Leukodepletion pathogen inactivation irradiation for some or everyone
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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?. Aleksandar Mijovic King’s College Hospital/National Health Service Blood & Transplant London, UK. Zadar 2011. Immunologic effects. Alloimmunisation Febrile non-haemolytic reactions Platelet refractoriness

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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?

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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?

Aleksandar Mijovic

King’s College Hospital/National Health Service Blood & Transplant

London, UK

Zadar 2011


Immunologic effects

Alloimmunisation

Febrile non-haemolytic reactions

Platelet refractoriness

Rejection of transplanted organ

Graft-vs-host disease

Immune modulation

Increased risk of bacterial infection (?)

Increased recurrence of malignancy (?)

Infectious disease transmission

CMV

HTLV-I

Epstein-Barr virus

vCJD?

Adverse effects of leukocytes in blood components

Modified from: McCullough 2005


vCJD

  • 4 cases in UK due to transfusion of non-leukodepleted red cells from donors who later developed vCJD.

  • Incubation period 6-8.5 years


Infectivity of experimental TSE’s in blood -intracerebral route(Brown et al, Transfusion 1998:38;810)


vCJD - What’s been done to prevent transmission?

  • Universal Leukodepletion (1999)

  • Import of plasma from USA

  • Donor selection – ban of donors who received transfusions after 1980

  • Donor testing not yet available

  • Prion-reduction filters (for children and patients with haemoglobinopathies) – 2012?


Universal Leucocyte Depletion -specification (UK SACBC)


Effect of Leukodepletion on NH-FTRYazer et al, 2004; Pruss et al, 2004

NH-FTR rate [%]


Effects of Leukodepletion on Platelet Refractoriness

  • TRAP study, 1997

  • Lymphocytotoxic antibodies

    • 45% controls

    • 17-21% in treated groups

  • Platelet Refractoriness

    • 13% controls

    • 3-5% if platelets filtered or UV light-treated

  • After leukoreduction in Canada:

  • Alloimmunisation reduced from 19% to 7%

  • Immune refractoriness reduced from 14% to 4%

    • Seftel et al 2004


Leukodepletion for cardiac surgery

  • Randomised study of: a) Buffy-coat depleted RBC; b) filtered, fresh RBC; c) filtered RBC, post storage

  • Infection rates:

    • 23.0% : 16.9% : 17.9%

  • Mortality:

    • 7.8 % vs 3.6% vs 3.3%

Van de Watering et al 1998


Leukodepletion in hospitalised patientsDzik W et al, Transfusion 2002

  • 2780 pts randomised to receive LD or non-LD blood products.

  • No difference in primary outcomes: 1) In-hospital mortality; 2) Length of hospital stay (LOS); 3) Hospital costs

  • Nor in secondary outcomes: 1) LOS in ICU;

    2) post-operative LOS; 3) antibiotic usage;

    4) re-admission rate


Risk for CMV disease in BMT(Ljungman et al 1998)


PREVENTION OF CMV INFECTION

  • Use of CMV Neg Blood Products

    • Incidence ofCMV Infection reduced to 0-7% (pneumonia ~ 0%)

    • Leukodepletion

    • Equally effective to donor screening(Bowden et al 1995)

    • Abandonment of CMV screening premature(Nichols et al 2003)


Leukodepletion vs CMV serology to prevent CMV infection

  • Both are effective

  • Neither is perfect

  • Not possible to decide if one is better than the other

  • Benefit of using both is unknown

Canadian Consensus Conference 2001


Pathogen Inactivation:in search of Zero-risk?


SHOT report 2010


SHOT report 2010


Estimated risk of viral transmission by transfusion in the UK [per million donations](2009)

www.hpa.org.uk


414 blood donors in 2005

340 blood donors in 2006

1500 clinical cases with 9 deaths 2006


PATHOGEN INACTIVATION/REDUCTIONkey issues

  • 1.Effective inactivation of a range of agents; no evidence of toxicity. Compare with current alternatives.

  • 2.Underlying residual risk in a given country.

  • 3.?Threat from new (or newly identified) microbial agents.

  • ?How to measure safety increment from PI.

  • Logistics; process control. Separate PI steps needed for each blood component

  • 6.?Cost-benefit.


HIV>6.2

HBV>5.5

HCV>4.5

CMV >5.9

West Nile >6.0

HTLV I/II 4.7-5.1

ParvoB19 4.0-4.9

E.Coli>6.4

S.Aureus6.6

P.Aeruginosa 4.5

B.Cereus >6.0

Yersinia E.>5.9

P.Falciparum 7.0

T.Cruzi >5.3

Inactivation of Pathogens in platelets by S-59 (Log)


Photochemical Treatment of Platelets – euroSPRITE trial

  • Randomised study (52 v 51 pts) of Amotosalen(S-59) treated BC platelets.

  • Average dose: 3.9 vs 4.3 x 1011 (p<.001)

  • 1-h increment: 27.5 vs 35.8 x 109 /L. Difference 8.3 (95% CI, 0.9 – 15.8) (p=.03)

  • 1-h CCI: 13.1 vs 14.9 x 103 (p=.11)

  • Bleeding/adverse events not different

Van Rhenen et al 2003


Photochemical Treatment of Platelets – SPRINT trial

  • Randomised study (318 v 327 pts) of Amotosalen(S-59) treated apheresis platelets.

  • Average dose: 3.7 vs 4.0 x 1011 (p<.001)

  • Grade 2 bleeding: 58.5% vs 57.5% (NInf)

  • Grade ¾ bleeding: 4.1% vs 6.1% (Ninf)

  • 1-h CCI: 11.1 vs 16.0 x 103 (p<.001)

  • Units received: 8.4 vs 6.2 (p<.001)

McCullough et al 2004


MIRASOL randomised trialMirasol Clinical Evaluation Group 2010

  • Mirasol: Riboflavin (vitamin B2) + UV light

  • RCT: 56 pts (303 transf.) received PR-platelets, 54 pts (238 transf.) received reference platelets.

  • Primary outcome: 1-hour CCI

  • PR-P vs REF-P: 11725 : 16939 (criteria for non-INF not met).

  • PLT/RC utilisation not significantly different; Safety profile similar.


Plasma - Spoiled for Choice?

  • Fresh Frozen Plasma

  • Solvent/Detergent treated plasma

  • Methylene Blue/UV light treated plasma


FFP vs S/D vs MB Plasma: risk of disease transmission


A.S., 18 y, TTP

22 Plasma exchanges

Pulmonary

Embolism

R Fem Vascath

L Fem Vascath

Prednisolone

= SD/Cryopoor plasma exchange


COMPARATIVE STUDY OF TWO TYPES OF PLASMA IN LIVER TRANSPLANTATION

RETROSPECTIVE, SINGLE CENTRE STUDY OF ADULT ORTHOTOPIC LIVER TRANSPLANT PATIENTS:

200 S/D FFP OCTAPLAS (1998-2001)

199 SINGLE DONOR FFP (after March 2001)

ENDPOINTS

PRIMARY:

AMOUNT OF BLOOD PRODUCTS USED

ESTIMATED BLOOD LOSS

USE OF OTHER HAEMOSTATIC PRODUCTS

SECONDARY

48HRS MORTALITY


RESULTS


S/D plasma or FFP ?

Viral safety

Reduced risk of TRALI

Reduced risk of vCJD?

Increased blood usage in OLT

Increased VTE risk

Cost


Conclusions

Use S/D PLASMA in:

  • Below age 16

  • Young patient with good immediate and long-term prognosis, anticipated to receive few blood products.

  • Thrombotic Thrombocytopenic Purpura


Transfusion related

onset 2-30 days

pancytopenia/BM aplasia

No response to Th

Mortality >90%

Post BMT/PBPCT

onset 35-70 days

rare BM aplasia

Incidence 20-70%

80-90% respond to Th

mortality 10-15%

Acute GVHD


Graft-versus-host disease of the skin


Transfusion-associated Graft-vs-Host disease: Prevention

Gamma/ X-ray Irradiation 25Gy

Leukodepletion – does it prevent TA-GVHD?

- No case since 2001 in UK

Pathogen Inactivation for Cellular Components


Indications for irradiation of blood components in the UK

A. Indication by patient condition

  • Intrauterine transfusions

  • Neonatal exchange transfusions

  • Congenital immune deficiencies

  • Allogeneic HSC transplant patients

  • Autologous HSC patients

  • Hodgkin’s disease

  • Purine analogue treatment

  • Aplastic anaemia treated with ATG or Alemtuzumab

    B. Indication by component type

  • Granulocyte transfusions

  • HLA-matched blood components

  • Blood components from relatives


Frequency of Homozygous HLA donors to recipients heterozygous for the same haplotype[1 : x]


Survey of Blood Use in France (1997)175 Hospitals, 3206 Transfused Patients

57% of transfusion recipients were > 65 years

Mathoulin-Pelissier et al, Transfusion 40:1140, 2000


“Greying” of the Population

  • Life Expectancy in UK (2001)

    • 80 y for Women

    • 75 y for Men

  • In 2007, people ≥ 60 were 21.8% of UK population.

  • The same year, people aged 65+ outnumbered those under 16 y for the first time ever.

  • UN Dept. of Economic & Social Affairs


    Who should we irradiate blood products for?

    • According to national guidelines

    • All recipients with malignant disease

    • Recipients > age 65 yr

    • Everyone


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