studies.

Two independent reviewers conducted the assessment of studies with a clinical trial design. The evaluation result indicates a low risk of bias, as demonstrated in Figure 7.

Figure 7 The percentage of risk of bias (high, low, or unclear) of the studies with a clinical trial design is included in the review.

Figure 8 summarizes the bias of the clinical trial studies assessed using the Rob2 scale. The main biases are related to allocation concealment (selection bias), blinding of participants and personnel (performance bias), and blinding of outcome assessment (detection bias), observed in 6 out of the 21 studies included in the review.

Figure 8 Summary of bias risk of the studies with a clinical trial design included in the review.

Figure 9 depicts the publication bias of the quantitative analyses. The graphs show that there is a certain asymmetry in the qualitative analysis, which may indicate publication bias, with a variety of accuracies among the studies.

Figure 9 Funnel plot showing publication bias of the quantitative analyses: A) in the effect of topical treatment on wound healing in patients with EB; B) in the subgroup analysis of the effect of topical treatment on wound healing in patients with EB; C) in the analysis of malnutrition presence by disease subtype.

3.5 Assessment of Evidence Certainty

Evidence certainty was evaluated using the GRADEPro [10] software. Table 1 compiles the Recommendation Grades for the certainty of evidence related to the outcomes studied in the review. Following the analysis, a very low recommendation grade was observed for all evaluated outcomes.

4. Discussion

The review provides a comprehensive synthesis of available evidence on wound healing and nutritional profiles in patients with EB. A total of 28 articles were included, encompassing both clinical trials and observational studies involving 994 patients with various subtypes of EB.

It is well acknowledged that malnutrition poses a significant challenge for children with EB, as noted in this review and supported by numerous studies. Malnutrition in EB patients is often attributed to both inadequate intake of essential macro and micronutrients and the body's inability to effectively process and utilize nutrients, which stems from the inherent difficulties faced by children with EB [36]. These difficulties are further compounded by issues such as blistering and open wounds in the mouth and gastrointestinal tract, leading to reduced food intake due to pain and discomfort [46,47].

The dietary challenges children with EB encounter result in poor nutritional intake, particularly in essential nutrients such as protein, vitamin D, calcium, and iron. High carbohydrate intake is emphasized as crucial for EB patients due to the impaired wound healing process resulting from frequent damage to the skin's basal membrane zone, which requires significant carbohydrate resources for repair. Additionally, protein and its constituent amino acids are highlighted as crucial building blocks not only for skin but also for other tissues, making adequate protein intake vital for EB patients who have numerous wounds and frequent blistering, necessitating a higher protein requirement compared to the average individual [47,48].

Regarding nutritional profiles, the review indicates a relative lack of focus on this aspect, with only six studies assessing the nutritional status of patients [32,34,35,36,37,38]. These studies employed various methods, including anthropometry, dietary intake analysis, and measurement of specific nutritional markers such as hemoglobin, albumin, zinc, vitamin D, ferritin, and vitamin B12, and only two analyzed patients' dietary intake and adequacy [37,38]. Despite limited attention, the findings suggest that malnutrition may be more prevalent in some subtypes of EB, such as JEB and DEB, than in other subtypes [35,37,38,39,40].

One notable finding from the review is the identification of an odds ratio indicating a higher prevalence of malnutrition among patients with DEB than JEB. Studies have demonstrated that this subtype presents a higher involvement of oral and gastric mucosa, thereby interfering with absorption and predisposing to malnutrition and other complications such as anemia, dental caries, constipation, and bacterial infection. Indirectly, these complications also contribute to malnutrition [49]. This underscores the importance of considering nutritional support as an integral part of the management strategy for patients with EB, particularly those with more severe clinical alterations.

In the management of individuals with EB, nursing intervention plays a paramount role. Nursing support extends beyond wound care to include crucial educational roles for patients and their families regarding the disorder and its effective management. Preventive measures against complications such as infections and pain management are also essential, alongside efforts to facilitate psychosocial balance. Well-trained nurses providing appropriate care can significantly enhance the quality of life for those affected by EB, ensuring support across both emotional and physical domains [48,50].

In terms of wound healing interventions, the primary research explored a diverse range of approaches, including dressings with collagen, cellulose, carboxymethylcellulose, and various topical creams such as mupirocin, birch triterpenes, allantoin, diacerein, henna, and calcitriol. Additionally, some studies investigated the use of fibroblasts and tissue-engineered skin [16,17,20,22,23,25,26,29,30,31,40,41,42,44,45]. This diversity highlights the ongoing efforts to find effective strategies for managing wound healing in EB patients once the molecular complexity of the subtypes leads to a wide range of clinical manifestations, from mild blistering to severe, life-threatening conditions, and necessitates tailored approaches to diagnosis, management, and potential therapeutic interventions. Subgroup analyses were conducted to assess the effectiveness of topical treatments in wound healing at different follow-up periods, as well as their impact on wound infection and itch control. Such analyses provide valuable insights into the efficacy of interventions over time and their broader effects on patient outcomes.

The results of this review are supported by the findings of a recent systematic review with meta-analysis [51], which evaluated topical treatment for wound healing in patients with EB. The meta-analysis revealed a shorter time for wound healing at 14 and 30 days with topical treatment compared to standard care. However, it is essential to note that the heterogeneous nature of the topical therapies assessed may limit the generalizability of these results, as they vary in administration method and treatment mechanism. Furthermore, the review identified differences in infection control with topical treatments but found no significant differences in itch control. This may suggest that topical measures may not effectively control itching, or it could be attributed to the limited number of studies assessing and measuring this effect, highlighting the need for further research to evaluate and quantify this effect on wound healing in EB patients.

Overall, the review highlights the complexity of managing EB, with many interventions being explored for wound healing, and underscores the need for further research into the nutritional aspects of the disease. By synthesizing existing evidence, the review provides valuable insights that can inform clinical practice and guide future research directions in EB management.

5. Conclusion

This review revealed a diverse range of interventions for wound healing, including dressings, creams, and tissue-engineered skin for patients with EB. However, there remains a limited understanding of the nutritional status of EB patients. The analyses suggested a higher prevalence of malnutrition among patients with the severe subtypes of EB, particularly Dystrophic EB (DDEB), compared to Junctional EB (JEB). This underscores the importance of addressing nutritional needs in comprehensive EB management.

Thus, this review provides valuable insights into the current research landscape on wound healing and nutrition in EB, laying the groundwork for future studies to advance our understanding and improve clinical management strategies for this complex and debilitating condition.

Author Contributions

All authors contributed to the study design. MLS collected and analyzed data. ACM, AN and SB wrote the original draft of the manuscript. PZ and AD reviewed and edited the manuscript.

Competing Interests

The authors have declared that no competing interests exist.