CBER Presentation

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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)

World map showing French territories

France is not restricted to te European territory.

Malaria in France

Malaria in France, imported and endemic

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

World map showing Imported malaria in France

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 malarial infection, southern type endemic and northern type non endemic

Transfusion transmitted malaria always severe, often lethal

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

France 1 Tunisia 1
Ireland 0 Israel 1
Italy 7 Japan 1
Spain 0 UK 2
Switzerland 0 Canada 3
Germany 0 USA ≥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?

Algorithm of French 2002 case and British 2003 case

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

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  • 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 situations Policy Lab. 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

Malaria serology: Decision algorithm ELISA: qualifying test

Information to blood donor:
IFA (not qualifying test)

Information to blood donor: IFA (not qualifying test

Interpreting serology (Pf)

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

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  • 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)
 
Updated: October 16, 2006