This is the current release of the guideline.

Chronic graft-versus-host disease (GvHD)

To provide recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular, and genital manifestations of chronic graft-versus-host disease (GvHD) and for the supportive care of these patients, including vaccinations and prophylaxis against infection

Adults and children in the United Kingdom with chronic graft-versus-host disease (GvHD) following allogeneic stem cell transplant

Evaluation/Treatment/Management

General Practices

1. Patient review by an experienced team
2. Creation of an established clinical network of specialists at transplant centres
3. Assessment of patient quality of life
4. Systemic treatment for patients with moderate to severe graft-versus-host disease (GvHD)
5. Blood pressure and glucose monitoring and gastric protection with long-term steroid treatment

Cutaneous GvHD

1. Referral to a dermatologist with GvHD experience
2. Annual skin exam by a dermatologist
3. Timing of referral
4. Emollients for symptom control
5. Topical therapy (e.g., steroids, calcineurin inhibitors) as first line therapy
6. Extracorporeal photopheresis (ECP) for second line therapy in steroid-refractory GvHD
7. Physiotherapy for patients with sclerodermoid disease

Gastrointestinal GvHD

1. Referral to a gastroenterologist
2. Upper endoscopy with duodenal aspirate and biopsies and lower endoscopy (flexible sigmoidoscopy) with biopsies for diarrhoea without jaundice or rash suggestive of GvHD
3. Assessment and review by a dietician with gut GvHD experience
4. Established protocol for nutritional issues

Genital GvHD

1. Questioning patients for symptoms
2. Referral to a specialist for difficult to manage symptoms
3. High potency topical steroids with or without topical calcineurin inhibitors as first line therapy

Liver GvHD

1. Referral to a hepatologist

Ocular GvHD

1. Review by an ophthalmologist
2. Counseling patients to seek ophthalmologic assessment if cataracts develop during prolonged systemic steroid use
3. Artificial tears and topical anti-inflammatory/antibiotic treatment as first line therapy

Oral GvHD

1. Referral to Oral Medicine
2. Topical therapies including steroid mouthwashes
3. ECP as a second line systemic therapy for steroid-refractory GvHD

Pulmonary GvHD

1. Referral to a respiratory specialist
2. Screening of all GvHD patients with pulmonary function tests
3. Systemic steroids
4. Pulsed steroids or imatinib for those who do not respond to systemic steroids
5. Supportive care (e.g., intravenous immunoglobulin, vaccinations, azithromycin)

Infection Prevention

1. Regular monitoring by polymerase chain reaction for cytomegalovirus infection throughout acute and chronic GvHD
2. Prophylaxis against viral, fungal, Pneumocystis jiroveci and Streptococcus pneumoniae infection for patients receiving immunosuppressive agents
3. Treatment with a mould-active azole (e.g., posaconazole, voriconazole, or itraconazole with regular monitoring of levels)
4. Avoidance of live vaccines
5. Vaccination against pneumococcus, influenza and Haemophilus influenzae

The production of these guidelines involved literature review to 17th June 2011 including Medline, internet searches, and major conference reports.

Not stated

Quality of Evidence

The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what is known or is certain.

(A) High: Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomized clinical trials without important limitations.

(B) Moderate: Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomized clinical trials with important limitations (e.g., inconsistent results, imprecision – wide confidence intervals or methodological flaws – e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient).

(C) Low: Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series, or just opinion.

The production of these guidelines involved the following step:

• The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature as used to evaluate levels of evidence.

The production of these guidelines involved the following steps:

• Establishment of a working group comprising experts in the field of allogeneic transplantation and specialists in managing graft versus host disease (GvHD) from the following specialities: dermatology, oral medicine, hepatology, gastroenterology, ophthalmology, respiratory, endocrinology, microbiology.
• Literature review to 17th June 2011 including Medline, internet searches, and major conference reports.
• Development of key recommendations based on randomized, controlled trial evidence. Due to the paucity of randomized studies some recommendations are based on literature review and a consensus of expert opinion.
• The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to assess the strength of recommendations. The GRADE criteria are specified in the British Committee for Standards in Haematology (BCSH) guideline pack and the GRADE working group website (see the 'Rating Scheme for the Strength of Recommendations' field). Further information is available from the following websites:
  • http://www.bcshguidelines.com/4_HAEMATOLOGY_GUIDELINES.html 
  • http://www.gradeworkinggroup.org/index.htm 

Strength of Recommendations

Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'.

Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.

A formal cost analysis was not performed and cost analyses were not reviewed.

The production of these guidelines involved the following steps:

• Review by the British Committee for Standards in Haematology (BCSH) committees, British Society of Blood and Marrow Transplantation (BSBMT) executive committee, the UK Photopheresis Society and the UK Paediatric Bone Marrow Transplant Group
• Review by sounding board of the British Society for Haematology (BSH) and allogeneic transplant centres in the UK

Note from the British Committee for Standards in Haematology (BCSH): The BCSH guidelines on graft-versus-host disease have been split into three documents, which are designed to be used together and to complement each other in order to provide an evidence-based approach to managing this complex disorder. In addition to the current document, the following National Guideline Clearinghouse (NGC) summaries are available:

• Diagnosis and management of acute graft-versus-host disease
• Diagnosis and management of chronic graft-versus-host disease

Definitions for the quality of the evidence (A-C) and strength of recommendation (strong [grade 1], weak [grade 2]) are given at the end of the "Major Recommendations" field.

Principles of Graft-versus-Host Disease (GvHD) Management

• Patients with chronic graft-versus-host disease (GvHD) should be reviewed by a team experienced in managing transplant-related complications (1C).
• Transplant centres should establish a clinical network of specialists with an interest in GvHD to allow for multidisciplinary management (1C).
• Assessment of quality of life is recommended in all patients with GvHD (1C).
• Systemic treatment is the mainstay of therapy in patients with moderate or severe GvHD (1A).

Cutaneous GvHD

• Referral to a dermatologist with experience in transplant dermatology should be considered in patients with moderate or severe cutaneous GvHD (1C).
• All patients with GvHD on prolonged immunosuppression should have an annual skin check by a dermatologist in view of the increased risk of cutaneous malignancy (1C).
• All growing/non-healing skin lesions should be referred within 2 weeks to a dermatologist (1C).
• Emollients should be used for symptom control in skin GvHD (1C).
• Topical therapy, including steroids or topical calcineurin inhibitors, is recommended as first line therapy (1B).
• Extracorporeal photopheresis (ECP) is recommended as a second line systemic therapy for steroid-refractory skin GvHD (1B).
• Physiotherapy is recommended in patients with sclerodermoid disease (1C).

Gastrointestinal GvHD

• Referral to a gastroenterologist should be considered in patients with suspected gastrointestinal GvHD (1C).
• In view of the wide differential diagnosis, patients with diarrhoea without associated jaundice or rash suggestive of GvHD should be investigated by both upper (with duodenal aspirate and biopsies) and lower (flexible sigmoidoscopy and biopsy) gastrointestinal endoscopy in preference to colonoscopy alone (1C).
• All patients should be assessed and reviewed by a dietician with experience of managing patients with gut GvHD and each unit should have an agreed protocol for nutritional issues (1C).

Genital GvHD

• All patients should be actively questioned about genital tract symptoms (1C).
• Referral for specialist advice should be considered in all patients with difficult-to-manage genital symptoms (1C).
• High potency topical steroids (+/- topical calcineurin inhibitors) are recommended as first line therapy (1C).

Liver GvHD

• Referral for specialist hepatology opinion should be considered in patients with significant liver GvHD (1C).

Ocular GvHD

• Patients with symptoms suggestive of significant ocular involvement should be reviewed by an ophthalmologist preferably with an interest in ocular GvHD (1C).
• Patients on prolonged systemic steroids for GvHD should be aware that their vision may be reduced if they develop cataracts and should seek ophthalmic advice if this occurs (2C).
• Supportive care with artificial tears and topical anti-inflammatory/antibiotic treatment may be helpful as first line treatment (2C).

Oral GvHD

• Referral to Oral Medicine should be considered in patients with significant oral symptoms (1C).
• Topical therapies including steroid mouthwashes are recommended as first line treatment (2C).
• ECP is recommended as a second line systemic therapy for steroid-refractory GvHD (1B).

Pulmonary GvHD

• Referral to a respiratory physician should be considered in all patients with suspected pulmonary GvHD (1C).
• All patients with GvHD should be screened using pulmonary function tests regardless of symptoms (1A).
• Systemic steroids are recommended in patients with pulmonary GvHD at a dose of 1 mg/kg of prednisolone and, for those not responding, consider pulsed steroids or imatinib (2C).
• Supportive care including intravenous immunoglobulin, vaccinations, and azithromycin is also recommended (2C).

Antimicrobial Prophylaxis for Infections in GvHD

• Prophylaxis against viral, fungal, Pneumocystis jiroveci and Streptococcus pneumoniae infection should be considered in all patients receiving immunosuppressive agents for chronic GvHD (1A).
• The prophylactic and/or pre-emptive strategy for prevention of cytomegalovirus (CMV) infection including regular monitoring of CMV polymerase chain reaction adopted for haematopoietic stem cell transplantation (HSCT) recipients should be continued throughout the period of acute and/or chronic GvHD (1B).
• A mould-active azole is recommended for prophylaxis in patients undergoing treatment for GvHD (1A); suitable agents include posaconazole and voriconazole (1A) or itraconazole with regular monitoring of levels (2B).

Vaccination

• Live vaccines must not be administered in patients with GvHD (1A).
• All patients with GvHD should receive vaccination against pneumococcus, influenza, and Haemophilus influenzae (1B).

Complications Associated with Long-Term Steroid Use

• All patients on long-term steroid treatment should have blood pressure and glucose monitored at clinic visits and should receive gastric protection (1A).

Definitions:

Quality of Evidence

(A) High: Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomized clinical trials without important limitations.

(B) Moderate: Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomized clinical trials with important limitations (e.g., inconsistent results, imprecision – wide confidence intervals or methodological flaws – e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient).

(C) Low: Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series, or just opinion.

Strength of Recommendations

Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'.

Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.

The original guideline document contains clinical algorithms for:

• A management approach to unexplained nausea, retching, vomiting, or anorexia
• Management of genital graft-versus-host disease (GvHD)
• Management of ocular GvHD
• Management of oral GvHD

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Appropriate organ-specific management and supportive care in chronic graft-versus-host disease (GvHD), which may lead to effective control of GvHD while minimizing the risk of toxicity and relapse

The administration of live vaccines is contraindicated in chronic graft-versus-host disease (GvHD) patients.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

British Committee for Standards in Haematology

Joint Working Group of the British Committee for Standards in Haematology (BCSH) and the British Society of Blood and Marrow Transplantation (BSBMT)

Working Group Members: Fiona L. Dignan, Section of Haemato-oncology, The Royal Marsden NHS Foundation Trust, London, St John's Institute of Dermatology, St Thomas' Hospital, London; Julia J. Scarisbrick, Department of Dermatology, University Hospital Birmingham, Birmingham; Jacqueline Cornish, Department of Haematology, Bristol Royal Hospital for Children, Bristol; Andrew Clark, Bone Marrow Transplant Unit, Beatson Oncology Centre, Gartnavel Hospital, Glasgow; Persis Amrolia, Department of Bone Marrow Transplantation, Great Ormond Street Hospital, London; Graham Jackson, Department of Haematology, Freeman Road Hospital, Newcastle; Prem Mahendra, Department of Haematology, University Hospital Birmingham, Birmingham; Peter C. Taylor, Department of Haematology, Rotherham General Hospital, Rotherham; Pallav Shah, Department of Respiratory Medicine, Royal Brompton Hospital, London; Sue Lightman, University College London/Institute of Ophthalmology, Moorfields Eye Hospital, London; Farida Fortune, Department of Oral Medicine, Barts and the London NHS Trust, London; Christopher Kibbler, Department of Medical Microbiology, Royal Free Hampstead NHS Trust, London; Jervoise Andreyev, Department of Medicine, The Royal Marsden NHS Foundation Trust, London; Assunta Albanese, Paediatric Endocrine Unit, St George's Hospital, London; Nedim Hadzic, Paediatric Liver Service and Institute of Liver Studies, King's College Hospital, London; Bronwen E. Shaw, Section of Haemato-oncology, The Royal Marsden NHS Foundation Trust, London, Anthony Nolan, London; Michael N. Potter, Section of Haemato-oncology, The Royal Marsden NHS Foundation Trust, London

All authors have declared any potential conflicts of interest to British Committee for Standards in Haematology (BCSH). Fiona L. Dignan and Bronwen E. Shaw have received research funding, honoraria, and speaker's fees from Therakos, a Johnson and Johnson company. Peter C. Taylor has received honoraria from Therakos, a Johnson and Johnson company. None of the other authors have declared any conflicts of interest.

This is the current release of the guideline.

Electronic copies: Available from the British Committee for Standards in Haematology Web site .

Print copies: Available from the British Committee for Standards in Haematology; Email: bcsh@b-s-h.org.uk.

None available

None available

This NGC summary was completed by ECRI Institute on July 30, 2012. The information was verified by the guideline developer on September 5, 2012.

This NGC summary is based on the original guideline, which is copyrighted by the British Committee for Standards in Haematology. For more information, contact the BCSH Secretary, 100 White Lion Street, London, UK, N1 9PF; Email: bcsh@b-s-h.org.uk.