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

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

Aleksandar Mijovic

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

London, UK

Zadar 2011


Leukodepletion pathogen inactivation irradiation for some or everyone

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


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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


Vcjd what s been done to prevent transmission

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

Universal Leucocyte Depletion -specification (UK SACBC)


Effect of leukodepletion on nh ftr yazer et al 2004 pruss et al 2004

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

NH-FTR rate [%]


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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 patients dzik w et al transfusion 2002

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

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


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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

Pathogen Inactivation:in search of Zero-risk?


Leukodepletion pathogen inactivation irradiation for some or everyone

SHOT report 2010


Leukodepletion pathogen inactivation irradiation for some or everyone

SHOT report 2010


Estimated risk of viral transmission by transfusion in the uk per million donations 2009

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

www.hpa.org.uk


Leukodepletion pathogen inactivation irradiation for some or everyone

414 blood donors in 2005

340 blood donors in 2006

1500 clinical cases with 9 deaths 2006


Leukodepletion pathogen inactivation irradiation for some or everyone

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.


Inactivation of pathogens in platelets by s 59 log

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

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

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 trial mirasol clinical evaluation group 2010

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

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

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


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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

RESULTS


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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


Acute gvhd

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

Graft-versus-host disease of the skin


Leukodepletion pathogen inactivation irradiation for some or everyone

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

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

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

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

“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

    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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