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Definition

A wide variety of haematological malignancies are treated with haematopoietic stem cell transplantation (Hymes et al. [70]). Transplantation is the use of donor peripheral stem cells, cord blood stem cells or bone marrow to reconstitute the immune system following myeloablative chemotherapy/radiotherapy with the aim to eradicate disease and extend survival (Fiuza‐Luces et al. [42]). For further haematological procedures, see Chapter c21. Graft‐versus‐host disease (GvHD) is the immunological interaction between the donor cells and host (patient) tissue and is a serious complication of transplantation (Rodgers et al. [118]). GvHD develops in up to 50% of all transplant recipients (Pavletic and Fowler [110]), commonly affects the skin, liver, gastrointestinal tract and lungs, and causes skin rashes, diarrhoea, deranged liver function and permanent pulmonary damage. GvHD can be divided into two categories: acute (aGvHD) and chronic (cGvHD). Historically, acute is defined as any time within 100 days post transplant, and chronic any time after; however, more recently it has been acknowledged that there are overlaps and it is the clinical features that determine GvHD as acute or chronic and not the time from transplant (Jagasia et al. [71]).

Skin GvHD

The skin is one of the organs most commonly affected by both aGvHD and cGvHD (Rodgers et al. [118]) with the skin integrity being damaged and the result of loss of skin function (Dignan et al. [31]). Severe or chronic GvHD is associated with skin ulcers, reduced skin integrity and poor wound healing (Jagasia et al. [71]).

Anatomy and physiology

It is important to understand the pathophysiology of GvHD when diagnosing and treating skin GvHD. Ferrara ([41]) describes the process of GvHD in three stages:

The first is a conditioning regimen that causes tissue damage in the host.
The second is the activation of T cells against the host and clonal expansion.
The third is the release of inflammatory cells and cytokines that cause further tissue damage.

Scheinfeld ([123]) describes acute skin GvHD as:

scattered erythematous macules and papules (a red rash that can either be flat or slightly raised)
a rash that covers a greater total body surface area as its severity increases
in its most severe forms, erythroderma and bullae (an intensely red and widespread rash that has larger raised areas containing serous fluid).

The clinical features of chronic GvHD include (Jagasia et al. [71]):

pigmentation changes
lichen planus like rash (shiny pinkish purple papules with varying configuration and distribution)
superficial sclerotic features (localized smooth or shiny skin, leather like)
deep sclerotic features (smooth, waxy, thickened or tightened skin caused by deep and diffuse sclerosis causing limitation of joint mobility)
lichen sclerosus like lesions (purple, grey‐white moveable papules or plaques, shiny appearance with cigarette paper like texture).

Making the correct diagnosis of skin GvHD is essential but complicated by the fact that other skin reactions such as drug reactions and infections can have a similar appearance; response to treatment and a skin biopsy are often the most reliable tools to make a diagnosis (Scheinfeld [123]).

Related theory

Diagnosing and treating skin GvHD early is essential to minimize the risk of developing wounds. However, there are also contributing factors related to GvHD that put patients at a high risk for wounds:

Immunosuppressive drugs such as cyclosporine are given as preventative medication for GvHD but increase the risk of infections (Hausermann et al. [65]).
Immunosuppression and/or steroids are given systemically as the first‐line treatment for both aGvHD and cGvHD and increase the risk of infection (Rodgers et al. [118]).
Patients with GvHD are at an increased risk of bacterial, viral and fungal infections (Rodgers et al. [118]).
The use of less toxic conditioning regimens prior to transplant has enabled stem cell transplant to be a treatment option for the older patient with potentially lower performance status (Pavletic and Fowler [110]). The risk of developing GvHD alongside other co‐morbidities will increase their risk of infection.
Long‐term use of steroids in the treatment of cGvHD has been proven to cause skin thinning and striae and slow the healing process (Dignan et al. [31]).
Acute skin GvHD is often associated with gastrointestinal and liver GvHD and chronic skin GvHD, and is also associated with oral GvHD. Gastrointestinal and oral GvHD affects nutrition and can lead to anorexia (Fiuza‐Luces et al. [42]), which will leave the patient vulnerable to wounds and poor healing.
In cGvHD, where there are sclerodermoid changes, joint contractures and limitations in joint movement are common. These cause immobility and are a risk factor for development of wounds (Scheinfeld [123]).
Bullae are a serious complication as they can break down into ulcers that are slow to heal and at risk of infection (Hymes et al. [70]).
The psychological impact of both aGvHD and cGvHD, especially if they overlap severely, affects quality of life, motivation and self‐care (Fiuza‐Luces et al. [42], Fraser et al. [44]), increasing the risk of developing a wound.
Recipients of donor stem cell transplants have a higher risk of secondary cancer and are therefore at a higher risk of developing a skin malignancy (Hymes et al. [70]).

Principles of care

Patients with GvHD should be treated by a team experienced in recognizing and managing transplant‐related complications. A referral to a dermatologist and tissue viability clinical nurse specialist (with experience in transplant dermatology) for patients with moderate or severe GvHD with all growing, non‐healing wounds should be made within 2 weeks (Dignan et al. [31]).

Treatment of xerosis (abnormally dry skin) is with an emollient such as Diprobase; treatment of pruritus and erythema is with emollients such as Diprobase and a topical corticosteroid. These are topical treatments: hydrocortisone 1% is low potency and can be used over the hands and face; betamethasone (Betnovate) is medium potency; and clobetasol (Dermovate) is high potency. If clobetasol is considered as a treatment choice, a referral to a dermatologist should also be made. If there is no response to topical treatment, systemic treatment with corticosteroids such as prednisolone and methylprednisolone is then advised. Application of Diprobase and other emollients should be 2–3 times a day to maintain skin integrity. It is recommended that steroid cream should be generously applied once a day for maximum effect as opposed to sparingly 2–3 times a day.

Second‐line treatment for skin GvHD is extracorporeal photopheresis (ECP), an immunotherapy that involves collecting the patient's leukocytes and exposing them to ultraviolet light. This causes apoptosis of the treated cells and a reduction in GvHD (Klassen [77]). Referral to a specialized consultant dermatologist who offers this type of treatment should be made if the patient is non‐responsive or refractory to first‐line treatment.

Management with the multidisciplinary team is essential. Physiotherapy can help relieve the symptoms of sclerodermoid disease and dermatopathic strictures. Occupational therapy can offer advice on complementary therapies for management of symptoms; however, use of essential oils should only be recommended by a qualified practitioner who has knowledge of GvHD. Slow wound healing in this cohort of patients is associated with not only immunosuppressive medications but also poor diet, therefore inclusion of the dietician is essential to monitor nutritional intake.

Prevention of a wound is the best treatment. Patients at risk of or known to have GvHD should be closely monitored, with early referral to the appropriate specialist. Management of a wound caused by GvHD would not differ from that of a normal wound (as described previously) but there must be a collaborative approach to the management of the wound that involves haematologists, dermatologists and wound specialists.