Graft versus host disease

Shri B. M. Patil Medical College and Reasearch Centre, Vijayapura

1

GRAFT VERSUS HOST DISEASE

Presenter – Dr. Deepak R. ChinagiGuide – Dr. L. S. Patil


2

• 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.


3

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%


4

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.


5

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.


6

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.


7

• Effector cells(Donor T cells)

• Proinflammatory Cytokines(IL1, IL2, TNF, IFN)

• Target Host tissues (Skin, Liver, Intestines)

• Allogenic recognition &• Autologous dysrecognition


8


9

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


10

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.


11

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.


12

• 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


13

• 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


14

• Pulmonary Manifestations-– Pneumonia – infectious and noninfectious.– Pleural Effusions – usually sterile.

• Other Manifestations- – Hemorraghic cystitis– Thrombocytopenia– Anemia– Hemolytic Uremic syn.


15

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 %


Diarrohea 1000 – 1500 ml/d

+++ Generalised Erythroderma


Diarrohea more than 1500 ml/d

++++ Desquamation and Bullae

Bilirubin > 15 mg/dl

Abdominal Pain ± ileus


16

Clinical Staging of Acute GVHDGrade Skin Liver Gut Functional

impairment0 (None) 0 0 0 0

1 (Mild) +/++ 0 0 0

2 (Moderate) +/+++ + + +

3 (Severe) ++/+++ ++/+++ ++/+++ ++

4 (Life-Threatening)

++/++++ ++/++++ ++/++++ +++


17

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.


18

• 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.


19

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


20

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


21

Investigations

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


22

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.


23

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)


24

Treatment

• Chronic GVHD– Prednisolone 1mg/kg ± Azathioprine.– TNF modulator- Thalidomide

– Steroid refractory cases –• Azathioprine , CSP / prednisolone, thalidomide• Clofazimine• PUVA / ECP

Health & Medicine

Graft versus host disease