INTRODUCTION

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication that severely affects transplant success and the patient’s quality of life following allogeneic hematopoietic stem cell transplantation (HSCT).1 Recurrent infection is a key factor leading to the morbidity and mortality of patients with cGVHD because of the disease’s severe immunosuppression, with a mortality of approximately 15%. The US National Institutes of Health statistics show that the cumulative incidence of cGVHD requiring systemic treatment over 2 years is between 30% and 40%.

The skin is the organ most affected by graft-versus-host disease (GVHD), although GVHD is an autoimmune disease that can affect multiple organs and a warning sign that the body is rejecting other organs.2 The clinical manifestations of cGVHD are similar to those of immune disorders such as scleroderma, lichen planus, and Sjögren syndrome, among others. The onset of cGVHD is insidious, with nonspecific skin manifestations such as dry skin and ichthyosis. Typical clinical manifestations (skin desquamation, blisters, crusty skin, macular papule-like rash, pruritus, and sclerosis) may only occur as the disease progresses.3,4 Few reports on skin ulcers related to cGVHD exist. Skin rejection in cGVHD usually begins around 4 months posttransplantation.3

Once diagnosed, cGVHD usually requires persistent immunosuppressive therapy with potentially severe adverse effects. Currently, cGVHD is treated with small-molecule inhibitors, antibodies, cytokines, and cell-based therapies,5 with oral corticosteroids or calcineurin inhibitors showing some effect.6 Case series have reported on splenic tyrosine kinase inhibitors, regulatory T cells, hydrogen,7 mesenchymal stem cells,8 systemic vitamin A, hydroxychloroquine, thalidomide, skin grafting, and other techniques for cGVHD management.2,9 However, only a few cases have reported details of daily supportive skin care (including cleansing, moisturizing, and maintaining skin integrity); wound management procedures including dressing and product selection; and pain, pruritus, and other symptom management.4

This report describes a patient with cGVHD with ulcers on the right lower leg that began 140 weeks after HSCT. The patient provided informed consent to publish the case details and associated images.

CASE REPORT

A 53-year-old woman was diagnosed with “acute myeloid leukemia, pulmonary infection” in April 2018 and received matched sibling donor HSCT on July 9, 2018. Bone marrow was donated by her sister. During the bone marrow vacuity period, diarrhea and urination discomfort occurred, which improved after supportive treatments such as administering antibiotics intravenously, hydration, alkalizing urine therapy, probiotics, blood transfusion, and the granulocyte hematopoietic reconstruction, which took place 13 days after the procedure. Platelets were detached from the infusion simultaneously. Peripheral blood short tandem repeats at 7 days were 48%. However, the regular assessments of 1,3-β-d glucan test, galactomannan test, cytomegalovirus-DNA, and Epstein-Barr virus-DNA were negative.

The patient underwent long-term follow-up after transplantation from July 2018 to May 2021, during which her doctor regularly assessed her blood drug concentration. The patient continued using tacrolimus capsules (to prevent graft rejection), chloroquine (to soften the muscles), ruxolitinib phosphate tablets (anti-graft rejection), and cyclophosphamide (immune inhibitor).

On March 15, 2021, the patient visited the hematology department and wound care clinic with a complaint of right leg ulceration classified as mild GVHD.10 The patient visited the authors’ outpatient clinic and was diagnosed with scleroderma and cGVHD. She had palpable dorsalis pedis and posterior tibial pulses, and an ankle-brachial pressure index of 1.10 in the right limb and 1.07 in the left limb. Both lower limb arteries had normal blood flow. A color ultrasound of the lower extremity venous return showed no obvious abnormality and reflux in the bilateral femoral and popliteal veins, respectively. A bacterial culture of the wound showed the presence of Staphylococcus aureus. Hematology doctors prescribed medications and the nurses at the wound care clinic treated the wound.

Triangle of Wound Assessment

At the patient’s first visit, both wounds 1 and 2 were noted on the lateral malleolus of the right lower limb. Wound 1 was 75% yellow and 25% black and 4 cm long, 4 cm wide, and 0.3 cm deep. Wound 2 was 100% black tissue, 2 cm long, 0.8 cm wide, and 0.1 cm deep. The wound border was red, and the surrounding skin was red and swollen, involving the entire ankle, with a diameter of approximately 7 cm. There was no exudate, and the surrounding skin was dry and desquamated, as shown in Figure 1.

Figure 1.:

DAY 1: MAY 18, 2021Wound 1, 4 × 4 × 0.3 cm; wound 2, 2 × 0.8 × 0.1 cm.

On day 16, wound 1 was 75% yellow and 25% red with a size of 3 × 3 × 0.1 cm, whereas wound 2 was 75% black and 25% red with a size of 1.8 × 0.8 cm (Figure 2). The wound border was flushed, without curling or dryness. The surrounding skin was intact and without dryness.

On day 62, wound 1 was 75% red and 25% yellow and 2.3 × 1.6 cm; wound 2 had healed (Figure 3). The wound edge and the surrounding skin were normal. On day 83, wound 1 was 100% red (granulation) and 1.7 × 1.5 cm (Figure 4). Again, the wound edge and the surrounding skin were normal. Wound 1 was completely healed on day 133 (Figure 5).

Figure 2.:

DAY 16: JUNE 3, 2021Wound 1, 3 × 3 × 0.1 cm; wound 2, 1.8 × 0.8 cm.

Figure 3.:

DAY 62: JULY 19, 2021Wound 1, 2.3 × 1.6 × 0 cm.

Figure 4.:

DAY 83: AUGUST 9, 2021Wound 1, 1.7 × 1.5 × 0 cm.

Figure 5.:

DAY 133: SEPTEMBER 28, 2021The wound is healed.

Wound Bed Preparation

Iodine volts were used to disinfect the skin around the wound, containing 0.45% to 0.55% iodine in a povidone liquid base (Shanghai Likang Disinfection High-Tech Co). Briefly, 0.9% sodium chloride solution was used to clean the wound, and conservative sharp debridement was used to remove necrotic tissue.11 Hydrogel (Hartmann Company) was used for water replenishment and wound debridement, and an antibacterial protease dressing containing lysostaphin (Baikerui; Shanghai Gaoke Biology Engineering Co, Ltd) was used. The outer dressing was covered with sterile gauze and fixed with a net to prevent slippage and adhesive injury to the skin. Based on the amount of exudate, the dressing was changed daily for 3 consecutive days and then changed every other day. Ultimately, the patient required 3 hydrogel dressings and 25 antibacterial protease dressings.

The patient rated her pain level using an 11-point numerical rating scale. Pain was assessed at every visit before, during, and 2 hours after changing the wound dressings. Pain was controlled at 0 to 5 points; if the patient complained of severe pain (6 points or more), providers stopped debridement and cleansing or prescribed pain relief medication.

The Barthel Index was used to assess the patient’s ability to pursue activities of daily living, with 85- and 100-point scores at the first and last visits, respectively.

Systemic Oral Medication Administration

In addition to the immunosuppressants and anti-graft immune rejection drugs, the patient was taking two capsules of moxifloxacin hydrochloride (antibiotic) and JiXueGanPian tablets (Chinese classic herbal formula, Fukang; prescribed to promote granulation tissue formation and reduce contracture) twice daily as advised by her hematologist. A hematologist regularly reviewed routine blood draws and biochemical indicators (Table). The patient’s tacrolimus concentration was within the reference range. The patient’s white blood cell count was consistently high: 7.05 × 109/L, 6.09 × 109/L, and 6.75 × 109/L at days 1, 16, and 50, respectively (reference range, 3.5 to 5.10 × 109/L). The count was the highest at the first visit and remained slightly above normal later, possibly related to her antirejection and immunosuppressant regimen.

Table. - LABORATORY INDICATORS Indicator Day 1 Day 16 Day 50 Reference Range Biochemical γ-Glutamyl transpeptidase, U/L 92.1 87.1 154.7 7-45 Uric acid, μmol/L 590 584.2 385 155-357 α-Hydroxybutyrate dehydrogenase, U/L 205 204.7 206 71-182 Creatinine, μmol/L 100 90.7 68 41-73 Hematologic White blood cell count/L 12.05 × 109 6.09 × 109 6.75 × 109 3.5-5.10 × 109 Platelet count/L 445 × 109 437 × 109 388 × 109 125-350 × 109 Platelet ratio, % 0.40 0.39 0.38 0.11-0.28 Red blood cell count/L 3.70 × 1012 3.60 × 1012 3.66 × 1012 3.80-5.10 × 1012 Hemoglobin, g/L 115 114 114 115-150
Hospital-Community-Home Continuous Care

The patient’s wounds healed after approximately 4 months under hospital-community-home continuous care. The patient’s residence was approximately 93 km from the clinic. Long-term use of immunosuppressive drugs weakened her immunity, and because she lived alone and did not have her own private transportation, being immunocompromised hindered her ability to travel frequently by public transportation to the clinic. The patient’s doctor, the wound therapist, and the patient discussed each therapy. The local community health service center changed the patient’s dressings under the guidance of the wound therapist; the instructions encompassed hydrogel usage, antibacterial protease dressing size selection, bandaging technique, and more. The wound therapist answered various questions and guided the patient at home via a mobile telephone messaging application (WeChat). The wound therapist signed a nondisclosure pledge addressing patient confidentiality. The education information included determining the amount of exudate and skin protection strategies (preventing trauma and moisturizing). The wound therapist changed the dressings personally during monthly visits. At that time, the wound care nurses were present to further communicate with the patient, maintain the relationship, and alter the management plan according to the patient’s needs. The hematologist guided antibiotic use and dosage and usage of other drugs monthly. Hospital-community-home continuous care may have decreased the risk of infection and reduced patient travel times in the postpandemic era.

Patient-Centered Education

Four wound care nurses aimed to conduct patient-centered education. The nurses used positive psychology and incentive-based language to encourage the patient, such as “your wound is becoming better” and “much better than before.” To strengthen the patient’s trust in the clinic and reduce the impact of her anxiety on wound healing, the wound care nurses used a common method to answer questions and address doubts, reduced inconsistent and ambiguous statements, and avoided any sentences that would undermine the patient’s confidence.

At the first visit, the patient’s Hospital Anxiety Depression Scale score was 21 points and was 10, 7, and 3 points on days 16, 50, and 133, respectively.

Skin Management

The patient’s periwound and extremity skin was dry and desquamated, and the patient was instructed to use a liquid dressing (Sanyrene; Urgo Laboratories) to moisturize the skin once daily. The patient was advised to avoid trauma and simultaneously monitor any skin induration closely. The patient was to report any new induration to the wound care nurse promptly. One month later, the patient’s dryness improved; no skin dryness occurred when the wound healed, and no induration was found in other areas of the skin.

DISCUSSION Antibacterial Protease Dressings

New wound dressings have developed rapidly alongside the principles of moist wound healing. Antibacterial protease dressings have been broadly studied but are seldom used in treating skin injury after transplantation. Studies have shown that antibacterial protease dressings affect microorganisms while safely promoting granulation tissue development and wound edge advancement.12–15 They can be applied to pressure injuries, burns, surgical incision infections, and perineum wound infections. Studies also found no adverse hematologic, hepatic, or renal reactions nor noted any signs or symptoms of allergic reactions such pain, skin rashes, or pruritus.16,17 A possible reason is that the protein, which is the biological component of antibacterial protease,18 can be degraded by human metabolism. Therefore, using antibacterial protease dressings may help immunodeficient hematology patients prevent the potential toxic reaction that may exist with silver ion dressings. In this case, no adverse reactions were found.

Patient-Centered Education

This case illustrates the patient-centered education provided in the wound outpatient setting, which differs from previous studies.19 The common goal of patient-centered education is to improve patients’ confidence in wound healing.20,21 Over 133 days of health education and management, the case patient’s anxiety and depression gradually decreased, and her confidence in wound healing increased.

This method is especially important in educating patients with chronic wounds. These patients frequently ask whether their wound can heal and about the healing time frame, and they are prone to lose confidence in treatment due to uncertainty.22 Anxiety can easily affect wound healing and result in a vicious cycle. When wound care nurses encourage and compliment patients’ performance, they are more likely to be convinced that the wound is getting better and that the nurses care about their eventual healing. This improves the patient’s positive cognition, relieves anxiety, enhances confidence, and promotes wound healing.

Hospital-Community-Home Continuous Care

Li et al23 highlighted that chronic wounds frequently lead to decreased patient mobility, increased transport costs, and reduced activities of daily living. Therefore, the community service capacity in wound care should be improved to enhance its role in resource utilization. Patients with cGVHD are immunocompromised and prone to infection. Normalized epidemic prevention in the post-COVID era has forced patients to reduce the number of trips they take to prevent infection. Therefore, hospital-community-home continuous care is a feasible plan for immunocompromised patients, which is reinforced by the present case.

Previously, patients with cGVHD with skin injury were mainly treated in the hospital. However, because of the mild classification of this patient’s cGVHD, community health service centers could also meet the patient’s needs. The patient was relatively young, could perform self-care, and could monitor the need for dressing changes. Hospital-community-home continuing care is an option for managing patients with mild cGVHD skin ulcers.

Case Limitations

Compression bandaging increases healing in inflammatory ulcers, vasculopathies, and drug-induced ulcers and controls the underlying vascular damage. It can also help to reduce prolonged therapy with systemic corticosteroids.24 However, no direct evidence exists for ulcers caused by other etiologies (such as infected ulcers secondary to cGVHD/sclerodermatous form) to prove compression’s effectiveness in promoting wound healing in immunosuppressed patients. This patient showed obvious signs of redness, swelling, heat, pain, and infection at the initial visit; therefore, no compression treatment was provided at first. Further, most immunosuppressed patients have more fragile skin than healthy patients,25 and providers could not determine if there would be any adverse reactions. Therefore, providers did not implement compression therapy in this case.

Case Strengths

In using the Wound Bed Preparation 2021 model, ulcer management principles do not vary much based on etiology, even for an ulcer secondary to cGVHD. However, this case report is unique in several aspects.

First, this case found scleroderma in the patient’s joints and body, and the patient denied trauma before ulceration occurred. Nofal and Salah’s26 review described the sclerodermoid phase characterized by dermal fibrosis and the destruction of adnexal structures. At the first encounter, the wound bed was covered with fibrosis and relatively firm without granulation tissue. Further, the wound in this case was deeper than in existing reports.27

Second, extant descriptions of the treatment of cGVHD include skin-directed therapy, systemic corticosteroids, calcineurin inhibitors (cyclosporine, tacrolimus), rituximab, mycophenolate mofetil, extracorporeal photopheresis, and ruxolitinib.28 The treatment of cGVHD skin ulcers is consistently discussed with a hematologist and a dermatologist.27 However, this case was nurse-led and instead collaborated with the hematologist. In addition, providers offered hospital-community-home continuous care with the assistance of the local community health service center.

Third, previously reported cases of cGVHD with skin ulcers describe local wound care, debridement, and topical treatment (comprising antiseptics, alginate or hydrocolloid dressings, topical corticosteroids, topical tacrolimus, silver sulfadiazine, silver nitrate, or petroleum jelly). Further, compression therapy with elastic bandages has been reported when tolerated by the patient. Patients have also received corticosteroids, extracorporeal photopheresis, sirolimus, mycophenolate mofetil, everolimus, or imatinib mesylate.27 However, only a few reports exist describing hydrogel and antibacterial protease dressings applied to local wounds in patients with cGVHD.29

Last, this case benefited from patient-centered education provided by wound outpatient providers, which differs from routine 1:1 nurse-to-patient education. Notably, four wound care nurses united to conduct patient-centered education to improve the patient’s confidence in wound healing.

CONCLUSIONS

This case occurred in a patient with mild cGVHD over 2 years after HSCT; she was treated using comprehensive management including topical and systemic wound care, hospital-community-home continuous care, patient-centered education, and skin management. After 133 days of nursing, the patient’s wound healed completely without complications or other skin issues, lending credence to a new potential management strategy for managing cGVHD skin ulcers in the future.

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