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Malaria donor deferral policy in France: French experience with malaria antibody screening

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Malaria donor deferral policy in France: French experience with malaria antibody screening

FDA Workshop on Testing for Malarial Infections in Blood Donors
July 12, 2006

Olivier GARRAUD
Marie-Hélène ELGHOUZZI
Azzedine ASSAL
Bertrand PELLETIER
Josiane RELAVE
Georges ANDREU


The French situation

  • Increasing immigration (7.4% of individuals living in France in 1999); 39.3% of immigrants originate from Africa; Of approx. 136.000 immigrants/year (2003), 90.000 came from Maghreb or Black Africa => approx. 40.000 from Central & West Africa;

     

     

  • Increasing circulation of individuals: in 2003, France delivered approx. 307.000 visas to travelers from Sub-Saharian Africa (including for transit and short stays)

     

     

  • Increasing travel and leisure: more than 3 million people living in France travel each year to tropical areas for vacationing, business or visiting relatives

     

     

  • The 1st cause of fever in returning travelers (from tropical areas) is malaria (42.5% in a French survey in Marseille,BEH-2006)

     

 

France is not restricted to te European territory.


Malaria in France

Over 7.000 imported cases p. y. in France (2005): 80% from Africa, 10% from Comores & Mayotte, less than 1% from Guiana


 

Imported malaria in France


Malaria in France

  •  
  • France records most imported malaria cases than any other European country ( ≥7,000 cases p. year; Danis, 2005; Legros 2005)

     

     

  • ≥ 80% imported cases from 13 West & Central African countries + 10 % from Comores and Mayotte (Mayotte is a French District) + a few % from French Guiana.

     

     

  • ≥ 75% occur in Africans residing in France

     

     

  • 83.5% P. falciparum, 6.5 % P. ovale, 4.5 % P. vivax (French Guiana) & 1.6 % P. malariae

     

     

  • 5% cases are "severe"

     


Transfusion transmitted malarial infection

Transfusion transmitted malaria always severe, often lethal


Transfusion-transmitted malaria observed cases over the past 10 years
(after H.W. Reesink, 2004)

France1Tunisia1
Ireland0Israel1
Italy7Japan1
Spain0UK2
Switzerland0Canada3
Germany0USA≥10?

History of transfusion-transmitted malaria in France
(after H. Rech, Montpellier, Fr; 2000)

  •  
  • From 1960 to 1989: approx. 120 reported cases, half of which having occurred between 1975-1989) 1990: 3 cases in the EU, of which 1 in France

     

     

  • Other cases in France since then:

     

    • 1 in 1993,
    • 1 doubtful case in 1998,
    • 1 near miss case in 1999,
    • 1 lethal case in 2002 (Of note: the 2003 British case was very similar to the 2002 French case).

Blood collection in France

  • Anonymous, voluntary, non-profit, neither direct nor indirect benefit
  • One single governmental organization - unified in 2000 - called "Établissement Français du Sang"
  • Subdivided in 14 regions in Metropolitan France and 4 Overseas Blood Centers

     

  • Collection of:

     

    • 2.2 million units of whole blood per year, relatively stable overtime
    • 218,000 plasma apheresis procedures, increasing over time
    • 169,000 platelet apheresis procedures, increasing overtime

Plasmodiae can be transmitted by labile products (RBC packs; PLT packs)
They do not survive freezing (therapeutic or fractionated plasma)


Transfusion-transmitted malaria prevention in France

  • Since the early 90'
    • Information and incitation to self-exclusion in case of self history of malaria
    • Questionnaire about malaria and exotic travels (1994)
    • Anti-malaria antibody testing by indirect single test (recommended: immunofluorescence/IFA) (1995)

Safe enough?

 


Serology/IFA

  • Implemented in 1995

     

  • IFA

     

    • Not standardized between the Biological Qualification platforms
    • Could be performed
      • Either in the EFS platforms
      • Or trusted with University Hospital Platforms
    • Results based on a "+" or "-" basis

     

  • Caveats

     

    • IFA difficult to perform and standardize - even within one platform
    • Difficult to trace if trusted with outside platforms
    • Numerous false positives
    • Do not detect Abs to species other than P. falciparum

Of note.

  •  
  • Lab testing = based on serology

     

    • Malaria and serology do not necessarily fit very well (see the recent TT-malaria case in the US reported by Purdy in 'Transfusion', 2004)
    • Parasites and serology do not fit very well in general (Garraud, 'TCB': 2002, 2005)
    • Malaria and parasites: '≠' (Garraud, 'Transfusion', in press)
    • P. falciparum ±, but P. vivax and P. malariae (and P. ovale) ???
    • Silent serological period whatever the test used (variable; depends on individual, prophylaxis, Plasmodium species.)

     

  • => NAT? --- Ag? --- ??? ---

     


Needs in term of serology to qualify blood => blood safety

 

  • Robustness
  • Reliability
  • Sensitivity
  • Specificity
  • Automation is an advantage

 

Biological qualification of Blood products is not Clinical Biology:
-different objectives
-different requirements

---------

 

  • Acceptability:
    • False positives: (but risk of blood product shortage)
    • No false negatives: risk of infectivity

 


Safety in question:
After the occurrence of the 2002 case =>
Revised measures in France (2005-2006
)

  •  
  • Aug. 2002: all natives (or equivalent) from endemic countries => serology (whatever the time elapsed since return)

     

    • Doubled the # of tests
    • Necessitates automation

     

  • Revision of certain measures after the 2002 French case (AFSSaPS/EFS consensus) (2005)

     

    • AFSSaPS is the French National Regulation and Authorisation Authority for Drugs and all products regarding health products (including cosmetics etc.);
    • => Blood, Cells, Tissues and grafts

     

  • Implementation of anti-malaria antibody testing by indirect single ELISA test (2005)

     

     

  • Implementation of the EU directive and novel consensus (EFS) (2006)

     

     

  • + Brainstorming about procedures of pathogen-inactivation! (safety, implementation and hemovigilance trials: platelets, plasma: Amotosalem, Riboflavin)

     


Revision of deferral policy

3 situationsPolicyLab. testing
Reporting of malaria-Permanent deferral for cellular products
-Plasma for fractionation
-No need of serology
-Reported travel in endemic area (listed)
- & Less than 3 mo
- & Symptomless
-Temporary deferral for 4 mo for cellular products
-Plasma for fractionation
-Serology to qualify the 1st donation during the period 4 mo -
- 3 y after return (one neg test: OK)
-Immigrant from endemic country
-or traveler for > 3 consecutive mo
- or traveler w. symptoms less than 4 mo after return
-Temporary deferral for 4 mo for cellular products
-Plasma for fractionation
-From 4 mo to 3 y: if symptomless & neg serology: OK
-OK after 3 y
-Serology to qualify all donations during the period 4 mo -- 3 y after return

Revision of lab testing (serology)

  •  
  • Observational period (2004-2005)

     

    • To obtain information on alternative assays (NAT/PCR, Ag)
    • To evaluate both ELISA kits and automated ELISA platforms
    • To compare to IFA

     

  • Test period (2005)

     

    • Evaluation of 2 CE-marked ELISA kits (from Diagast, Fr. and from Diamed, CH.)
    • Large scale comparison study of ELISA vs IFA
      EFS: 4,000 samples from exposed and non-exposed + certain tricky samples from collections
    • External expertise commissioned
    • IPPTS: 10,600 samples from Pf and/or Pv exposed individuals =>IFA vs ELISA
      Exploration of false positives and negatives by means of PCR

Selection of an ELISA kit

  • CE-marked
  • Approved by Regulation authority and experts

     

  • One national market (EFS)

     

    • The Diagast ELISA (4 unidentified rec. Ags) did not pass the evaluation
    • The Diamed ELISA (x rec. Ags from Pf and one? from Pv) passed the evaluation

     

  • Diamed ELISA vs IFA

     

    • Same sensitivity
    • Limited # of false negatives
    • False ELISA+ different than false IFA+ => ?
    • Detects Abs to non-Pf species contrary to IFA, in particular Abs to Pv
    • Detects lower Ab titers than IFA (to be confirmed in an even larger series)

Malaria serology: Decision algorithm
ELISA: qualifying test

 


Information to blood donor:
IFA (not qualifying test)

 


Interpreting serology (Pf)

 


Lab. results

  • X serology assays per year in France
  • Y positive (x%)
  • Doubts subsist on
    • Robustness
    • Window period
    • Detection of Abs to Ags on species other than P. falciparum

------------------------

 

  • Medical interview and lab. testing: Discards approx. 10% total blood donations

 


Conclusion

  • The measures taken in France and in most European countries to prevent Transfusion-Transmitted malarial infection are [almost] sufficient
    • The « zero » risk does not exist!

Acknowledgements

  • Pr Ermanno CANDOLFI, Strasbourg, France
  • Pr. A. Kitchen, UK
  • Pr H. Klueter, Germany
  • The network of biologists in charge of the qualification of blood donations at EFS
  • The Hemovigilance network in France (EFS, hospitals)