transfusion Associated Graft versus host disease. A delayed immunogenic transfusion reaction.

2. Case 1

3.  Background history:
- She was gone through her first caesarean section on 4th august,23
-Transfused 1 unit whole blood from younger brother
-On 7th PBT day she developed high grade fever(12.8.23)
-On 9TH PBT day erythematous rash appeared on trunk
-Diagnosed as neutropenic fever with viral rash for unknown cause
-Within a week spread all over the body and jaundice developed
-Admitted on Rajshahi medical College(20.8.23)
-Bonemarrow biopsy and cytology was done on 20th PBT day
-Admitted on to Dhaka medical college 0n 22nd PBT day(28.8.23)[PBT-pist
transfusion day
Case 1: continued…

4.  On Examination
• Anaemia - positive
• Jaundice – positive
• Ulcer in oral mucosa and angle of mouth
• Dry,scaly skin
• Erythematous maculopapular rash in whole
body
• Temp-N
• Pulse-68b/m
• Bp-140/80mmhg
Case 1: continued…

5. • SGPT-50 U/L (10-50U/L)
• APTT-45sec
• PT-24 sec
• S.Bilirubin-3mg/dl
• S.Albumin-2.4g/dl (4-5gm/dl)
• LDH-812U/L (M:135-225U/L;F-35-104U/L}
• ANA-negative
• D-Dimer->10.0 microgm
• S.creatinine-0.7 mg/dl (0.68-1.36)
• Urine RME-Albumin ++
pus cell-8-10/HPF
• Bone marrow study-Bone marrow
aplasia
• Hb-10.2g/dl 9
• WBC-130/cumm
• Neutrophil-1950 /microL
• Lymphocyte-10000/microL
• Plt-38000/cumm
• PBF-RBC
normocytic,normochromic &
moderate roulex formation
WBC are mature with
leucopanea and lymphocytocis
Platalet are decreased
• Reticulocyte count-0.28% (0.90-
2.40)
 Lab Report:
Case 1: continued…

6.  CBC report:
Case 1: continued…
CBC 20.8.23 22.8.23 26.8.23
HB g/dL 12.3 11.3 10.2
ESR mm in 1st hour 70 80 85
RBC m/µL 4.19 4.00 3.58 million/cumm
TC / cumm 2500 1500 1200
Neutrophil % 75 315 1950
Lymphocyte % 2375 1110 10000
Hct% 34.85 32.4 28.8
Platelet / cumm 1,30,000 47,000 38,000

7. • Developed Cough on 23rd BT day that worsen with the time with breathlessness.
• Diagnosed as pneumonia and Treated accordingly
• She developed severe dysphagea that she couldn’t even eat so NG feeding was
advised(27th BT day)
• Patient went to shock(29th BT day)
• But before complete resuscitation Patient party took DORB 0n 4.9.23
• Patient died on same day (30th PBT)
Case 1: continued…

8. Case 1: continued…
 Photographof patient:

9. Treatment given:
1. NG feeding 200mg/2 hrly not more than 10 feed/24hr
2. Inf. Normal saline
3. Inj.Methylprednisolone 160mg/day
4. Inj.Meropenem 1gm-IV tds
5. Tab.Acyclovir 400mg -BD
6. Cap.Fluconazole 50mg- OD
7. Tab.Cyclosporine 400mg BD
8. Tab.Paracetamol 1000mg tds
9. Nystatin oral drop-tds for oral application
Case 1: continued…

10. Mr. Abul Mia 60 years old man hailing from Cumilla got admitted in hospital for CABG.
During and after operation 3 units of whole blood were transfused. Donors were his
younger brother, his nephew and his son.
• After 1 week, he developed high grade fever with dry, scaly erythematous lesion
that gradually spread from trunk to whole body.
• He consulted with several doctors. They diagnosed and treated him as a case of
Steven Johson Syndrome. Dermatalogist suggest for skin biopsy,after final diagnosis
refd to DMCH
• With high grade fever(103ºF), mucositis, skin exfoliation, progressive pancytopenia,
altered Liver function with feature of shock he admitted in DMCH on 24.8.23
@2.30pm
• Immedietly shock management and Broad spectrum antibiotic, GCSF, Blood
tarnsfusion was given but at 11.30pm patient died after an episode of convulsion. (3
week of PBT). [PBT-post blood transfusion ]
Case 2

11. Case 2: Continued…
 General finding:
• Anaemia ++
• Jaundice-+
• Temp-103F
• Pulse-110b/m
• BP-70/40mmhg
 Investigation:
• Hb-7gm/dl
• Platlet –15000/cumm
• S.bilirubin-5 mg/dl
• S.Creatinine-1.6 mg/dl
• PBF-Pnacytopanea
• Skin biopsy-
 Proliferation of lymphocyte in
epidermis involves adnexal structure.
 Hydropic change in basement
membrane.

12. Mrs.Sanjida a 29 yrs lady from cumilla had her 3rd c/s on 20.7.23 (Hb-11.3gm/dl)and
had 1 unit whole blood transfusion from her younger brother. After a week she
developed high grade fever (105ºF), then on next day reddish, painless rash on
chest. On 16th day of blood tarnsfusion she admitted to DMCH with high grade fever,
dry, scaly erythematous rash, sloughing out mucous membrane of mouth, cough,
back pain, watery diarrhoea, yellowish coloration of skin and urine.(S.Bi-11 mg/dl).
Her Serial CBC report
CBC 3.8.23 8.8.23 10.8.23 11.8.23 12.8.23 19.8.23
Hb g/dL 13.8 12 11.7 11.5 11 3.9
Neutrophil % 65% 03% 45% 46% 00 04
Platelet /cumm 1,90,000 1,50,000 1,30,000 80,000 440 400
Case 3

13. At first they thought it could be a case of drug reaction. After a week of admission
in gynaecology department finally she diagnosed. But condition already worsen.
With mucosal and severe P/V bleeding patient went into shock.
Management of shock with blood transfusion (RCC,Apheretic platelet,FFP), broad
spetrum antibiotic (piperacillin+tozabectum), Methylprednisolone, Filgrastim was
given. But on next day she died when her youngest child was only 28days old.
Case 3: Continued…

15. )
Dr.Faria Shamso Tusi
DBS&T-5
Transfusion Medicine departmen
Dhaka Medical College

17. What is TA GVHD?
• It is a delayed immune transfusion reaction due to
immunologic attack by viable donor lymphocytes
contained in the transfused blood component against
the transfusion recipient.
• It occurs when immunocompetent allogenic lymphocyte
in blood component engraft in the recepient,proliferate
and mount an attack against the host tissue.
Source:MBB&TP-6th edition

18. When TA GVHD occure?
• Clinical manifestation of TA-GVHD usually begins 8-10 days after transfusion,
although symptoms can occure 3-30 days following transfusion.

19. Epidemiology
EPIDEMIOLOGY
• This is a rare complication incidence is <1 per million transfusion. But may be under
reported as confuse with consequence of present disease or drug reaction.
• Death rate about >90% and its usually occurs Within 3 weeks of first symptoms of TA-
GvHD
• The most common causes of death in TA-GvHD are infections, hemorrhages secondary to
pancytopenia and liver dysfunction.
HISTORY:
Although Murphy reported in 1916 about a syndrome GVHD due to chicken spleen injection
to a chick.But TA GVHD was first reported by Shimoda on 1955 in post surgical patient who
had pre and post operative tarnsfusion .Initially named as post operative
erythroderma(POE) source:Wiley online library

20. Grading of acute GVHD
Grade Skin Liver Gut
1 Stage 1-2 None None
2 Stage 3 or Stage 1 or Stage 1
3 - Stage 2-3 or Stage 2-4
4 Stage 4 or Stage 4 -

21. Pathophisiology
The three prerequisites for development of TA-GVHD are as follows:
1.The graft (blood components) must contain immunologically competent cells
2.Presence of antigenic difference between the donor and the recipient
3.The recipient must be sufficiently immunocompromised.
So donor lymphocyte can engraft in recipient and mount an effective immune response against the
recepient cells.Though immunocompetent individual can develop TA-GVHD.But it”s a very rare event.
The three consecutive phases in the development of GVHD are as follows:
• The presentation of host protein by host’s antigen presenting cell(APC) to donor T cells
• Activation,proliferation and migrantion of donor T-cells
• Damage of host target tissue

22. Cytokine
IL-23,IL-12
1
IL2
IL6
Host cell
Host cell
Donor T cell containing
blood
NK

23. Mechanism
In immunocompromised cases:
 Due to disease,infection,high dose radio and chemotherapy tissue demage
occure.Damaged tissue secret LPS ,cytokine,which stimulate APC cell to activate T
lymphocyte.
 But due to incompetent immunity APC cell can not recognize the recipient as foreign
and present antigen to donor T lymphocyte
Donor T lymphocyte recognized host cell as foreign ,it proliferate
and attack host tissue and cause symptoms of tissue damage in
different part of body.
Symptoms begins from 8-10 days after transfusion,although can occure
within 3-30days

24. A1
B8
DR
17
Child 4
A3
B7
DR1
1
Causing initially fever,with skin menifestation,GI menifestation,,Hepatic
dysfunction,Bonemarrow failure with pancytopanea
Death usually occure due to infection,bleeding within 1-3 weeks of first
symptom
Mechanism: continued….

25. In immunocompetent cases:
When donor is homozygous and recipient is heterozygous for an HLA haplotype
host does not recognize T lymphocyte as Foreign and cause TA GVHD. Most of the
patients underwent cardiac surgery involving cardiopulmonary bipass.
Mechanism: continued….

26. Sign and Symptoms
Hepatic menifestation:
Lymphocyte infiltrate in bile duct ,Damage bile duct epithelium ,Destruction of bile duct. peiportal inflammation
canalicular cholestatsis
Causing-hepatomegaly
-Increased liver enzyme
-Increased bilirubin
GI tract menifestation:
T lymphocyte infiltration,apoptosis of crypt epitheliai cell,ulceration of intestinal and stomach epithelium
causing-Nausea,vomiting,anorexia,abdominal pain and Watery diarrhoea
Skin manifestation
T lymphocytes infiltrate epidemis,ki cause
necrosis of keratinocyte,bullae formation
Causing-
Erythematous maculopapular rash.Itchy,dry,scaly skin Involbe
whole body including pulm and sole .Blister and ulcer in
severe cases
Bonemarrow
T lymphocyte infiltrate in bone marrow attack stem cell causing depletion of
production of all three cell lineage –Pancytopanea(16th day)
Causing-Anaemia,Infection(3 wks),Bleeding manifestation

28. Clinical risk factor for developing TA-GVHD-
1. Leukemia
2. Lymphoma
3. Immunosuppresive drug
4. Congenital immunodeficiency disorder
5. Neonatal age
6. And partial/Shared HLA matched people
– Donor is homozygous for HLA haplotype
– Depends on the heterogenecity of the population
– HLA matched platelet
– Recipient is heterozygous for HLA haplotype
– Directed donation from first degree relative

29. Any non frozen component containing viable lymphocyte
Whole Blood
Packed Red Cell
Platelet
Granulocyte
Fresh plasma
HIGHER RISK:
1. Blood stored less than 3weeks
2. Granulocyte transfusion
3. Donation of any components from relative
Blood Products that can cause TA-GVHD:
 NOT In FFP and Cryoprecipitate

30. Prevention
1. Irridiation of blood: Single reliable method. Must be labeled Irridiated
 Process: Irridiation may be achieved by using either radioactive source (cesium
137 or cobalt 60) or x-ray for cellular blood component.AABB standards
requires a minimum dose of 25 Gy (2500cGy) delivered to the central portion of
the container and a minimum 15Gy(1500cGy) dose elsewhere in the container.
It inactivates lymphocyte leaving platelets,RBCs,Granulocytes relatively
undamaged
Shelf life-28 days post irradiation.
Effect on cells-Where hyperkalaemia( eg: intrauterine or neonatal exchange
transfusion) is concern red cell should transfuse within 24hr
No significant effect on platelet function.Patelet may be irriadiated at any stage
during their 7 days storage
Granulocyte –Should transfuse as soon as collection and irridiation

31. Prevention: Continued…

32. Indication:
1.Immunocompromised patients (Indicated by patient condition)–
 Intrauterine transfusion
 Low birth weight infant
 Neonate receiving a whole blood exchange
 congenital immunodeficiencies
 Hematopetic progenitor cell transplant recipient
 Solid organ transplantation
 Acute Leukemia
 Hodgkin disease
2.Immunocompetent State
 Directed donation from blood relatives
 HLA-matched plateletor granulocyte
 Crossmatched platelet or granulocyte
 Granulocyte component

33.  Available Irradiation centre for blood product in Bangladesh-
1.Evercare hospital
2.Square Hospital
3.CMH
2.HLA typing before blood donation

34. 3.Deferral System:
First degree relatives(Parents,Children,Siblings) are deffered in Transfusion Medicine dept
of DMCH

36. 1. Steven johnson syndrome
2. Lichen palnus
3. Lupus Erythomatous
4. Viral eruption
5. Thymoma-associated multiorgan autoimmunity(TAMA)
Investigation
1.Biopsy and histopathology- SKIN:perivascular lymphocyte infiltrate,necrotic
keratinocyte,vacular dermatitis
-LIVER:Degenaration,intense periportal inflammation lymphocytic
infiltration .Scattered lymphocytes invading bile duct,epithelium
-GI TRACT:mucosal denudation with prominenetmucosal
hemorrhage,reactive epithelial changes and focal apoptosis
Differential Diagnosis:

37. 2.Bonemarrow study : Hypocellular or aplastic marrow.Marrow space replaced with
macrophage
5.DNA based analysis-Dmeonstrate foreign
DNA in recipient
4.HLA typing of donor and recipient
other
1. CBC-pancytopanea
2. LFT-increase bilirubin and eleveted liver
enzyme
3. S.creatinine –increase

38. Treatment
• I/V Glucocorticoids:
– such as Prednisolone (0.5-2mg/kg)
– With or without cyclosporine
• Stem cell transplant (survival rate was 82% who showe improvement within 1 month
and 72% who showe response after 1 month)
• Symptomatic management
– Broad spectrum antibiotic,
– Liver friendly antifungal
– Antiviral
– GCSF
source –annoucement of canadian health regulator

39. Take home massage
Avoid unnecessary transfusion
If you suggesting for blood transfusion,this is your liability
also to ask about donor too
Inhibit and Defer all first degree relative as donor to prevent
fatal TA GVHD
Knowledge about cause of TA GVHD should spread among all
health personals including Doctors in every corner of country
Spread awareness among doctors that all rash is not only due
to virus or drug, think twice about your diagnosis if patient
have transfusion history
Where ever possible use leucodepleting filter for safe blood
transfusion
Avoid unnecessary transfusion
If you suggesting for blood transfusion to a patient,
ask about their donor too
Inhibit and Defer relatives as donor who can cause
fatal TA GVHD
Knowledge about cause of TA GVHD should spread
among all health personals including Doctors in
every corner of country
Raise awareness among doctors to think twice
about their diagnosis of viral or drug reaction rash if
patient have transfusion history
Where ever possible use irradiated blood
TAKE HOME MESSAGE