Graft versus host disease

GRAFT VERSUS HOST DISEASE
Presenter – Dr. Deepak R. Chinagi
Guide – Dr. L. S. Patil
Shri B. M. Patil Medical College and
Reasearch Centre, Vijayapura
1

• Greetings
• At the end of this topic, we will understand:
– Define GVHD and its mechanism,
– How is it different from graft rejection,
– Identifying GVHD and differentials.
– How to treat and how to prevent.
– Future perspectives.
2

Introduction
• Graft versus host disease (GVHD) is an immune
mediated disease due to complex interaction between
donor (lymphoid tissue) and recipient’s immunity
occurring after transplantation.
• Two types
– Acute (less than 100 days)
– Chronic (more than 100 days)
• It occurs when immunologically competent T cells or
their precursors are transplanted into recipients who
are immunologically compromised.
• Incidence - 1-2 %
• Mortality - up to 75%
3

Procedures with risk of GVH disease
• Allogenic HSC Transplantation (hematopoietic stem cell
transplantation)
– Bone marrow transplantation.
– Umbilical cord blood.
– PBSC (peripheral blood stem cell) transplantation.
• Solid organ transplantation (esp. organs containing rich
lymphoid tissue)
– Kidney transplantation.(rare)
– Liver transplantation. ()
– Heart transplantation
• Transfusion of unirradiated blood products.
• It can also be caused by whole blood transfusion in
patients with severe combined immunodeficiency.
4

Pathophysiology of GVHD
• Immune-competent T cells transplanted into
immune-compromised host.
• Host cannot reject the graft due to decreased
immunity. But graft T cells perceive the
recipients tissue as foreign and react against
it.
• This leads to activation of CD4 and CD8 T cells
ultimately causing inflammation and killing of
host cells.
5

Pathophysiology of GVHD (Future
Scope)
• GVHD can be minimized but cannot be eliminated
– HLA typing is useful
– Donor T cell suppression before transplant – mixed
blessing
– Multi-functional T cells not only mediate GVHD but
are also required for efficient engraftment of
transplanted HSC s and elimination of leukemic cells
• The disease is less understood due to its complex
mechanism. It is known to occur in autologus
form also. Usually after PBSC transplantation.
6

• Effector cells(Donor T cells)
• Proinflammatory Cytokines(IL1, IL2, TNF, IFN)
• Target Host tissues (Skin, Liver, Intestines)
• Allogenic recognition &
• Autologous dysrecognition
7

8

Clinical Features
• Types of manifestations
– Hyperacute
– Acute
– Chronic
• Severity of GVHD depends on the degree of HLA
disparity and other factors like…
– Cryopreservation of BMT and Cord blood are known
for lower incidence of GVHD.
– Allogenic PBSC has high incidence of chronic GVHD
– Post-transplanational prophylaxis (immuno-
supression) decrease the incidence of GVHD
9

Hyperacute Form - GVHD
• Usually develops after 7-14 days after
transplantation
• Symptoms are …. Fever, generalized
erythroderma, desquamation may occur.
• Later follows a similar course as acute form.
10

Acute GVHD
• Triad of dermatitis, hepatitis and enteritis.
• Skin Manifestations- ( onset 5-50 d, M=19 d)
– Pruritic and Painful rash
– Red to Violet lesions, first appear on palms and soles,
cheeks, neck, ear, trunk.
– In severe cases, bullae and vesicles may form.
• In cases of chronic GVHD,
– Lichenoid lesions or sclerodermatous thickening can
be seen.
– Contractures can occur,
– Joints get restricted mobility.
11

• Hepatic Manifestations-
– Jaundice
– Pruritis
– Skin excoriations due to scratching
– Rare manifestations are cirrhosis, portal
hypertension, hepatic coma and death.
– Raised serum bilirubin, ALT, AST, ALP
12

• Gastrointestinal Manifestations-
– Upper GI Symptoms-
• Anorexia ,
• Dyspepsia
– Lower GI Symptoms-
• Diarrohea, Intestinal Bleeding, Cramping Abdominal
Pain and Ileus.
• Diarrohea is usually described as voluminous, secretory,
green, mucoid, watery, associated with exfoliated cells
13

• Pulmonary Manifestations-
– Pneumonia – infectious and noninfectious.
– Pleural Effusions – usually sterile.
• Other Manifestations-
– Hemorraghic cystitis
– Thrombocytopenia
– Anemia
– Hemolytic Uremic syn.
14

Clinical Staging criteria of Acute GVHD
Criteria Skin Findings Liver findings Gut findings
+ Maculo –Papular
rash < 25 %
Bilirubin = 2 – 3
mg/dl
Diarrohea 500 –
1000 ml/d
++ Maculo –Papular
rash 25 – 50 %
Bilirubin = 3 – 6
mg/dl
Diarrohea 1000 –
1500 ml/d
+++ Generalised
Erythroderma
Bilirubin = 6 – 15
mg/dl
Diarrohea more
than 1500 ml/d
++++ Desquamation and
Bullae
Bilirubin > 15
mg/dl
Abdominal Pain
± ileus
15

Clinical Staging of Acute GVHD
Grade Skin Liver Gut Functional
impairment
0 (None) 0 0 0 0
1 (Mild) +/++ 0 0 0
2 (Moderate) +/+++ + + +
3 (Severe) ++/+++ ++/+++ ++/+++ ++
4 (Life-
Threatening)
++/++++ ++/++++ ++/++++ +++
16

Chronic GVHD
• May occur as extension of already existing disease or
de novo. Usually it emerges after an interval after
acute GVHD.
• Skin Manifestations-
– Lichenoid lesions, sclerodermatous thickening,
contractures of skin and restricted joint mobility.
• Ocular Manifestations-
– Burning sensation of eyes, irritation, photophobia, pain,
dryness of eyes.
– Hemorrhagic conjunctivitis, pseudo membrane formation,
lagophthalmos, keratoconjunctivitis sicca, punctate
keratopathy, corneal erosions.
17

• Oral Manifestations-
– Dryness of mouth, atrophy of mucosa, dysphagia,
odynophagia, weight loss
• Pulmonary Manifestations-
– Wheeze, dyspnea, chronic cough.
– Bronchiolitis obliterans.
• Neuromuscular manifestations-
– Weakness , neuropathic pain and muscle cramps.
18

Differentials
• Chronic GVHD has similar manifestations as
that of systemic sclerosis, SLE, lichen planus,
sjogrens syn., eosinophilic fasciitis,
rheumatoid arthritis, primary biliary cirrhosis.
• Erythema Multiforme(SJS)
• Viral Hepatitis
• Malabsorption
• Mixed Connective Tissue Disease
19

Investigations
• CBC
• LFT
• Serum Electrolytes
• USG Abdomen- liver and gall bladder
• Barium swallow
• Schirmer test – ocular manifestations
• PFT , ABG
• Biomarkers
– IL2 receptor α
– TNF receptor 1
– IL8
– Hepatocyte growth factor
20

Investigations
• Skin Punch Biopsy
• UGI endoscopy
• Sigmoidoscopy/Colonoscopy
• Liver Biopsy
21

Treatment
• Primary prophylaxis
– CSP A /Tacrolimus for 6 mths and short course
MTX and added with prednisolone.
– ATG decerases severity but doesn’t alter survival
– ECP – 8methoxy-psoralen . After UV light , cell
undergoes apoptosis.
22

Treatment
• Primary therapy
– Topical steroids / continue immunosupressive prophylaxis.
– ATG , CSP alone , Mycophenolate Mofetil
• Secondary therapy steroid refractory cases
– ATG / multiple pulses of methylprednisolone
– Mycophenolate mofetil 2g/d
– Muromomab
– Anti IL2 receptor
– PUVA
– Tacrolimus, Visilizumab, Daclizumab, Infliximab,
– TNF α inhibitor (etanercept)
23

Treatment
• Chronic GVHD
– Prednisolone 1mg/kg ± Azathioprine.
– TNF modulator- Thalidomide
– Steroid refractory cases –
• Azathioprine , CSP / prednisolone, thalidomide
• Clofazimine
• PUVA / ECP
24

Graft versus host disease

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