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Fahed A. Mohareb, FACP

Malaria can be transmitted by the transfusion of any blood component containing red blood cells. It was first reported in 1911 by Woolsey;1 however, transfusion malaria in nonendemic areas is an uncommon complication of blood transfusion. Malaria parasites of all species can remain viable in stored blood for at least one week.2 Plasmodium falciparum malaria has been transmitted by blood stored for 19 days.3 Parasites may even survive well in frozen blood.4 In nonmalarious areas, because of delay in diagnosis, transfusion malaria has a relatively high fatality rate. It can be particularly serious in pregnant women and in splenectomized or immunocompromised patients.4 Because of the morbidity and mortality and cost of investigations and treatment caused by transfusion malaria, we reviewed our experience at KKUH during the period from 1989 to 1992 to highlight this complication and suggest a practical approach to its prevention. Methods Patients who have never been to malarious areas or developed fever after a recent blood transfusion or were found to have malaria parasites in peripheral blood during the period from 1989 to 1992 were reviewed. Patient evaluation included symptoms, signs, investigations, course and treatment. Donors of infected blood were traced from the blood bank records. The blood donor selection was according to standards of the American Association of Blood Banks (AABB). Travelers who are permanent residents of nonendemic countries but have been in an area considered endemic for malaria may be accepted as regular blood donors six months after return to the nonendemic area, provided they have been free of unexplained febrile illnesses and have not taken antimalarial drugs. Prospective donors who have had malaria shall be deferred for three years after becoming asymptomatic. Prospective donors who have taken antimalarial prophylaxis and have

been in an endemic area shall be deferred for three years after cessation of therapy and after departure from the area if they have been asymptomatic in the interim.6 Address reprint requests and correspondence to Dr. Mohareb: Consultant Hematologist, Department of Medicine 38, College of Medicine and King Khalid University Hospital, P.O. Box 2925, Riyadh 11641, Saudi Arabia. Accepted for publication 22 June 1994. Results Twelve patients were found to have malaria post blood transfusion. There were two neonates,5 two thalassemic patients on regular blood transfusion, one patient with renal failure on hemodialysis before the availability of erythropoietin and seven neutropenic patients with acute leukemia post induction chemotherapy. Symptoms started in one to three weeks for the nonleukemic patients. For leukemics, it was difficult to find the exact time of developing symptoms as well as finding the blood donor because of the large number of blood products given. In one leukemic patient, the donor could be traced when symptoms appeared within one week of platelet transfusion. All patients had fever (38.5C to 40C) which was continuous or appeared more than once a day and was associated with fatigue and malaise. There were no chills and no sweating. Patients were investigated for the cause of fever with complete blood count, differential count, erythrocyte sedimentation rate; blood, urine, and throat cultures; viral studies, chest x-ray, ultrasound, computerized axial tomography scan, gallium scan and cerebrospinal fluid (CSF) examination were done when indicated. Initially these patients were considered to have septicemia and were treated with broad spectrum antibiotics until malarial parasites were seen in the peripheral blood films.

Annals of Saudi Medicine, Vol 15, No 1, 1995

All had negative results of the septic workup. A CSF examination had to be done in two patients. Initially the diagnosis of malaria was accidental but later, investigation for evidence of malaria was part of the routine septic workup. All patients were treated for septicemia with broad spectrum antibiotics without response. Blood smears of all patients were found to have Plasmodium falciparum malaria and were given the standard dose of chloroquine with complete recovery. During that period, there were 21,800 units of red blood cells and platelets transfused, of which 400 units were transfused to these patients. Seven donors from endemic areas (two Saudis [southern region], two Ghanaian, one Sudanese, one Yemeni and one Afghani could be traced from blood bank records; however, testing their blood for malaria was not possible because they were either unavailable or declined to come for further testing. Discussion The frequency of post transfusion malaria has been estimated to vary from less than 0.2 cases per million in nonendemic countries to 50 or more cases per million in endemic countries.7 In nonendemic countries, the frequency of reported transfusion malaria is relatively low, e.g. in the United Kingdom, eight cases in 50 years; in the United States of America, 26 cases in 10 years from 1972 to 1981 and in France, 110 cases in 20 years.7 Here we have 12 cases in four years in one center in Riyadh as well as at least 20 unreported cases from other centers in the Kingdom (personal communication). The type of species depend on the donor's country of origin.1 However, according to the WHO reports, Plasmodium malariae was the dominant species although recently P. vivax was found to be the most common parasite.1 Although all our patients contracted P. falciparum, it is expected that other species will be involved since we have residents from areas where all other malaria species are endemic. The incubation period for malaria is influenced by the number of parasites introduced, the type of parasites, and the condition of the host, but usually ranges from 10 to 60 days.9 In our patients, it ranged from one to three weeks since all were P. falciparum. The parasites may be viable in stored blood for up to three weeks, but with less potential infection, and therefore older blood can still transmit malaria, but to a lesser extent.

The carrier state varies but may last for 13 years in P. falciparum, 47 years with P. malariae and six to eight years for P. vivax and P. ovale. This means that accepting donors on the basis of time after exposure to the infection may not be enough to prevent transfusion-transmitted malaria.8 Delay in diagnosis of malaria usually takes 12 to 43 days and depends on the awareness of this possibility. In an unusual case, it took one year to diagnose a transfusiontransmitted P. vivax.1 This delay will no doubt increase the morbidity and mortality as well as the cost.8 Riyadh is a nonendemic area; nonetheless, transfusion malaria is a complication of transfusion that should be recognized and exposed to vigorous evaluation so that proper solutions be found. This is because Riyadh has a large population of resident workers originating from areas where malaria is endemic. Therefore, eradication of transfusion-transmitted malaria (TTM) can best be tackled by eliminating resident workers from the donor population, but this step cannot be undertaken until the number of donors recruited from the local long-term residents covers the blood transfusion requirements. The morbidity and mortality associated with malarial infections are particularly severe in splenectomized patients, immunosuppressed patients and patients under treatment for malignancies, sometimes with early cerebral involvement or even death.10 In addition, the cost of investigation and management is quite high. Transfusion-transmitted malaria compared to natural infection often has a short incubation period because there is no pre-erythrocytic development. Also, radical chemotherapy with primaquine in P. vivax and P. ovale is unnecessary.11 Besides, the use of AABB transfusion guidelines for donor selection may not be practical to apply to the relatively large donor population coming from endemic areas, as it obviously excludes a significant number of potentially healthy donors. Methods or parasite detection include Giemsa staining and Acride Orange (AO) staining of blood smears. The AO staining is marginally better for detecting the parasites, but species differentiation could not be determined by this technique. However, both staining techniques give poor results and have their limitations (mainly due to their low sensitivity).9,12 Since these asymptomatic donors have very low levels of parasitemia, it is important to prepare several blood smears over several hours of examination in the hope

of attaining a moderate degree of success in detecting the infection.12 Immunological diagnosis is possible by looking for malarial antibodies using immunofluorescent antibody (IFA) in addition to enzyme-linked immunofluorescent assay (ELISA) methods. These tests are approximately four times as sensitive as the blood smear methods. 13,14 IFA is sensitive and relatively simple but costly and cannot be automated. ELISA is also sensitive, simple, costeffective and can be automated, but both are less efficient for the detection of low levels of the antibody.13,15,16 These immunological methods give indirect evidence of exposure to malaria but not to parasites or antigens.17 A recent 1. diagnostic approach is the use of DNA or RNA probes 2. which detect malaria antigens, but these are costly, 3. complex and time consuming.14,18 Prophylactic treatment of the recipient with chloroquine 4. has also been used.9 Another approach is adding chloroquine to the anticoagulant in the blood collection 5. bag. These methods may be practical in endemic areas but certainly not in nonendemic areas.19 The good response of 6. only 12 patients to chloroquine treatment should not lessen the emphasis on the widely known chloroquine resistance and the anxieties it creates among clinicians managing 7. patients with malaria. A promising new method for detection of the parasites 8. is by using specific monoclonal antibodies (Mo Abs).20 9. These could be used to detect parasites in washed red cells or by using a double-antibody ELISA which can be applied in lysed, washed or unwashed red cells. This technique seems to have good sensitivity and specificity.12 Another method which is adopted by some centers in Saudi Arabia and worldwide is the acridine orange staining in the quantitative buffy coat (QBC) tube system, which is provided with a simple fluorescence microscope system (Becton Dickinson, USA), consisting of a battery-powered light and a special ultraviolet lens and a battery-powered centrifuge. This method is reported to be more sensitive than the Giemsa staining for detection of malaria parasites. It is much easier for inexperienced workers and is less time-consuming,21,22 with up to 99% sensitivity and specificity.23 It may be worthwhile to perform a comparative study using the QBC in two groups of donors, one coming from malaria-endemic areas and the second group of donors from nonendemic areas. This will allow us to test the detection rate of QBC and give us insight into the

sensitivity and specificity of the QBC. In conclusion, the results of this small study in a university hospital raises an alarm to the existence of a significant risk of transfusion-transmitted malaria. The magnitude of this risk is probably much higher than what we found since not all affected transfusion recipients reported back for further investigation. The acridine orange in the QBC tube system may help in prevention of this complication at this particular time. References Woolsey G. Transfusion for pernicious anemia: two cases. Ann Surg 1911;53:132-4. Hutton EL, Shute PG. The risk of transmitting malaria by blood transfusion. J Trop Med Hyg 1939;42:309. De Silva M, Contreras M, Barbara J. Two cases of transfusion-transmitted malaria (TTM) in the UK (Letter). Transfusion 1988;28:86. Kark JA. Malaria transmitted by blood transfusion. In: Infectious complications of blood transfusion. E. Tabor, ed. Academic Press, New York 1982;93-126. Vijayakumar E, Shaheed MM, Katugampola MS, Haque KH. Transfusion malaria in newborn infants: report of two cases. Ann Saudi Med 1990;10:569-71. Standards Committee, American Association of Blood Banks. Donors and Donor Blood. In: Standards for blood banks and transfusion services by the American Association of Blood Banks, Bethesda 1993:5-6. Bruce-Chwatt LJ. Transfusion associated parasitic infections. In: Infection, immunity and blood transfusion, RY Dodd, LF Barker, eds. Alan R. Liss, New York 1985;101-25. Bruce-Chwatt LJ. Transfusion malaria revisited. Trop Dis Bull 1982;79:827-39. Bruce-Chwatt LJ. Transfusion malaria. Bull Wld Hlth Org 1974;50:337-47. 10. Walzer PD, Gibson JJ, Schultz MJ. Malaria fatalities in the United States. Am J Trop Med Hyg 1974;23:328-33. 11. White NJ, Plorde JJ. Malaria. In: Harrison's principles of internal medicine. McGraw-Hill, Inc., New York 1991;782-8. 12. Choudhury N, Jolly JG, Mahajan RC, Ganguly NK, Dubey ML, Agnihotri SK. Malaria screening to prevent transmission by transfusion: an evaluation of techniques. Med Lab Sci 1991;48:206-11. 13. Voller A, Draper CC. Immunodiagnosis and seroepidemiology of malaria. Br Med Bull 1982;38:173-7. 14. Bruce-Chwatt LJ. From Laveran's discovery to DNA probes: new trends in diagnosis of malaria. Lancet 1987;2:1509-11. 15. Ambrise TP. International forum: which are the appropriate modifications of existing regulations designed to prevent the transmission of malaria by blood transfusion, in view of the increasing frequency of travel to endemic areas? Vox Sang 1987;52:139-40. 16. Perrin LH. International forum: which are the appropriate modifications of existing regulations designed to prevent the transmission of malaria by blood transfusion, in view of the increasing frequency of travel to endemic areas? Vox Sang 1987;52:145-7. 17. Wells L, Ala FA. Malaria and blood transfusion. Lancet 1985;1317-8. 18. Barker RH, Suebsang L, Roney W. Specific DNA

probe for the diagnosis of P. falciparum malaria. Science 1986;231:1434-6. 19. White NJ. Chloroquine for donated blood? Lancet 1987;100-1. 20. Souher JP. Abstracts of 18th Congress of the International Society of Blood Transfusion. Munich, Germany. Karger 1984. 21. Spielman A, Prerrone JB, Teklehaimanot A, et al. Malaria diagnosis by direct observation of centrifuged

samples of blood. Am J Trop Med Hyg 1988;39:337-42. 22. Rickman LS, Long GW, Oberst R, et al. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet 1989;1:68-71. 23. Parzy D, Raphenon B, Martet G, et al. Quantitative buffy coat test (QBC test), Monofluo Kit falciparum: comparative value in the rapid diagnosis of malaria. Medicine Tropicale 1990;50:97-101.