Risk-benefit of screening blood supply for malaria unknown

August 2006

BETHESDA, Md. – A universal screening test for evidence of malaria risk in blood donors presents too many unknowns and should not replace the current United States policy of deferment.

“I do not think we know the answer,” Louis Katz, MD, executive vice president of medical affairs at Mississippi Valley Regional Blood Center, said. “There are complications with regard to test sensitivity and specificity. Until we resolve those, we do not know how to answer the question of cost.”

Katz was a member of an expert panel convened by the FDA to discuss whether the United States should replace its policy of deferment to avoid malaria in the blood supply with a policy of universal screening.

“I would be very concerned about the idea of having an antibody test instead of something, but I think there is great merit to adding it,” said Peter Chiodini, MB, professor at the Hospital for Tropical Diseases in London.

Under current United States policy, individuals with malaria are deferred from donating blood for three years after becoming asymptomatic. Travelers from nonendemic countries with no previous history of malaria are deferred for a one-year period after departing from an endemic area. Prior residents of malaria-endemic countries are deferred for a three-year period after each departure from an endemic country.

During the four decades before 2000, the rate of transfusion-transmitted malaria remained stable at 0.25 cases per million units of blood collected. However, between 1995 and 2005, the rate declined to approximately 0.07 cases per million units collected. The most recent case occurred in 2005.

“Although current donor deferral policies have been effective in reducing the incidence of transfusion-transmitted malaria, this approach leads to a sizeable loss of otherwise suitable donors,” Hira Nakhasi, PhD, director of the Division of Emerging and Transfusion Transmitted Diseases at the FDA, said during the conference.

Steve Anderson, PhD, deputy director of the Office of Biostatistics and Epidemiology at CBER, FDA, said approximately 150,000 potential blood donors are deferred every year due to malaria concerns, but the number could be as high as 880,000 if the estimate includes self-deferrals.

“However, there would be significant costs associated with testing and re-testing more than 14 million units a year. We need further exploration of the cost of each option,” Anderson said.

Malaria — United States

In the United States, there are approximately 1,000 to 1,500 cases of malaria annually, of which 99% are imported; about 10 cases of malaria are locally acquired each year.

“Our highest risk is from immigrants and through exposure in Africa,” Monica E. Parise, MD, chief of the Parasitic Diseases Branch at the CDC, said at the workshop.

However, travel-based deferrals create a problem as well. Jesse Goodman, MD, director of the Center for Biologics Evaluation and Research at the FDA, said he was deferred from donating blood following international travel, as was former Secretary of Health and Human Services Tommy Thompson.

Parise said the risk from travel abroad is lower than the risk presented by immigration, but it still exists.

“We have been told before that resorts are safe places and we could accept donors who spent all their time at resorts, but we have seen data to suggest that is not always the case and we often differentiate rural from urban resorts,” Parise said. “Also, given the microepidemiology of malaria, it should be remembered that assumptions based on data for the average traveler may not hold up for all.”

UK experience: screening

Currently, there are no approved malaria parasite detection tests in the United States, according to Freddie M. Poole, associate director of the Division of Microbiology Devices at the FDA. However, several European countries and Australia now test deferred at-malaria-risk donors. The most commonly used test detects antibodies in only two out of four human Plasmodium species, P. falciparum and P. vivax, by enzyme-linked immunosorbent assay.

In the United Kingdom, there were 1,754 cases of malaria in 2005, according to Chiodini. However, between 1986 and 2006, there were five cases of transfusion-transmitted malaria all due to P. falciparum; four of these cases were from African migrants.

In one 1980 study, testing by immunofluorescence antibody (IFAT) was evaluated in United Kingdom residents and immigrants with malaria. Researchers found that 78% of United Kingdom residents one week after onset of malaria symptoms and 100% immigrants were seropositive one week after onset of symptoms.

Identification of exposure to malaria parasites by ELISA (P. falciparum antigen-based) antibody screening was tested more recently in 1997, but in 1999 the assay was withdrawn from use due to concerns over its performance.

Chiodini said the United Kingdom now uses malaria antibody EIA (Newmarket Laboratories). Also, the United Kingdom policy of selective malarial antibody screening of otherwise deferred donors facilitates earlier donor reinstatement.

“However, while antibody testing provides a safeguard which is both additional and complementary to history taking and time exclusion, it should not be seen as a replacement for those measures in the prevention of transfusion-transmitted malaria,” Chiodini said.

France: increased travel

Olivier Garraud, MD, PhD, professor of medicine at the University of Saint-Etienne & Etablissement Francais du Sang in France, said more than 3 million people living in France travel each year to tropical areas for vacation, business or visiting relatives.

“The first cause of fever in returning travelers from tropical areas is malaria,” Garraud said.

Garraud said France records the most imported malaria cases of any other European country, with more than 7,000 cases per year. More than 90% of these cases come from 13 west and central African Countries.

Since 1995, French blood banks have used immunofluorescence/IFA screening as a single-test antimalaria antibody, but the method is not completely fail safe; they went on testing by an ELISA-based test, along with revision of deferral policy.

“The measures taken in France and in most European countries to prevent transfusion-transmitted malarial infection are almost sufficient, but the zero risk does not exist,” Garraud said.

Available malaria tests

Newmarket Laboratories Ltd., based in the United Kingdom, currently offers an antibody-screening test for use in Europe. According to literature provided by the company, malaria EIA 96 and 480 test kits use four recombinant antigens in a sandwich test to produce a test that is both highly specific and sensitive.

“The antigens will detect P. falciparum and P. vivax –specific IgG, IgM, and IgA, enabling the test to detect antibodies during all stages of infection,” according to company literature.

P. Nigel Appleton, director of New Market Laboratories, said the test was able to detect antibodies to P. falciparum 94.4% of the time and P. vivax 100% of the time during pre-launch testing.

“These numbers were seen with very low backgrounds, high signal to noise ratios and a very economic use of materials,” Appleton said.

However, malaria infections are also caused by P. malariae and P. ovale. Newmarket Laboratories Ltd’s test identified P. malariae 80% of the time and P. ovale 67% of the time, although Appleton conceded these numbers may not have been robust.

“These numbers are not statistically valid, however, because there are such a low number of samples with these latter infections. More intensive work on genomes of these two rarer species is only just beginning,” Appleton said.

Jay Epstein, MD, director of the Office of Blood Research & Review at the FDA, said such a test would probably not pass muster under American regulations.

“Although the data suggest that the risk of malaria from P. malariae and P. ovale have been decreasing, we do not yet know how low it actually is. As long as we consider these infections a threat, we would not want to reenter a donor in a testing environment where their presence could not be determined,” Epstein said.

Panel members agreed that screening by DNA testing was not a near-future possibility.