Intact fish skin graft a new hope for the treatment of diabetic foot ulcers: A case report

Abstract

BACKGROUND

Diabetic foot ulcers (DFUs) are a real public health problem which carry a high risk of amputation. The treatment of DFUs is based on general management such as the treatment of infection, arterial disease, and offloading, but recent studies have shown that the quality of the local covering can impact the healing rate.

CASE SUMMARY

We report the case of a 39-year-old man, living with diabetes since the age of 15, who developed DFU on the dorsum of his left foot, with muscle and tendon involvement. Conventional management with intensive diabetes control, surgery, treatment of infection and negative pressure therapy gave only limited results. The patient benefited from the application of an intact fish skin graft with complete epithelialisation of the ulcer after 10 weeks of treatment.

CONCLUSION

The use of intact fish skin graft appears to be a promising option for deep DFUs.

Key Words: Intact fish skin graft; Diabetic foot ulcer; Foot amputation; Case report

Core Tip: Diabetic foot ulcers (DFUs) are a real public health problem which carry a high risk of amputation. The treatment of DFUs is based on general management such as the treatment of infection, arterial disease, and offloading, whereas the application of an intact fish skin graft may be a new hope for the treatment of DFU.

INTRODUCTION

Diabetic foot ulcers (DFUs) are a real public health problem the quality of patients’ lives[1]. Once a DFU is diagnosed, the patient’s 5-year mortality index increases 2,5-fold compared to a diabetic patient without a foot ulcer[2]. The proportion of persons with diabetes and a history of foot ulceration is understandably higher than the proportion with an active ulcer without diabetes; 3.1 to 11.8% of persons with diabetes are living with DFU, or 12.9 million to 49.0 million persons worldwide, and 1.0 million to 3.5 million in the United States alone, have a history of foot ulceration[3]. The lifetime incidence of foot ulcers has previously been estimated to be 15% to 25% among persons with diabetes[4,5]. Barring the presence of primary arteriopathy DFU is classified as DFU with or without infection[6]. More than half of diabetic ulcers become infected[7]. It has already been confirmed that if a DFU is managed by a multidisciplinary team, the risk of amputation is lessened[8,9].

The treatment of DFUs consists of general actions such as vascular assessment, infection control, and offloading. Recently, the management of local dressings has appeared as an element that can impact on the healing process[10]. The Explorer study, a double-blind randomised control trial (RCT) demonstrated the efficacy of local treatment in the management of DFUs[11]. In this RCT (muti-center, in five European countries), 240 participants living with diabetes complicated by DFUs were randomised into two groups: 126 to receive a sucrose octasulfate dressing and 114 to receive a control dressing. At 20 weeks 60 patients (48%) in the sucrose octasulfate dressing group and 34 patients (30%) in the control dressing group attained wound closure (18 percentage difference, 95%CI: 5-30; adjusted odds ratio 2.60, 95%CI: 1.43-4.73; P = 0.002), whoever 80% of the ulcers treated in explorer RCT were superficial (UT grade 1), had somewhat poorer glycemic control (hemoglobin A1c 8.2%-8.6%)[11].

In contrast, cell- and tissue-based wound treatment agents have made slow progress in the management of unhealed wounds over the past 20 years. The first major trials of cell- and tissue-based wound treatment agents-were reported in early for the treatment of venous lower leg ulcers[12]. The most significant of these trials used porcine enteric small intestine as the experimental arm. Subsequently, a number of other tissue types have been explored and used, principally decellularised mammalian membrane organs, as well as skin cell counter parts and frozen amnion membranes. In 2013, a new material received approval from the United States Food and Drug Authority: Decellularised fish skin (Kerecis^® Omega3 Wound™, Kerecis, Iceland). Supplied as a sterilised and freeze-dried material, the fish skin graft, which was originally a by-product of fish manufacturing, has the advantage of not having to be processed with antibiotics and viral inhibition processes, allowing the natural omega-3 fatty acids to be retained. Clinically, they have contributed to the healing of long-term wounds[13], so their inclusion in the management of DFU is justifiable.

CASE PRESENTATION

Chief complaints

We report the case of a 39-year-old man, living with diabetes since the age of 15, who developed DFU on the dorsum of his left foot, with muscle and tendon involvement.

History of present illness

The patient is 35 years old and has been living with type I diabetes since the age of 15 years. He contacted the diabetology department for a DFU that appeared after the use of inappropriate footwear. The lesion was located on the dorsum of his right foot with signs of inflammation and infection, and necrotis of the 4^th toe. The DFU communicated with a plantar lesion on the same foot (Figure 1).

Figure 1 Patient’s diabetic foot ulcer affecting deep skin, muscle and bone structures at the first consultation. A: Pantar face of wound; B: Dorsal face of the wound.

History of past illness

Biological assessment showed a glycated haemoglobin level of 9.2%, a C-reactive protein (CRP) level of 230 milligrams per litre, and hyperleukocytosis with 13890 white blood cells (WBC) per microlitre. The patient was admitted to hospital, and intravenous antibiotic therapy with amoxicillin/clavulanic acid administered for 7 days. An arterial Doppler ultrasound was performed showing adequate patency of the involved arteries. This young patient had sensory neuropathy confirmed by an abnormal response to monofilament test. Surgical management was undertaken as an emergency with amputation of the 4^th toe and surgical cleaning of the entire lesion. Following surgical management, the patient received negative pressure therapy (VAC). After 15 days the VAC therapy was stopped due to the deterioration of the wound (Figure 2).

Figure 2 Poor evolution after 15 days of Vacuum Assisted Closure™ therapy use.

Lab values showed CRP was still high at 140 mg/L, and WBC at 14500/L. Clinically the wound was deep, dry, and infected involving the whole dorsum of the foot. The surgical opinion was to perform a trans-metatarsal amputation, but the patient refused this option and was included in a then ongoing study on the use of intact fish skin on severe DFUs (Odin) a multicenter, randomised, open-label, controlled, concurrent trial performed in 15 specialist diabetic foot unit care centres in France, Italy, Germany and Sweden in patients with profound diabetic ulcers and peripheral arterial disease evaluated by an ankle brachial index equal to or greater than 0.6. The trial has parallel arms: Group 1 therapy with Kerecis^® Omega3 Wound™ vs group 2 therapy with standard care. The main aim is to test the assumption that more patients with serious diabetic ulcers and amputation wounds, including those with moderate arterial disease, will heal within 16 weeks when treated with Kerecis^® Omega3 Wound™ than with standard care[14].

The application of the fish skin graft was done according to protocol, once per week. The use of the product is allowed after a non-surgical mechanical debridement of the DFU. The first two applications were done during the hospitalisation and after that by nurses in the patient’s home. After the third application of the fish skin graft, biological assessment revealed CRP had decreased to 34 mg/L, and WBC dropped to 10500/L. The patient reported a decrease in pain and there was a significant reduction in the amount of analgesic treatment prescribed (initially morphine derivate was prescribed). Mechanical debridement of the lesion was performed by the home nurse before each application of the fish skin, and surgical debridement was not required (Figure 3).

Figure 3 The application of the Kerecis matrix performed by nurse as new treatment for deep diabetic foot ulcer. A: The application of the matrix to the wound; B: The Kerecis matrix.

Application of the fish skin graft was performed according to research protocol once per week for a period of 10 weeks, and then once every two weeks after the 10th week. By the end of this period, a complete healing of the lesion was observed (Figures 4 and 5) with complete epithelisation of the DFU.

Figure 4 Improvement of the local appearance after 4 weeks of Kerecis application.

Figure 5 Complete epitalization of diabetic foot ulcer after week 10.

It should be noted that the patient was never hospitalised during the period of care, and the analgesic therapy was suspended after 6 applications of the fish skin graft.

Personal and family history

The patient denied any family history of diabetic ulcer.

Physical examination

On physical examination, the vital signs were as follows: Body temperature, 36.5 ℃; blood pressure, 117/68 mmHg; heart rate, 82 beats per min; respiratory rate, 19 breaths per min. Furthermore, a painful nodular mass, with a diameter of 1.5 cm, was found on the left penis. There was no obvious redness and swelling. The glans, testis, and epididymis were normal. No secretion was found at the urethral orifice. Digital anal examination was not performed.

Laboratory examinations

Lab values showed CRP was still high at 140 mg/L, and WBC at 14500/L.

FINAL DIAGNOSIS

We report the case of a 39-year-old man, living with diabetes since the age of 15, who developed DFU on the dorsum of his left foot, with muscle and tendon involvement.

TREATMENT

Decellularised fish skin (Kerecis^® Omega3 Wound™, Kerecis, Iceland) applicated once per week for a period of 10 weeks, Intensive insulin therapy by un association of Glargine 30 unites/day + Aspart 10 unites before each meal.

OUTCOME AND FOLLOW-UP

Application of the fish skin graft was performed according to research protocol once per week for a period of 10 weeks. The patient was admitted once every 15 days to the diabetic foot ambulatory unit to assess the wound and reassure himself that the matrix was well tolerated and, above all, that he was using an offloading device. once the wound had healed, a pair of customised shoes was made to reduce the risk of the ulcer reoccurring.

DISCUSSION

The value of local treatment in the management of DFUs was highlighted by the randomised controlled trial Explorer, conducted in 43 hospitals with specialised diabetic foot clinics in France, Spain, Italy, Germany, and the United Kingdom. The Explorer subjects had diabetes and an uninfected neuroischaemic DFUs greater than 1 cm² and grade IC or IIC (as defined by the University of Texas Diabetic Wound Classification System (UT)[15], This innovation in the management of DFU has had a real impact on the use of local treatment and has been included in the recommendations of the International Working Group on the Diabetic Foot[10]. The Explorer study, however leaves a knowledge gap on the local tissue treatment of the severe infected DFU, as in our patient.

Treatment of DFUs with acellular fish skin graft has so far only been used in a very small number of cases[16,17]. The rationale for the use of Kerecisâ acellular fish skin graft is to substitute the extracellular membrane (ECM) of chronic wounds, an inflammatory tissue that cannot facilitate healing. Fibroblasts in deep wounds cannot rearrange the ECM and are impervious to the presence of growth factors and other signalling factors[18] Intact fish skin has been well characterised as containing proteoglycans and glycosaminoglycans, as well as active endogenous growth factors[18]. Multiple studies have confirmed the link between depth of ulcer size and risk of amputation. The larger the ulcer size, the higher the risk of amputation (average size over 3 cm). DFU grade 3 of the Texas University Classification, as our patient had is confirmed as a predictor of amputation more than 30%[19]. Surgical management had failed with persistent signs of infection and the inability to save the foot without transmetatarsal amputation.

The case we describe seems to present a ray of hope for the management of DFU classified as UT III, whose duration of management challenging with a significant risk of amputation[20]. In addition to these DFUs, when they are infected, management switches to another stage with the need for complicated antibiotic therapy and long-term hospitalisation[21] again, associated with adverse effects that could further impair the quality of life of diabetic patients, and increase the social and economic burden, morbidity, and premature mortality of the disease[22].

CONCLUSION

Pending publication of the results of the Odin study, the case presented offers new hope for the local management of deep DFU associated with infection.