12.1 What Is Graft Versus Host Disease (aGvHD)?

12.1.1 Definitions

Acute graft versus host disease (aGvHD) is a reaction of donor immune cells against host tissues. The three main tissues that acute GvHD affects are the skin, liver and gastrointestinal tract (Zeiser 2019).

Chronic graft versus host disease (cGvHD) is a syndrome of variable clinical features resembling autoimmune and other immunologic disorders. Manifestations of chronic GvHD may be restricted to a single organ or site or may be widespread, with profound impact on quality of life (Jagasia et al. 2015).

12.2 Background to GvHD

The New England Journal of Medicine reported the infusion of bone marrow into patients by E. D. Thomas and colleagues in 1957, following radio- or chemotherapy. Pre-clinical animal studies revealed that transplantation of splenocytes from non-oncogenic donor strains facilitated haematopoietic recovery but led to a severe illness characterised by anorexia, reduced weight, diarrhoea, ruffled fur and eventual death. It was labelled at the time ‘secondary’ or ‘runt’s disease’ and later became known as graft-versus-host disease (GvHD). It was clear that the effect was not one of the conditioning therapies but was associated with an immune-mediated syndrome (Wolff et al. 2012).

GvHD, both acute and chronic, is the leading cause of non-relapse mortality and is associated with a high morbidity that increasingly affects quality of life (Gooptu and Antin 2021). However, the success of allogeneic haematopoietic stem cell transplant (HSCT) depends on simultaneous graft-versus-tumour (GvT) effects. There is a fine line with aGvHD. The symptoms and side effects can be unpleasant and sometimes harmful and, in severe cases, life-threatening. However, it is well documented that some level of aGvHD is beneficial. It has been found that relapse rates post allograft were lowest in patients with aGvHD versus those without (Baron et al. 2012). Therefore, broad-based immunosuppressive strategies are less attractive as these may dampen the GvT benefit. Relapse accounts for a significant proportion of treatment failures after HSCT; thus, strategies for GvHD prevention with minimal impact on GvT are the holy grail of transplantation (Magenau and Reddy 2014). The introduction of post-transplant cyclophosphamide may well be a step toward better prophylaxis and prevention of GvHD in several protocols (Gooptu and Antin 2021).

Historically, GvHD is termed ‘acute’ before day 100 and ‘chronic’ any time after day 100. However, it has since been recognised that there can sometimes be ‘overlap’ between the types, so signs and symptoms are used to aid and determine the diagnosis. The skin is the most common organ affected followed by the gastrointestinal (GI) tract and then the liver. Typically, the skin develops a rash, which often but not always appears on the palms of hands and soles of the feet first and can rapidly spread to the rest of the body. GI and liver GvHD symptoms such as nausea, vomiting, diarrhoea, abnormal liver enzymes and jaundice are similar in both acute and chronic forms of GvHD.

According to the 2014 NIH consensus, aGvHD includes classic aGvHD (maculopapular erythematous rash, gastrointestinal symptoms or cholestatic hepatitis), occurring within 100 days after HCT or donor leukocyte infusion. The broad category of aGvHD also includes persistent, recurrent or late-onset aGvHD, occurring more than 100 days after transplantation or donor leukocyte infusion. The presence of GvHD without diagnostic or distinctive cGvHD manifestations defines the broad category of aGvHD (Vigorito et al. 2009; Jagasia et al. 2015).

12.3 Acute GvHD

Overview: aGvHD occurs following an allogeneic haematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues and remains a major cause of morbidity and mortality (Greinix 2008). High-dose chemotherapy +/− radiotherapy inflicts cellular damage, and this leads to an inflammatory process; the activated donor T-cells interact with the host epithelial cells. Approximately 35–50% of HSCT recipients will develop aGvHD (Dignan et al. 2012). There are several factors that can influence the development of aGvHD: the stem cell source, age of the patient, conditioning regimen and GvHD prophylaxis used. All aGvHD can be associated with culture-negative fever. Biopsies of skin and GI tissue (more rarely liver) are often obtained, although the diagnosis of aGvHD is regularly made based upon clinical signs and symptoms. A biopsy is useful to help differentiate from other diagnoses, which may mimic GvHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). The modified Glucksberg-Seattle criteria (Przepiorka et al. 1995), International Bone Marrow Transplant Registry (IBMTR) (Rowlings et al. 1997) and Mount Sinai aGVHD International Consortium (MAGIC) criteria (Harris et al. 2016) are widely used and give a stage and grade (grade 0–IV) for each organ and its degree of involvement. The lack of standardisation of grading has led to difficulties comparing patient groups at different centres.

12.4 Pathophysiology of GvHD

In the 1960s, Billingham (1966) proposed three central tenets for the development of GvHD. These are:

  1. 1.

    The presence of immunocompetent cells from the donor.

  2. 2.

    The inability of the recipient to reject donor cells.

  3. 3.

    The histocompatibility differences between the donor and recipient.

Donor T-cells are now recognised as occupying a central role in mediating GvHD following interactions with activated host and donor antigen-presenting cells (APC). A complex network of cytokines, chemokines, cellular receptors and immune cell subsets then modulates T-cell/APC interactions that result in the initiation and maintenance of GvHD (Magenau and Reddy 2014).

The three-phase process for aGvHD comprises:

A flow diagram of the stages of G v H D is initial tissue damage from the conditioning therapy, activation of host A P C, and activation and then proliferation of donor T cells.

Finally, inflammatory cytokines are released such as interleukin-1 and tissue necrosis factor alpha that produce tissue necrosis.

Acute GvHD is modulated in part by the presence of cells capable of inhibiting immune responses, most notably regulatory T-cells (Magenau and Reddy 2014) (Fig. 12.1).

Fig. 12.1
A circular illustration of 3 acute G V H D phases. They are 1. recipient conditioning, 2. donor T cell activation, and 3. cellular and inflammatory effectors, and their various process.

The three phases of acute GVHD, as described by Ferrara and colleagues (From Hill and Ferrara 2000. Reproduced with permission)

Both prevention and treatment of aGvHD attempt to disrupt the three-step pathophysiological cycle. Most current treatment options of aGvHD affect more than one event in this cycle through relatively non-specific immunosuppressive and anti-inflammatory mechanisms (Greinix 2008).

Reduced intensity conditioning will usually contain drugs that deplete T-cells, such as Campath-1H or ATG. This reduces the initial risk of aGvHD but increases the risk of infective complications such as CMV and also the risk of late-onset aGvHD and cGvHD. Up to 50% of patients will develop some aGvHD despite prophylaxis (Mohty et al. 2020).

12.4.1 Risk Factors

Factors that can increase the likelihood of aGvHD include older recipient/donor, sex mismatch and specifically a multiparous female donor into a male donor. Furthermore, the intensity of the preparative regimen does appear to correlate with increased incidence of aGvHD. This effect may occur due to greater tissue damage from the preparative regimen, predisposing these tissues to more inflammation from the alloreactive cells. Higher doses of radiation also give rise to more GvHD. Equally, more recent use of non-myeloablative preparative regimens has led to lower incidence of aGvHD in some studies (Jacobsohn and Vogelsang 2007).

12.4.2 Signs and Symptoms of aGvHD

12.4.2.1 Skin

Acute GvHD can cause a rash which is usually flat and red and often occurs on the hands, feet and around the ears and upper chest, at first. This can quickly spread to cover the whole body. It is often, but not always, itchy and sore and can feel like sunburn. A biopsy may be taken but is not always diagnostic. On examination, the features may include apoptosis at the base of epidermal rete pegs, dyskeratosis, exocytosis of lymphocytes, satellite lymphocytes adjacent to dyskeratotic epidermal keratinocytes and perivascular lymphocytic infiltration in the dermis (Ferrara and Deeg 1991).

12.4.2.2 Gastrointestinal

Signs and symptoms include weight loss, stomach discomfort and pain, nausea, vomiting and diarrhoea. The diarrhoea can be profuse with secretions and may also result in bleeding from ulceration of the mucosa. The effects of high-dose therapies and infection need to be excluded. Biopsy in this group of patients is more informative and may show apoptotic bodies at crypt bases, crypt ulceration and flattening of surface epithelium (Dignan et al. 2012).

12.4.2.3 Liver

Jaundice from hyperbilirubinaemia is the hallmark of advanced liver GvHD with a cholestatic pattern of elevated conjugated bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase (GGT) and may be associated with pruritis. There is a wide range of differential diagnoses, which should be considered and excluded such as veno-occlusive disease, drug toxicity and infection. It is often extremely difficult to perform biopsy due to the increased risk of bleeding, but, if taken, histology shows endothelialitis, lymphocytic infiltration of the portal areas, pericholangitis and bile duct destruction (Dignan et al. 2012).

12.4.3 Classification of Acute GvHD: Grades I–IV

Acute GvHD carries a significant transplant-related mortality (TRM) with grades 0–I (mild) having a TRM of approx. 28% and grades II, III and IV (very severe) TRM of 43%, 68% and 92%, respectively (Greinix 2008).

12.4.4 Prevention of GvHD

Prophylaxis: GvHD prophylaxis for full-intensity allografting is based around calcineurin inhibitors (CNI) along with short-course methotrexate (MTX) (Gooptu and Antin 2021). This works by interfering with calcium-dependent interleukin-2 (IL-2) gene activation and de novo purine metabolism, respectively. CNI and MTX act synergistically to non-selectively inhibit lymphocyte activation and proliferation. The combination of ciclosporin and MTX or tacrolimus and MTX as prophylaxis for aGvHD compared to any single-agent treatment has been shown to be superior (Greinix 2008).

12.4.5 GvHD Prophylaxis Medications

The standard medications used across the transplant community are listed below.

Ciclosporin (CsA) is given as an intravenous infusion commencing usually 1–2 days prior to HSCT infusion to load the bloodstream and is eventually converted to an oral preparation when the patient is able to tolerate tablets again. Ciclosporin binds to cyclophilin and prevents generation of nuclear factor of activated T-cells (NF-AT), which is a nuclear factor for initiating gene transcription for lymphokines including interleukin-2 and interferon gamma. This action leads to suppression of cytokine production and subsequent inhibition of T-cell activation (Greinix 2008).

Methotrexate (MTX) is an anti-proliferative agent given intravenously on days 1, 3, 6 and 11 after HSCT for those patients receiving a full-intensity transplant. It prevents the division and clonal expansion of T-cells. It is important to receive all four doses, but severe mucositis (grade IV) often prohibits administration of the fourth and final dose and is given at the clinician’s discretion.

Mycophenolate mofetil (MMF), used mainly in reduced-intensity transplant conditioning regimens, is an anti-metabolite that results in non-competitive reversible inhibition of inosine monophosphate dehydrogenase. This leads to selective inhibition of lymphocytes, purine synthesis and proliferation. Patients have less mucositis and faster neutrophil recovery compared to methotrexate (Greinix 2008).

Tacrolimus binds to FK506 protein 12, a different protein to the one that CsA does, but their final common pathway is identical (Greinix 2008).

Sirolimus is a natural macrolide antibiotic that exerts its immunosuppressive effect by inhibiting cytokine-driven signalling pathways of the T- and B-cell via mTOR blockade and specifically inhibiting the progression of cells from the G1 phase to the S phase. The advantage is that sirolimus has a completely different toxicity profile to calcineurin inhibitors and can be used in combination with them (Dignan et al. 2012).

Campath-1H or alemtuzumab is given in a variety of doses from 30 to 90 mg and is dependent upon the cell source and degree of mismatch between donor and recipient. It is an unconjugated humanised IgG1 kappa monoclonal antibody that targets the CD52 antigen on the T and B lymphocytes as well as on monocytes, macrophages, eosinophils and dendritic cells. The major disadvantage of this drug is the increase of infections due to the extended period of lymphopenia. CMV reactivations and infections are particularly troublesome in this patient cohort, necessitating strict surveillance (Dignan et al. 2012).

Anti-thymocyte globulin (ATG) decreases T-cells and also leads to viral infections. Epstein-Barr virus (EBV) reactivations can be problematic and can result in post-transplant lymphoproliferative disease (PTLD).

Post-transplant cyclophosphamide (PT-Cy) used in haploidentical transplants and allows mismatched transplantation to occur, addressing both host rejection and GvHD.

Abatacept is a fusion protein that selectively inhibits T-cell co-stimulation and is effective as aGvHD prophylaxis (Ngwube et al. 2020).

12.4.5.1 Initial Treatment of Acute GvHD

Despite all of the recent advances in the understanding and treatment of GvHD, steroids remain the best and first-line therapy. The mechanism of action of steroids for aGvHD is unclear but most likely relates to the suppression of cytokines such as prevention of synthesis of interleukin-1 by antigen-presenting cells and lymphocyte activities (Greinix 2008).

  • Grade I: should not require systemic treatment. If CsA levels are optimised, then topical steroids in conjunction with an emollient may be introduced along with antihistamine for itchy skin.

  • Grade II: anything at or above grade II is likely to require systemic treatment. If the patient progresses from grade I to grade II following optimisation of CNI and topical therapy, then systemic corticosteroids are indicated. Patients presenting with grade II signs should commence systemic steroids for their anti-inflammatory properties, and local guidelines should be followed for dosage. Some patients with GI symptoms may benefit from budesonide as a steroid-sparing treatment as it is regarded as a non-absorbable therapy.

  • Grades III and IV: requires treatment with systemic steroids. If GI symptoms are the major feature, then the steroids should be given intravenously to prevent problems with absorption because of vomiting, diarrhoea and abnormal mucosal lining.

Steroids are effective treatment in approximately 40% of people, with 30% having a long-lasting response and a probability of survival at 1 year of 53%, with the skin being the most responsive at 40% with a response rate of 15–35% for those with liver involvement and 45% in GI. The lower the grade of aGvHD and the fewer organs affected, the better the response to steroids (Greinix 2008). Mohty et al. (2020) suggest that corticosteroid refractoriness occurs after 3 days of treatment with 2 mg/kg of methylprednisolone or no improvement after 7 days or progression to a new organ or recurrence during or after a taper.

12.4.6 Second-Line Therapies for aGvHD

Once first-line therapy has failed, there are multiple options such as the following:

  • Ruxolitinib: approved in the USA in May 2019 for corticosteroid-refractory GvHD in adults and children over 12 years. The REACH 1 trial supplied the clinical evidence (Jagasia et al. 2020) and was reinforced by REACH 2, which was ruxolitinib versus best available therapy. Ruxolitinib targets several signal pathways and may cause neutropenia and increase infection risk (Wolff et al. 2021).

  • Extracorporeal photopheresis: 8-methoxypsoralen (8-MOP) is a photoactivated drug that covalently binds to DNA pyrimidine bases, cell surface molecules and cytoplasmic components in the exposed nucleated white cells, causing a lethal defect. It is added to a patient’s blood following withdrawal by a cell separator machine; the cells are then exposed to ultraviolet light A (UVA) and returned to the patient. Once reinfused, the cells undergo apoptosis over the next 24–48 hours. The mechanism of action is not currently fully understood (Cho et al. 2018). The reinfusion and subsequent phagocytosis by antigen-presenting cells (APCs) may regulate immune homeostasis through modulation of cytokine production and tolerance induction of APCs (Bladon and Taylor 2006). ECP is a safe treatment as it has fairly minimal side effects, hypotension, fevers, drop in haemoglobin, photophobia and tiredness post-procedure. The procedure is performed in most centres by highly trained apheresis nursing staff.

Further second- and third-line therapies are discussed below.

Second-line therapies

Antitumour necrosis

Infliximab

Etanercept

  

Mammalian target, rapamycin inhibitors mTOR

Sirolimus

   

Mycophenolate mofetil (MMF)

Interleukin-2 receptor antibodies

Daclizumab,

Denileukin diftitox

Inolimomab

Basiliximab

Third-line therapies

Mesenchymal stem cells MSC

    

Alemtuzumab

    

Pentostatin

    

Methotrexate

    

Tyrosine kinase inhibitor

Imatinib

   
  1. Often, at least two second-line therapies will be used before moving on to a third-line treatment

12.4.7 Nursing Care Considerations for aGvHD

In addition to systemic treatments, there are often topical management techniques as well as general care that nurses can offer to patients that will lead to relief from frequently troublesome symptoms of aGvHD. Below are a few pointers for consideration when caring for patients with aGvHD affecting their skin or gastrointestinal system.

12.4.8 Cutaneous

Basic Skin Care

The key issue with patients who have cutaneous aGvHD is to maintain the integrity of the skin, and the following suggestions are key factors in doing this: Regular application of preferred emollients (e.g. QV, Hydromol, Diprobase). Advise application of a thin layer (enough to make the skin appear ‘shiny’), in the direction of hair growth. Try not to ‘rub’ as this will increase any pain or itch. As guidance for amounts, it would be suggested that an adult would use on average 500 g/week and a child, 250 g/week. Use of bath/shower preparations (e.g. Dermol, QV, Hydromol) rather than soap, use of high SPF sunscreen (e.g. SunSense SPF 50+) and localised use of topical antipruritic agents (e.g. Dermacool 0.5–1%) if required. If the skin is still flaky, the patient can be advised to apply lipids (e.g. coconut oil) in addition to the emollients. Equally good-quality creams containing aloe vera gel are often very soothing (note: do not use aloe vera gel alone as this will dry the skin).Topical immunomodulation (e.g. steroid/tacrolimus cream) should be prescribed as per local protocol; however, there are a few general rules about the use of topical steroids: think about the potency/duration of the product used in relation to the age of the patient and the area of the body it is being applied to. Always apply thinly – once daily is usually enough. Think about whether the skin is weepy, when a cream/lotion is appropriate or dry/scaly, in which case, an ointment may be preferable. Steroids should be applied at a different time to emollients (at least a 30-min gap between) to ensure effective absorption, and remember that broken skin is a contraindication to use.

Topical Management of Specific Stages of Cutaneous aGvHD/Maculopapular Rash (Pruritic/Painful).

Emollients are key to management at all stages. With sensitive, irritated skin, an emollient that is too thick will just not be used, whereas one that is too ‘thin’ will be perceived as ineffective.

Topical steroids: each hospital will have its own protocol for prescription of topical steroids, and this should be adhered to.

Menthol cream (0.5–1%, e.g. Dermacool) can be useful for management of painful and pruritic skin but must be used with care as they can make the patient feel very cold with widespread use and so are better used only on focal areas with extreme itchiness/pain.

Medical-grade silk clothing (e.g. Dermasilk, Espere Healthcare): it is important to explore the holistic care of the patient. Many clothing materials can cause irritation – even natural materials such as cotton. If there are widespread areas of the torso affected, it is worth suggesting the use of medical-grade silk as this is manufactured to cause minimal irritation and, in some countries, can be prescribed. If this is not available, clothing made from bamboo can be suggested as an alternative.

Your hospital may have a protocol specifically for patients with bullous desquamation, and treatment would be similar to those people who suffer severe burns. An example would be to irrigate with sterile water, apply an antibacterial cream (e.g. Flamazine) and protect the area from the air to minimise pain and risk of infection. The cream can be applied directly to sterile theatre gauze and wrapped around the patient to prevent trauma.

12.4.9 Gastrointestinal

Patients who develop GI symptoms affecting upper, lower GI as well as their liver may have multiple problems: reduced appetite, bloating and early satiety with nausea and frequent retching or vomiting and abdominal discomfort related to liver pain or as a consequence of increased bowel activity. Nurses should ensure that stool samples are sent to exclude infective components. Once ruled out and treatment started, nursing care may aid in a more rapid recovery and maintenance of weight. Ensuring an adequate oral input with high-calorie supplements and strict fluid balance are of primary importance. Options for enteral feeding or intravenous total parental nutrition in the short term to rest the bowel need to be kept in mind if the above actions are not sufficient, with procedures such as a radiologically inserted gastrostomy (RIG) used for long-term issues. Those with upper GI disturbance, nausea and vomiting need advice on small and frequent meals as well as supplements. For itch associated with jaundice, topical or oral antihistamines can be used. Patients who develop grade IV GI aGvHD will benefit from use of flexi-seal faecal collection devices if they have high faecal output.

12.5 Chronic Graft-Versus-Host Disease

Chronic GvHD is a serious and life-threatening condition and is a major cause of late morbidity and mortality after allogeneic haematopoietic cell transplantation occurring in 30–70% of patients (Miklos et al. 2017). Chronic GvHD prevalence and severity has increased with the increasing use of HSCT for treatment of older-age patients, the widespread use of mobilised blood cells instead of marrow for grafting and improvements in survival during the first several months after allograft. Preventing cGvHD remains challenging (Inamoto et al. 2021). Typically occurring in the first 12 months, it can be seen as early as 2 months and as late at 7 years at onset, although onset at >1 year from transplant occurs in <10% of cases (Flowers and Martin 2015). The risk of infection due to the delay in immune reconstitution and use of immunosuppressive therapies to treat cGvHD remains, however, the leading cause for death in this group of patients (Couriel et al. 2006). Supportive care advances have decreased the morbidity, but survival has not changed significantly since the 1980s. Patients with cGvHD have a 5-year survival of 40–70%, with only 50% being able to stop immunosuppression at 5 years, with 10% needing treatment beyond this time point. The other 40% either die or develop a further malignancy before cGvHD resolves (Martin et al. 2006).

12.6 Chronic GvHD Grading

Historically if patients developed signs and symptoms of GvHD after day 100, this was labelled as chronic, even if clinically the patient appeared to have acute features. The criteria for the diagnosis of cGvHD are based on pathological changes occurring in the skin, lung, mucous membranes, gastrointestinal tract and musculoskeletal system (Greinix 2008).

Chronic GvHD includes classic cGvHD, presenting with manifestations that can be ascribed only to cGvHD; however, it also includes an overlap syndrome, which has diagnostic or distinctive cGvHD manifestations together with features typical of aGvHD (Vigorito et al. 2009).

The National Institute of Health (NIH) described a reliable and reproducible scoring scheme to evaluate the individual organ severity of four grades with scores 0–3:

  • None; score 0.

  • Mild involvement (no significant impairment of daily living); score 1.

  • Moderate involvement (significant impairment of daily living); score 2.

  • Severe impairment (major disability); score 3.

The clinical score describes how affected the patient is by their inability to perform activities of daily living. This evaluation covers the involvement of individual organs and sites. For example, if they are unable to work due to ocular loss, they would be scored as 3, severe (Carpenter 2011). The scoring should be undertaken initially at 3 months post-transplant and at 3 monthly intervals and more frequently if new signs or symptoms are found or there is a change in treatment.

The NIH in 2014 provided a Diagnosis and Staging Working Group Report. A revision was made to the diagnostic criteria for involvement of the mouth, eyes, genitalia and lungs. Schirmer’s test was removed, and an ophthalmology review is recommended. Also, if an unequivocal explanation can be made for a specific abnormality that is not GvHD, then that organ should be regarded as not affected by GvHD (Jagasia et al. 2015). Earlier recognition is important, and the NIH published a series of papers in 2021 (Inamoto et al. 2021) to describe features that did not yet meet the NIH 2014 criteria. This was to enable less experienced practitioners the ability to recognise and make appropriate referrals. There were also descriptions of the use of electronic tools such as the eGvHD app to aid in earlier diagnosis (Kitko et al. 2021).

Chronic GvHD commonly occurs in patients who have previously had aGvHD although it is not simply a case of evolution from one to another. Chronic GvHD usually occurs within 3 years of allograft and is a disease of deregulated immunity with protean manifestations that mimic autoimmune disorders such as Sjogren syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis obliterans, immune cytopenias and chronic immunodeficiency (Jagasia et al. 2015).

Single organs alone may be affected and can progress to other organs; however, cGvHD nearly always affects multiple sites, having major impact upon a patient’s quality of life. There is a wide range in severity and how this relates to compromise in patients’ QoL, with some manifestations being more problematic to treat (Flowers and Martin 2015).

12.6.1 Diagnosis of cGvHD

For a diagnosis of cGvHD to be made, the NIH 2014 working group suggest that at least one diagnostic manifestation of cGvHD or at least one distinctive manifestation, with the latter confirmed by pertinent biopsy, laboratory tests, evaluation by a specialist or radiology in the same or other organ be present, unless stated otherwise. It is important with any organ considered for a diagnosis of cGvHD that other causes for the symptoms are excluded such as infection or recurrent or new malignancy (Jagasia et al. 2015). The features should also differ from the typical dermatitis, enteritis and cholestatic liver manifestations of aGvHD (see Appendix 12.A.2 for the full tables of assessment).

12.6.2 Chronic GvHD of the Skin

For a clinical diagnosis of skin cGvHD, features of poikiloderma, lichen planus-like eruption, deep sclerotic features, morphea-like superficial sclerotic features or lichen sclerosus-like lesions are needed (Jagasia et al. 2015). Assessment of the skin is performed to look at the four anatomic levels of involvement, and the score is based on the percentage of area involved and the differentiation between non-sclerotic and sclerotic features:

  1. 1.

    Erythematous rash (epidermal involvement).

  2. 2.

    Movable sclerosis (dermal involvement).

  3. 3.

    Non-movable sclerosis, hidebound skin or involvement of subcutaneous tissue and facia (subcutaneous involvement).

  4. 4.

    Ulceration (full-thickness loss of epidermal tissue).

Points 1–3 are assessed using the ‘rule of 9s’ body surface area score. Local skin involvement below 20% body surface and the absence of sclerotic features are classified as ‘mild’. Skin involvement between 20% and 50% is ‘moderate’, with more than 50% becoming ‘severe’ (Greinix 2008). This scoring system is effective in adults but less so in children; however, it is still used in children over the age of 1 year. Ulceration is recorded by measuring the diameter of the largest ulcer (Pavletic et al. 2006). The skin is often very fragile and becomes damaged easily with poor healing of any wound. Distinctive features of cGvHD that are not seen in aGvHD are depigmentation, although this occurs gradually and may only be perceptible over long time periods, and papulosquamous lesions, although this alone is not enough for a diagnosis. It must be made in combination with other signs or confirmed with biopsy. Common features of both acute and chronic GvHD are erythema, maculopapular rash and pruritis (Jagasia et al. 2015). Itching is common and, therefore, should be recorded using a scale of 1–10 for severity, with the patient asked what was the highest score this week (Pavletic et al. 2006).

Distinctive signs of nail cGvHD are longitudinal ridging, splitting or brittleness, onycholysis and loss of nails that is usually symmetric and affects most nails (Jagasia et al. 2015).

Loss of hair can be a devastating effect of cGvHD for patients, and in this context, it is considered a distinctive feature alone. Hair has often returned following chemotherapy or radiotherapy, and the loss is often patchy and happens across the whole body. Patients may suffer with premature greying, thinning or brittleness of their hair (Jagasia et al. 2015).

12.6.3 Chronic GvHD of the Oral Cavity

Patients with oral cGvHD complain of a sore mouth that is not dissimilar to the pain suffered with oral mucositis post-chemotherapy/radiotherapy. Tolerance of spicy food stuff is poor, toothpaste burns are common and hot drinks such as tea and coffee are almost impossible to take. It is important to rule out infection as this will cause pain to be worse. Frequent swabs for virus, bacterial and fungal infection should be taken and acted upon promptly. To aid with oral pain management, Caphosol, Gelclair, lidocaine, paracetamol mist and Difflam mouthwash can be used.

Advise patients to frequently swill the mouth after eating to remove any debris using plain water. This is refreshing and ph7 so comfortable to do. Encourage the use of products to aid in production of saliva as the mucosa is usually very dry. Artificial saliva or sugar-free gum and, in some centres, pilocarpine may be used.

Many medications have side effects of dry mouth. Look to see if there are any alternatives that could be prescribed for your patient.

Early referral to the dentist is vital, as the risk of dental caries and secondary oral cancers is higher in patients with oral GvHD. Advice to perform regular oral exercises to reduce the risk of contractures.

For patients who have received stem cells derived from the bone marrow (BM), oral cGvHD is the most common site of involvement, and the oral cavity is the second most common site with PBSC (Meier et al. 2011). There are three components to mouth and oral mucosa assessment:

  1. 1.

    Mucosal involvement.

  2. 2.

    Salivary gland involvement.

  3. 3.

    Sclerotic involvement of mouth and surrounding tissues (Couriel et al. 2006).

Within the oral cavity, clinical diagnostic features include lichen planus-like changes. These are described as white lines and lacy-appearing lesions or plaque-like changes. This can occur on any oral surface including the tongue and lips. The mouth will be dry (xerostomia) and have mucoceles, mucosal atrophy, ulcers and pseudomembranes. Common features of both acute and chronic GvHD are gingivitis, mucositis, erythema and pain (Jagasia et al. 2015). If new lesions occur >3 years post-transplant, secondary malignancy should be excluded with biopsy. The lesion often starts as leukoplakia and can be confused with cGvHD but may be a squamous cell carcinoma (SCC) (Couriel et al. 2006).

Chronic GvHD of the mouth is scored as 3 areas using the standard 0–3 scale with a percentage of area involved:

  1. 1.

    Erythema.

  2. 2.

    Lichenoid.

  3. 3.

    Ulcers.

Oral sensitivity is measured on a self-score system from 1 to 10, with the worst and therefore highest score it has been for the past week recorded (Pavletic et al. 2006). The consequences of oral cGvHD in cases of hypo-salivation and xerostomia are in relation to the function of saliva and lack thereof. Poor protection against oral infections and mechanical and chemical epithelial injuries can occur. Remineralisation is impaired that can lead to dental caries, speech may be altered and eating becomes problematic (Meier et al. 2011; Treister et al. 2013).

12.6.4 Chronic GvHD of the Eyes

New onset of dry, gritty or painful eye with cicatricial conjunctivitis, keratoconjunctivitis sicca and confluent areas of punctate keratopathy are distinctive features and may occur in isolation with no other active cGvHD (Couriel et al. 2006). Lacrimal dysfunction or destruction is responsible for dry eye symptoms (Pavletic et al. 2006). Infection should be excluded and treated if apparent. Patients may describe photophobia, burning, irritation, pain, a foreign body sensation, blurred vision and paradoxically excessive tearing.

Scoring of eyes is based on frequency of use of eye drops and the occurrence of keratoconjunctivitis sicca. Asymptomatic keratoconjunctivitis sicca or need for eye drops less than three times per day is classed as ‘mild’, whilst symptomatic and the need for more than three times daily eye drops +/− punctual plugs is ‘moderate’. Those with ‘severe’ ocular cGvHD are unable to work because of ocular symptoms or require special eyewear such as dark glasses to relieve pain or have loss of vision due to keratoconjunctivitis sicca (Greinix 2008).

12.6.5 Chronic GvHD of the Genitalia

Patients who suffer from oral or skin cGvHD are also very likely to have some degree of genital cGvHD. This affects both men and women and is significantly under-reported. Some basic nursing input can help with symptoms of pain and discomfort experienced. Asking patients if this is a problem for them is the first step as patients are often reticent about mentioning genital problems to the medical team. In women, vaginal scarring and clitoral/labial agglutination occur, and in men, phimosis and urethral/meatus scarring are features. In both sexes, lichen planus-like and lichen sclerosis features are diagnostic. It is essential due to the under-reporting of symptoms that patients are examined for early signs especially if oral features are present. Studies suggest that 3–15% of women have vulvar or vaginal cGvHD (Couriel et al. 2006). The diagnosis relies heavily on sign and symptom reporting. Symptoms in women may include dryness, burning, pruritis, pain to touch, dysuria and dyspareunia. Signs include patchy or generalised erythema, mucosal erosions or fissures, labial resorption, circumferential fibrous vaginal banding, vaginal shortening and complete vaginal stenosis. Female genital tract involvement is scored as ‘mild’ if any erythema on vulvar mucosal surfaces, vulvar lichen planus or vulvar lichen sclerosis exists. Those with any erosive inflammatory changes of the vulvar mucosa or fissures in the vulvar folds are scored as ‘moderate’. Severe scores are when there is labial fusion, clitoral hood agglutination, fibrinous vaginal adhesions, circumferential fibrosis vaginal banding, vaginal shortening, synechia, dense sclerotic changes and complete vaginal stenosis (Couriel et al. 2006).

In the absence of diagnostic manifestations of cGvHD in other organs, histological evidence is strongly recommended and ruling out of oestrogen deficiency or infection with yeast, HPV or bacteria (Couriel et al. 2006). A referral pathway to the gynaecologist and if possible one with an interest in assessing these patients should be implemented.

There are a variety of treatments that may offer some symptomatic benefit. With female patients, application of an emollient to the vulval region and use of dilators with a lubricant such as olive oil or coconut oil will help minimise the risk of contractures. Vaginal moisturisers may make women feel more comfortable. Referral through to endocrinology for discussions about hormone replacement therapy (HRT) with oestrogen can be initiated by nursing staff. Mechanical and chemical irritants should be avoided. Washing with warm water, using products from such ranges as Oilatum or Dermol if required (rather than soap), cleaning in a front-to-back direction and then air-drying are to be advised. Bacteriostatic gels such as Replens may be used in the vagina for comfort as this adheres to the vaginal wall and has a long-lasting effect. Vulval and vaginal topical management can include steroid/immunosuppressant cream. In extreme cases, surgical interventions may be required to release strictures and adhesion formation. In all cases, particularly if the woman is not sexually active, dilators lubricated with, for example, a lipid, such as coconut oil, should be thought about as a way of maintaining vaginal patency and capacity. Men may have painful intercourse and a burning sensation on micturition. Signs include non-infectious balanoposthitis, lichen sclerosis-like or lichen planus-like features, phimosis or urethra or meatus scarring or stenosis (Jagasia et al. 2015). Signs of lichen planus-like features are classed as ‘mild’, lichen sclerosis-like features or moderate erythema is ‘moderate’ and ‘severe’ signs are phimosis or urethral or meatal scarring. Application of emollient is suggested alongside good hygiene to help reduce tightening of the foreskin.

Body image and sexual dysfunction are significant problems for both men and women post-transplant and are especially problematic upon development of cGvHD. Counselling and early involvement with psych-oncology services are important to aid in maintaining normality in an abnormal situation.

In a first case series describing vvGvHD in a paediatric and young adult population, 42% of patients were asymptomatic at the time of diagnosis. This may be due to a misunderstanding and under-reporting of genital symptoms in paediatric patients. It may indicate that paediatric patients are at greater risk than adult women for delayed or missed diagnosis. Larger, prospective studies are needed to evaluate treatment regimens and establish clinical care guidelines for paediatric vvGvHD (Cizek et al. 2019).

12.6.6 Chronic GvHD of the Gastrointestinal (GI) Tract

Gastrointestinal tract symptoms occur frequently, and oesophageal web, stricture or concentric rings demonstrated on endoscopy or imaging are diagnostic features for GI cGvHD. Patients may have dysphagia, odynophagia, heartburn, anorexia, nausea, vomiting, abdominal pain, cramping, diarrhoea, weight loss and malnutrition, and these are all common features present in both acute and chronic GvHD as well as other aetiologies. It is important to make a firm diagnosis before commencing treatment. Diarrhoea should be investigated with stool culture and virology examination to exclude C. diff and CMV in particular (Couriel et al. 2006). Patients may also suffer from pancreatic atrophy and exocrine insufficiency that causes malabsorption and can respond to pancreatic enzyme supplementation (Jagasia et al. 2015). For upper GI, early satiety, anorexia and nausea and vomiting are scored on occasional symptoms with little reduction in oral intake during the past week being ‘mild’; a ‘moderate’ score of cGvHD as intermittent symptoms with some reduction in oral intake during the past week; and ‘severe’ if the patient has persistent symptoms throughout the day with a marked reduction in oral intake on almost every day of the past week. Lower GI disturbance with diarrhoea will score ‘mild’ if the patient has occasional loose or liquid stool on some days throughout the week. If the patient is having intermittent loose or liquid stool throughout the day, on almost every day of the last week, without requiring intervention to prevent or correct volume depletion, it is scored as ‘moderate’. Those with ‘severe’ disease have voluminous diarrhoea on almost every day of the past week, requiring intervention to prevent or correct volume depletion.

12.6.7 Chronic GvHD of the Liver

The liver has no firm diagnostic features of cGvHD, and all other causes need to be excluded, e.g. viral infections, biliary obstruction and drug toxicity. A biopsy, if possible, can help carry a high risk of bleeding and is therefore not frequently performed; imaging may be useful to exclude liver abscess, infiltration or gall bladder disease (Couriel et al. 2006). Patients may present in two ways, with a liver function test showing a steep rise in serum ALT, with or without jaundice or transaminitis, or as a progressive cholestatic picture with elevation of serum alkaline phosphatase and GGT followed by jaundice (Jagasia et al. 2015). Any elevation of liver enzymes greater than twice normal may be regarded as ‘mild’, 2.5 times upper limit of normal as ‘moderate’ and ‘severe’ if five times.

12.6.8 Chronic GvHD Pulmonary System

Historically, for a firm diagnosis of pulmonary cGvHD, a biopsy was essential to prove bronchiolitis obliterans (BO); however, as there was a high risk of bleeding, it is now accepted that a diagnosis of bronchiolitis obliterans syndrome (BOS) can be made following pulmonary function testing (PFT). Pre-transplant screening is essential to obtain a baseline PFT with post-transplant PFT at 3 months and 1 year or more frequently if the patient develops signs as patients remain asymptomatic with an insidious onset of symptoms (Flowers and Martin 2015). A new onset of an obstructive lung defect is indicative of BOS. Clinically, the patient may be short of breath on exertion and have a cough or wheeze, but these may be later effects. There are strict criteria for BOS, and all need to be met for a diagnosis:

  1. 1.

    FEV1/VC < 0.7 or the fifth percentile of predicted.

  2. 2.

    %FEV1 < 75% of predicted with >10% decline over less than 2 years. %FEV1 should not correct to >75% with salbutamol, and the rate of decline for the corrected values should still remain at >10% decline over 2 years.

  3. 3.

    Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as radiologic studies (radiographs or computed tomographic scans) or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, bronchoalveolar lavage).

  4. 4.

    Either one distinctive manifestation of chronic GvHD or another supporting feature of BOS.

Air trapping by expiratory chest high-resolution CT or small airway thickening or bronchiectasis or trapping on PFT where there is a residual volume of >120% or residual volume/total lung capacity >120% predicted is supporting evidence for BOS (Jagasia et al. 2015).

Chronic lung GvHD may be treated with bronchodilators, inhaled corticosteroids, systemic steroids, montelukast and referral to a physical rehabilitation programme (Couriel et al. 2006). Lung GvHD has a somewhat dismal outcome as it is not very responsive to any modality. Nurses and physiotherapists can help patients manage distress and possible panic situations the patient may feel due to increasing breathlessness by teaching complementary self-management skills such as breathing techniques, focused relaxation and stress management.

12.6.9 Chronic GvHD of the Musculoskeletal System

Diagnostic features of the musculoskeletal system include fascial involvement usually of the forearms or legs, but frequently affecting the abdomen and chest wall with sclerosis of the overlying skin and subcutaneous tissue and joint stiffness or contractures that can develop and severely impact on quality of life (Jagasia et al. 2015). The degree of functional impairment is scored as ‘mild’ if there is mild tightness of arms or legs, normal or mild decreased range of movement (ROM) and does not affect activities of daily living (ADL). Where there is tightness of arms or legs or joint contractures or erythema thought due to fasciitis, a moderate decrease of ROM and mild-to-moderate limitation of ADL, it is scored as ‘moderate’. For ‘severe’ then, the patient will have contractures with significant decrease of ROM and significant limitation of ADL, e.g. unable to tie shoelaces, button a shirt or dress self.

12.6.10 Scoring of Chronic GvHD

The global scoring system of NIH 2014 was developed to be suitable for clinical trial assessments and reflects the clinical impact of cGvHD on the patient’s functional status and organ impairment and is defined by Jagasia et al. (2015) in Table 12.1.

Table 12.1 NIH global severity of chronic GvHD

Jagasia et al. (2015) with permission.

12.7 Assessment of Response

Pavletic et al. (2006) proposed a set of measures for assessing the response to treatment of cGvHD patients. These should be performed at three monthly intervals or whenever a major change occurs. Organ-specific measures should be recorded from clinical signs and symptoms and a global rating of mild/moderate/severe made. Assessment with non-specific ancillary measures such as grip strength, 2-min walk test (or Activity Scale for Kids (ASK)) and Karnofsky score with a quality of life (QoL) score is recommended. Quality of life assessment tools such as SF-36 or FACT-BMT in adults or CHRIs (Child Health Ratings Inventories) in children can be used.

12.8 Treatment of Chronic GvHD

The long-term aim of cGvHD therapy is for the patient to develop immune tolerance and reduce morbidity. This is recognised by the ability to withdraw immunosuppression without a flare of symptoms. Most therapeutic options focus on the development of immunosuppressive agents and the ex vivo removal of the unfractionated donor T-cell population from the stem cell graft (Greinix 2008). The mainstay of treatment has for more than 30 years been the use of systemic steroids, usually with a starting dose of 1 mg/kg per day with or without calcineurin inhibitor (CNI). Steroids have a multitude of side effects such as toxicities, diabetes, weight gain, bone loss, myopathy, hypertension, mood swings, cataracts, avascular necrosis and an increase in infections (Flowers and Martin 2015).

Treatment for cGvHD is far from satisfactory with only approximately 50% of patients responding to systemic steroids with or without calcineurin inhibitors and less than 20% of patients alive without disability at 4 years. Combinations of steroids with azathioprine, thalidomide, mycophenolate mofetil or hydroxychloroquine in randomised trials have not yielded any benefit over steroids alone for survival or duration of therapy (Flowers and Martin 2015). However, the recent REACH 3 trial results found that ruxolitinib significantly improved outcomes across a range of efficacy measures when compared to best available therapy in steroid-refractory/steroid-dependent patients (Zeiser et al. 2021). Steroids still offer the best first-line treatment choice for those with cGvHD and should be started as soon as a diagnosis is made.

The ROCKstar study looked at belumosudil in steroid-refractory cGvHD and found promising efficacy and favourable safety profile in patients with fibrotic manifestations who had previously received at least three prior therapies. This has the potential to improve the outlook for patients with difficult lung and skin symptoms (Cutler et al. 2021).

12.8.1 Second-Line, Third-Line and Other Therapies for Chronic GvHD

Below is a brief list of second- and third-line therapies for cGvHD; it is not exhaustive by any means, and many treatments are used following limited evidence from small non-randomised trials. The choice for further therapies is in most part governed by the features of cGvHD and the toxicities that may be inflicted as well as the availability of the drug locally. The lack of consistently effective treatment in this setting underscores the need for high-quality clinical trials. Please refer to local policies and guidance with respect to second-line and subsequent therapies.

Ruxolitinib is an oral JAK 1 and 2 tyrosine kinase inhibitor originally used for polycythemia or myelofibrosis patients. It is widely used as a second-line therapy following the REACH 3 trial (Zeiser et al. 2021).

Ibrutinib, a Bruton’s tyrosine kinase and interleukin-2-inducible T-cell kinase inhibitor, targets B- and T-cells. It can interfere with platelet function, leading to bleeding problems (Wolff et al. 2021). In pre-clinical models, it delayed progression and improved clinical manifestations (Miklos et al. 2017).

Extracorporeal photopheresis (ECP) is widely used in mucocutaneous cGvHD as a second-line therapy in steroid-refractory patients and has been shown to be effective in up to 80% of patients (Couriel et al. 2006). A UK consensus paper supported the findings and recommended ECP use in this group, with paired sessions every 2 weeks with reassessment at 3 months (Scarisbrick et al. 2008).

Imatinib, a tyrosine kinase inhibitor licenced for use in chronic myeloid leukaemia (CML), has gained popularity over the past few years. Experiments have shown reduction in fibrosis possibly from a dual inhibition process of transforming growth factor beta and platelet-derived growth factor pathways (Dignan et al. 2012).

Sirolimus, an mTOR inhibitor, may be used in combination with other agents but with caution in CNI due to increased risk of thrombotic microangiopathy and hyperlipidaemia.

Rituximab is commonly used in haematology for B-cell malignancy and is a potent anti-CD20 monoclonal antibody, and there is some limited evidence of its use in cGvHD for musculoskeletal and cutaneous manifestations (Dignan et al. 2012).

Mesenchymal stem cells (MSC) (Ringden and Keating 2011) have generated considerable interest in treatment of aGvHD following initial studies from the group at the Karolinska Institute. There was some evidence from early experiments that MSC worked in autoimmune disorders, and given the fact that cGvHD may resemble this in some ways, MSC have been used for cGvHD treatment but remain mainly within clinical trials.

Belumosudil (REZUROCK™), a selective ROCK2 inhibitor (Rho-associated coiled-coil-containing protein kinase), is important in tissue response to injury. It has gained first approval in the USA for use in patients ≥12 years with cGvHD after failure of at least two prior lines of systemic therapy as it has shown to be able to restore immune homeostasis and reduce fibrosis (Zanin-Zhorov and Blazar 2021).

12.8.2 Topical Treatments for cGvHD of the Eyes

The aim of treatment is to give symptomatic relief of dry eye, and care should be coordinated with an experienced ophthalmologist. Focus is placed upon increasing ocular surface moisture via lubrication and decreasing tear evaporation and tear drainage from the eye and decreasing ocular surface inflammation. Preservative-free drops coat the eye surface, minimising dry spots on the cornea, decreasing ocular symptoms and improving vision. It may take several different trials of drops to find one that works, as patients may be more sensitive to one solution. Temporary (with punctual plugs) or permanent (with cauterisation) occlusion of the tear duct may offer a solution to those with severe dry eye. Where there is inflammation of the ocular surface, direct application of steroid eye drops may be beneficial especially if the patient is on a taper of systemic immunosuppression and eye flare symptoms (Couriel et al. 2006). If available, autologous or allogeneic serum eye drops may decrease surface inflammation.

Dark glasses will reduce irritants such as wind and block any debris that may blow into the patient’s eyes. There are a variety of graded dark glasses that may be obtained through an optician that can block up to 90% of light and reduce photophobia significantly. It is often useful to wear glasses inside the house to reduce discomfort. Cold compress with ice packs and chamomile tea bags are useful in some instances.

Ciclosporin eye drops appear to offer a solution, but they cause irritation in most patients, and thus compliance is often poor. Specialist ophthalmology clinics may have access to scleral lens replacement in severe cases.

12.8.3 Topical Treatments for Oral cGvHD

Management of oral cGvHD aims to alleviate symptoms of dry mouth, sensitivity and pain whilst maintaining oral function and restoring mucosal integrity (Meier et al. 2011). It may appear obvious, but the single most important action for patients is to maintain good oral hygiene (daily care and regular dental visits). Children’s toothpaste causes less irritation and should be used with a soft toothbrush, with the addition of lip salve if appropriate. Avoidance of potential triggers for flares of cGvHD such as spicy or hot food or sharp foodstuffs that can cause damage is also suggested. Sip water and chew sugar-free gum to improve xerostomia.

Often, patients require systemic therapy as multiple sites are involved. However, the oral cavity can be refractory to systemic therapy; thus, complementary topical treatment is needed. There are a variety of topical steroid mouthwashes that are the first line of therapy, including prednisolone, budesonide or betamethasone. Tacrolimus 0.1% mouthwash is well tolerated and has shown to be an effective option and may be used alongside steroid mouthwashes as second-line therapy. It is important to describe adequately how to use these preparations as in many cases, this is not their usual route of administration.

To relieve oral pain, topical application of local anaesthetics such as lidocaine can be applied, either as a gel, mouthwash or spray. These should be used with caution as the gag reflex may be compromised and lead to choking and aspiration.

12.8.4 Ancillary and Supportive Care for cGvHD of the Skin

The skin remains the most affected organ for chronic GvHD, which is often debilitating when in extremis. Topical treatments are a vital therapy in addressing the manifestations of itch, rash, pain and dyspigmentation, whilst the use of physical therapy helps patients with limited range of movement maintain some degree of functionality. Other healthcare providers such as tissue viability and infection control teams can offer help, guidance and support when the skin becomes friable and breaks down, leaving ulcers, erosions and superadded infections. The patient with cutaneous cGvHD is at an increased risk of skin cancer, and regular monitoring and assessment are advised. Any suspicion should be followed up with biopsy. Advice with respect to UV exposure should be given regularly: avoiding direct sun exposure and using sunblocks and sunscreens and loose-fitting clothing with hat and glasses.

One of the major challenges for topical management of cutaneous cGvHD is the often severe sclerotic features—characterised by thickened, tight and fragile skin. This is frequently associated with poor wound healing, inadequate lymphatic drainage and skin ulcers from minor trauma or idiopathic origin. The following are important points to be given and regularly reinforced to all patients:

  • Take care to minimise risk of bumps/knocks.

  • Pat skin dry—no rubbing.

  • Wear loose clothing to minimise risk of friction/irritation.

  • Avoid sun exposure as much as possible.

  • Maintain good water intake.

  • Minimise/avoid the use of perfumes directly onto the skin (advise to spray onto clothes instead); if using make-up, suggest minimal skin applications, researching into good-quality products, and protect the skin with initial application of a moisturiser.

  • Provide clear, consistent and repeated reinforcement regarding the importance of regular use of emollients.

  • Contact clinical team as soon as possible if skin lesions are noted to facilitate initiation of appropriate care plan and reduce risk of wound infection.

12.8.5 Connective Tissue Involvement in cGvHD

Patients with cGvHD affecting skin, joints and connective tissue will benefit from inclusion in an exercise rehabilitation programme along with occupational therapy. Functional losses associated with muscle loss, weakness, contractures and limb swelling lead to fatigue and a decreased ability to perform activities of daily living and often preclude patients from being able to return to work. Rehabilitation should aim to improve strength and mobility of joints and muscles and ideally should occur before permanent and lasting damage has set in (Couriel et al. 2006). Such programmes should include family members where possible, as exercises need to be carried out on a regular basis to be effective, with the patient often needing support to do this. It can also be psychologically helpful to any family/carers involved as it allows them to feel confident to be part of the care of their loved one.

In addition to exercise, regular massage can help maintain flexibility and function of affected limbs. If there is fascial involvement, any massage provided will need to access these tissue layers to be effective. It is therefore important that the therapist providing this treatment has been trained in using such techniques. Again, it is possible to teach family members appropriate massage skills, which will improve the efficacy of therapy provided.

12.8.6 Quality of Life

QoL is severely compromised in cGvHD, with reports of fatigue, pain and GI upset. FACT-BMT QoL questionnaire studies have revealed that physical, sexual and social functioning is also lower with higher rates of depression and anxiety and adverse effects on social and family interactions. Depressive symptoms are more severe and last longer and often manifest when patients complain of loss of memory or poor concentration. Fatigue may be considered as a separate entity but is often mixed with QoL, anxiety and depression. It may be described as a persistent and subjective state of tiredness that interferes with usual functioning and can continue for several years after transplant (Couriel et al. 2006). Using questionnaires to assess these issues with individual patients is something which nurses can instigate to identify the impact of psychological morbidity in specific cases. These can be used as a framework to enable patients to express their concerns and structure a support programme to help manage specific issues—including onward referrals to appropriate professionals. de Vere et al. (2021) carried out a qualitative exploration of quality of life issues in patients with GvHD. They found that there was significant variation in symptoms and the extent that the symptoms affected each patient, a key point that nurses should note to be able to individualise care.

12.9 The Future

HSCT numbers continue to increase annually, and the morbidity and mortality associated with GvHD remains a significant problem. There is emerging understanding of the pathophysiology, and several new therapies have emerged in the past 2 years that have significantly improved the outlook for patients. Success in prophylaxis and treatment of GvHD will depend on whether GvHD can be prevented without losing the antitumour effect. Risk stratification and the emergence of a bedside GvHD test based on proteomics may be on the horizon and will ultimately then improve the outlook for this difficult-to-treat group of patients (Greinix 2008).

12.10 GvHD in Children

Data and research on GvHD in the paediatric population are limited with only a few studies specifically focused on children. Most studies are small, and children are often grouped into larger adult series (Baird et al. 2010; Gatza et al. 2020). In this short review, we will emphasise on the specific aspects of paediatric GvHD, primarily focusing on cGvHD.

In a recent publication, the Paediatric Diseases Working Party of the EBMT surveyed centres performing paediatric HSCT, looking at real-life approaches of prevention and treatment strategies in aGvHD. The findings highlight the need for standardised paediatric approaches towards aGvHD prophylaxis/treatment differentiated for malignant and non-malignant diseases (Lawitschka et al. 2020). Adolescents and young adults have increased rates of aGvHD when compared to children, and it is multifactorial, related to both biological and psychosocial factors. This likely contributes to a substantially greater risk of TRM (Friend and Schiller 2021). MacMillan et al. (2020) report a single-centre large paediatric series of 370 patients, examining the clinical phenotype of aGvHD at diagnosis and response to upfront steroid therapy. They conclude that aGvHD is different in children, with a higher incidence of isolated skin involvement, less liver involvement and less multi-organ involvement than adults. Children respond to steroids as upfront GVHD therapy to a similar extent as adults.

Most of the literature on cGvHD has focused on adults. Although the clinical manifestation of cGvHD in children is similar to that in adults, the consequences of treatment and non-responses are remarkably different in a growing organism (Lawitschka et al. 2012). Children with cGvHD are of particular interest, given their longer life expectancy and developmental issues following the complications of cGvHD and its therapy (Jacobsohn 2010; Jacobsohn et al. 2011). Compared with childhood cancer survivors who did not undergo transplantation, HSCT survivors have a substantially increased burden of serious chronic conditions and impairments involving every organ. A history of GvHD or presence of cGvHD contributes to increased rate of long-term complications in the paediatric transplant survivors (Chow et al. 2016). Chronic GvHD has negative effects on an individual’s physical and mental health and can lead to the development of functional impairments and activity limitations over their lifetime (Baird et al. 2010) as well as reduced quality of life (Inagaki et al. 2015). However, paediatric cGvHD remains an understudied area of research (Jacobsohn et al. 2011; (Cuvelier et al. 2019)); therefore, large paediatric multicentre studies are needed (Watkins et al. 2016).

12.10.1 Incidence and Risk Factors

Overall the rates of cGvHD are lower in children than adults (Champlin et al. 2000; Rocha et al. 2000). However, the incidence of cGvHD in the paediatric population is still substantial and has increased recently in association with the expanded use of peripheral blood stem cells and unrelated donors (Baird et al. 2010). Zecca et al. (2002) in a large paediatric study reported a cumulative probability of cGvHD of 27%; this probability is nearly half of the estimated probability of 40–50% described in adults. Flowers et al. (2011) published a large single-centre study of risk factors for aGvHD and cGvHD. The sample included both adult and paediatric patients; cGvHD was defined according to the NIH cGvHD criteria (Filipovich et al. 2005). The incidence of moderate-to-severe cGvHD in the paediatric patient was 28% (Watkins et al. 2016).

The risk factors for cGvHD in childhood are still poorly defined. Zecca et al. (2002) reported the risk factors associated with cGvHD in children: male patients transplanted from a female donor experience more cGvHD. Children with non-malignant disorders had a reduced risk of developing cGvHD. This might be due to the fact that children with these diseases do not benefit from GvHD since they do not need any graft-versus-malignancy effect, and therefore the most effective pharmacologic strategies for both prevention and treatment of aGvHD were used in these patients. The condition of mixed donor chimerism is associated with reduced susceptibility to GvHD. Some of the children with non-malignant disorders (those with aplastic anaemia or with congenital immunodeficiencies) are given less intensive preparative regimens, and it has been hypothesised that the cytokine storm, which is dependent on the intensity of the conditioning regimen, triggers development of GvHD. Malignant diseases and the use of myeloablative protocol as well as TBI as part of the preparative regimen offer an increased risk of classic aGvHD (Faraci et al. 2012). Older recipient and donor ages are another risk factors for cGvHD (Watkins et al. 2016).

12.10.2 Treatment

The major emphasis in GvHD has been on prevention, as results with treatment have been disappointing. Currently, most centres use a combination of a calcineurin inhibitor (cyclosporine or tacrolimus) with short-course methotrexate (Jacobsohn 2008), with differences between malignant and non-malignant diseases and myeloablative and reduced-intensity conditioning (Lawitschka et al. 2020).

The treatment of cGvHD in paediatrics is highly variable and mostly extrapolated from the experience in adults. Although there is no proven standard therapy, prednisolone and cyclosporine are commonly used as front-line therapy. As steroids remain the basis of cGvHD therapy, the consequences of long-term steroid use in children are well described, and long-term harmful effects on growth and bone density persist even after discontinuation of therapy.

Other potential treatment strategies include extracorporeal photopheresis (as discussed earlier in this chapter) and the infusion of allogeneic human mesenchymal stem cells (MSC) for the treatment of aGvHD and cGvHD. Multiple MSC infusions are safe and effective for children with steroid-refractory aGvHD, especially when employed early in the disease course. Early treatment may be associated with reduced treatment-related mortality and better overall survival (Ball et al. 2013). MSC offer new potential modalities of treatments for paediatric cGvHD refractory to standard treatments (Lawitschka et al. 2012). The treatment in paediatric patients must take into consideration the potential effect on growth, nutrition, organ function, bone metabolism, hormonal balance, psychosocial aspects and immune reconstitution (Baird et al. 2010; Lawitschka et al. 2012).

Recently, the FDA has approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and paediatric patients 12 years and older (Przepiorka et al. 2020). Ruxolitinib is a promising treatment in SR-GvHD. There are a few studies in children that demonstrated it is an effective option in acute and chronic SR-GVHD (Moiseev et al. 2020) with moderate-toxicity profile (Mozo et al. 2021) and with high overall response for acute and chronic GvHD, with a high ORR of 77% and 89%, respectively (González Vicent et al. 2019).

Ibrutinib is another novel medication indicated for the treatment of adult patients with cGvHD after failure of one or more lines of systemic therapy. A small study of 22 paediatric patients concluded that administration of ibrutinib shows promising responses in cGvHD as salvage and second-line therapy, but further studies are needed (Teusink-Cross et al. 2020).

The nursing management and care of children with GvHD are complex and require expert skills and knowledge as well as adjustment to the child’s/adolescent’s developmental need. Patients and families, who initially felt great relief to be cured from their primary disease, now face the challenge of a chronic devastating disease, for which preventative and treatment strategies are suboptimal (Baird et al. 2010). The treatment and support of the children and their families require a multidisciplinary team care that will be able to provide a comprehensive response to all their needs.