Graft Versus Host Disease Flashcards
In what setting does graft versus host disease usually occur?
Allogeneic hematopoietic stem cell transplants
- Can also occur in transfusion of non-irradiated blood to immunocompromised hosts, maternal-fetal transmission and solid organ transplant (small intenstin>lier>kindey>heart)
What is the most important predictor of graft versus host disease occurring?
HLA compatibility
Why is the rate of graft versus host disease increasing in recent years?
There is increasing use of matched unrelated donors.
These pts are more likely to have small differences in HLA mismatch compared to matched related donors
What sources of stem cells most increase the risk for graft versus host disease?
Peripheral blood (PB-HSCT) > bone marrow > cord blood
- There is increased popularity of the peripheral blood HSCT in the US due to ease of collection, but need to consider GVHD risk
How can the pre-conditioning technique affect the risk for graft versus host disease?
Myeloablative preconditioning increases the risk of GVHD due to damage to host tissues.
- Many centers now do non-myeloablative reduced-intensity conditioning but this can also delay the onset of GVHD to beyond the classic 100 days (delayed-onset acute GVHD)
What are the risks of developing graft versus host disease in HSCT recipients?
HLA-matched = 40%
HLA-mismatched = 60-70%
What organ is most affected by graft versus host disease?
The skin
How is a periphereal blood HSCT done?
The patient is treated with a colony-stimulating factor (filgrastim) which mobilizes the donor stem cells into the peripheral blood and then this can be aphoresed off and infused into the recipient
What is the pathogenesis of acute graft versus host disease?
- Activation of host antigen-presenting cells
- Host antigen-presenting cells bind altered host proteins/neo-antigens
- Donor lymphocytes recognize altered host protein antigen-presenting cell complexes and proliferate and target host tissue in skin, GI tract, and liver
What is the pathogenesis of chronic graft versus host?
Largely unknown
- Early: IFN-gamma, increased regulatory T-cells, and T-cell cytokine response (IL-2Ralpha).
- Late: Lack of Th2 shift, B-cell activation via soluble BAFF, induction of Toll-like receptor 9 highly expressing B cells, and autoantibody formation
- Chronic lichenoid GVHD shows some Th1/th17 signature suggesting these treatments could be helpful
What is the timing of acute GVHD?
Occurring within the first 100 days after transplant (this is considered not essential for diagnosis now)
What is the typical timing of acute graft versus host disease after HSCT?
2-6 weeks after (peak incidence is 30 days after)
What is the most common presenting morphology of acute graft versus host disease?
Morbilliform eruption on the acral surfaces (hands, feet, ears)
Clues: Acral erythema, violaceous hue on-ear, follicular/peri-eccrine erythema (darker punctate lesions help distinguish from simple morbilliform eruptions)
What systemic effects can be seen in acute graft versus host disease?
GI tract: nausea, voluminous diarrhea, abdominal pain
Liver: transaminitis, cholestasis, bilirubin elevation)
What are the 3 components of acute graft versus host disease staging?
- Skin: severity assessed by % BSA
- GI: severity assessed by the volume of diarrhea (and severe abdominal pain)
- Liver: severity assessed by the degree of bilirubin elevation
Note that there are also histologic gradings of acute graft versus host disease
How many grades of acute graft versus host disease are there?
There are 4 stages ranging from 1-4.
What are the 4 stages of histologic acute graft versus host disease?
- focal vacuolar change of basal keratinocytes
- Grade I plus necrotic keratinocytes in the epidermis and/or hair follicles and dermal lymphocytic infiltrate
- Grade II plus a fusion of basilar vacuoles to form clefts and microvesicles
- Grade III plus large areas of separation of the epidermis from the dermis
What is the classic definition for the timing of chronic graft versus host disease?
>100 days (now considered to be arbitrary and not part of diagnosis)
How often is chronic graft versus host disease preceded by acute graft versus host disease?
50% of the time
What are the two classifications of clinical graft versus host disease?
Non-sclerotic GVHD vs sclerotic GVHD
What are the clinical features of non-sclerotic chronic graft versus host disease?
Often but not always precedes sclerotic chronic graft versus host disease
- Most common presentation is the lichenoid eruption (80% of cases): coalescent, slightly scaly, violacious-to-pink papules arranged in a reticulate pattern. Most common sites for this are dorsal hands/feet, forearms, and trunk
- Other forms include atopic dermatitis-like psoriasiform, poikilodermatous, lupus-like and keratosis pilaris-like
What is the most common clinical morphology of non-sclerotic chronic graft versus host disease?
Lichenoid: dorsal hands/feet, forearms, trunk –> coalescent, slightly scaly violaceous -to-pink papules arranged in reticulate pattern
What is the clinical presentation of sclerotic graft versus host disease?
Favors areas of pressure, many morphologies
- Lichen sclerosis-like
- sclerodermoid/morphea-like plaques: unlike true scleroderma, the distribution is more patchy and lacks classic features of scleroderma (bird faces, puffy/indurated hands, sclerodactyly)
- eosinophilic fasciitis like
What can help distinguish GVHD from drug reactions?
Apoptotic cells in adnexal structures (hair follicles and sweat ducts)
What epidermal changes are seen in acute GVHD?
Epidermal dysmaturation (looks like Bowenoid AK or chemotherapy effect)
Histologic findings in chronic GVHD?
Lichenoid: similar to LP but less dense of an infiltrate
Sclerotic: dermal sclerosis plus-minus subcutaneous and fascial fibrosis, may see overlying vacuolar or lichenoid interface
What workup should be performed for graft versus host disease?
Tissue biopsy in both
Acute: bilirubin, CMP (liver enzymes), diarrhea volume measured
Chronic: MRI can detect fasciitis and may eliminate need for fascial biopsy
What prophylaxis is used for graft versus host disease?
Often MTX + cyclosproin or tacrolimus
Treatment of acute graft versus host disease?
If it is limited/skin only disease can use topical steroids, TCIs, and phototherapy
- For most cases that have skin + internal organ involvement) systemic steroids are the first line and are added to existing immunosuppressants
How effective are systemic steroids for graft versus host disease involving skin + internal organs?
Only 50% tend to respond, in those that don’t respond mortality is high (70%)
What is the treatment for chronic graft versus host disease?
Very difficult to treat, can try topical and systemic corticosteroids added to the immunosuppressive regimen, but again only 50% respond
- Second line, nothing shown to be effective, can try ECP, PUVA +/- isotretinoin, imatinib, and mTOR inhibitors
What is the prognosis of acute graft versus host disease?
Overall: 30-50% mortality if moderate to severe dz
- If steroid-resistant 70% mortality
What is the most common cause of death in chronic graft versus host disease?
Infection
What medication can decrease the incidence of visceral graft versus host disease and how does it do it?
Maraviroc (CCR5 inhibitor) can decrease visceral GVHD by blocking CCR5 mediated CD8+ T-cell recruitment to the liver and gut
- Can be considered in pt’s with high risk for GVHD
Does the addition of Maraviroc decrease the incidence of graft versus host disease?
No, only decreases the incidence of visceral involvement
What other organs can be involved in chronic graft versus host disease?
Eyes (keratoconjunctivitis sicca, blepharitis, corneal erosions), salivary glands (sicca syndrome), and lungs (bronchiolitis obliterans)
Less commonly: esophagus (strictures/webs, less common), liver and pancreas (exocrine insufficiency)
