Discussion
This is the first case of transfusion-induced malaria reported in Sri Lanka in five decades, and the first during the prevention of reintroduction (POR) phase of malaria. The recipient, who suffered from beta thalassaemia major and gave no history of overseas travel but of receiving a recent blood transfusion, was diagnosed with P. falciparum malaria. This was established as a case of blood transfusion-induced malaria by the fact that his last transfusion of blood was found to be infected with P. falciparum. The blood donor was a returnee from South Sudan having been on a mission there for a year and four months. Although microscopy at the time of blood donation was reported as malaria-negative, retrospective re-examination of the donor’s blood smear at the time of donation, as well as when he was tested after the recipient was diagnosed with malaria revealed that he had a P. falciparum malaria infection throughout, although he had remained free of signs and symptoms of malaria ever since he returned to Sri Lanka.
The beta thalassaemia patient had a clinically complicated malaria infection with co-morbidities, and prolonged parasite clearance. The possibility that this malaria infection imported from South Sudan was a drug-resistant strain, or even one with a reduced sensitivity to artemisinin or the partner drug lumefantrine was considered, but was dismissed on the grounds that the infection in the blood donor responded well, both clinically and parasitologically to the same medication. The prolonged parasite clearance is likely, instead, to have been due to the absence of the spleen. Such slow responses of malaria infections to treatment have been reported previously in splenectomized patients [
7‐
9]. Intravenous artesunate was given to this patient following a full course of oral artemether-lumefantrine because of the persistent parasitaemia and deteriorating clinical condition, and also because the second-line medicine DHAPPQ was contraindicated on account of a cardiomyopathy he suffered from. The long duration of anti-malarial treatment with artemether-lumefantrine and intravenous artesunate resulted in eventual clearance of asexual parasites on day 7, and gametocytes on day 15, the latter in response to the single dose of primaquine.
Delays in the diagnosis of malaria has been a frequent feature during the POR phase in Sri Lanka [
10,
11], as is also common in most countries where malaria is no longer endemic [
12,
13]. However, in this patient malaria was diagnosed within 3 days of his seeking health care and soon after admission to hospital. The malaria infection was missed by the General Practitioner who was the patient’s first contact with the health system. However, on admission to hospital the malaria diagnosis was not delayed. This was due to a proactive case surveillance mechanism in operation by the AMC where PHFOs visit hospital wards daily and screen all patients with fever for malaria. Early diagnosis was particularly important in this patient in whom a further delay in treatment might have been life-threatening because of his co-morbidities. It reaffirms the important role of active surveillance for malaria during the POR phase.
This case is a reminder that the risk of transfusion-induced malaria in the country persists even after elimination because of imported malaria from overseas. It demonstrates that even the current very rigorous POR strategies being implemented in Sri Lanka are not infallible, due, not to flaws in the strategy itself, but due to lapses in operations and implementation. The blood donor was duly screened for malaria on entry to the country but was found to be negative by both microscopy and RDT. This could have been due to a very low parasite density, below the microscopic threshold of detection, which is corroborated by the fact that the person was asymptomatic and was even well enough to have considered donating blood 4 months later. There have been numerous incidents in the past 9 years since malaria elimination, of arrivals in Sri Lanka from malaria endemic countries being screened on entry to the country and found negative, but who, weeks to months later developed a clinically patent malaria infection, even with
P. falciparum [
14]. Clearly
Plasmodium vivax and
Plasmodium ovale infections can remain dormant as hypnozoites in the liver, but it appears that even
P. falciparum parasites can persist in a “dormant” state in the blood to manifest as clinical infections later. The asymptomatic blood donor, by the fact that he was not even anaemic, whilst harbouring a
P. falciparum infection over several months, must have developed a partial clinical and parasitological immunity to
P. falciparum while in South Sudan through repeat parasite inoculations, aided by his intermittent recourse to prophylactic anti-malarial medicines which may have led to a persistent low-grade malaria infection.
Plasmodium parasites can survive in whole blood and plasma when stored at 4 °C for up to approximately 18 days, and parasites can be detectable even up to 28 days when frozen, although with diminished infectivity [
15,
16]. Consistent with WHO recommendation and the National Institute of Health Consensus conference outcomes in 1995, every blood donor in Sri Lanka is screened for HIV, hepatitis B and C, syphilis and malaria, and for the latter by microscopic examination of Giemsa-stained thick blood smears. Although this blood donor was screened for malaria and a negative report was issued, the blood was found, retrospectively, on re-examination of the preserved smear to be malaria-infected. As has been reported previously, as much as 40% of approximately one million blood smears examined every year for malaria by the AMC are from the blood bank and not a single smear has been positive for the past 9 years; data for the years 2017–2019 have been published [
2]. Given this large volume, and because the test positivity rate is extremely low, malaria being a very rare disease in the country now, microscopic screening of blood donors for malaria cannot be expected to have a high sensitivity even in the hands of a highly trained microscopists. Under these circumstances, other, automated and more objective methods of blood screening such as immunological assays (e.g. ELISAs based on antigen and antibody detection [
17]) may have to be considered as alternatives to microscopy for screening of blood donors for malaria. A recent meta analysis of transfusion malaria data compares the sensitivities of microscopy, serological methods and molecular techniques [
18] in screening of blood donors, and concludes that although molecular methods may provide the highest degree of sensitivity, given their high cost and low feasibility in some situations, a careful consideration of the circumstances and available resources will have to determine which of these methods should be deployed. This incident highlights the need to sustain a high-quality microscopy service, which can be quite challenging when the disease burden is as low as it is in Sri Lanka today. The country is, in fact, engaged in a WHO scheme on External Competency Assessment of Malaria Microscopy (ECAMM) and has one of the highest proportions of high quality (Level 1 and 2) malaria microscopists amongst countries in the region as assessed by this scheme [
19]. A National Competency Assessment of Malaria Microscopy (NCAMM) scheme has also been established in the country, and these efforts are expected to increase the competencies of malaria microscopists more widely across the country. Following this event of transfusion-induced malaria, a more stringent policy has also now been adopted by the national blood bank to prevent such events in the future: The period during which persons who have returned from a malaria endemic country are not permitted to donate blood has been extended from the previous policy of 3 months, to 3 years from their return.
The blood donor, a member of the armed forces and a returnee from South Sudan was duly screened for malaria at the airport on his return together with 51 members of the same contingent, and all were negative on microscopy and RDT. It is standard practice that all such groups of armed service personnel returnees are kept under surveillance for a period of one year for the possibility of developing malaria. If they reside in a malaria receptive area, they are each provided with a LLIN as a precautionary measure to minimize the risk of their transmitting malaria, in the event that they develop an asymptomatic malaria infection. He was traced on the AMC database even before details emerged from the Blood Bank, as a member of the group that was under surveillance. However, a lapse in the follow-up procedure led to this person who was asymptomatic, to donate blood. The prevailing COVID 19 epidemic which led to several restrictions being imposed on routine follow-up work of the AMC might have contributed to this unfortunate breach in procedure [
20]. The fact that he was parasitaemic with mature gametocytes in the circulation
albeit at a very low parasitaemia for at least 18 days, and possibly longer, had presented a daunting risk for the re-establishment of malaria in Sri Lanka had his infection been transmitted to mosquitoes. This case has now led to the AMC greatly strengthening its surveillance on armed forces returnees from malaria endemic countries, they being a high-risk group for imported malaria including considering the routine use of more sensitive malaria detection methods than microscopy, such as the polymerase chain reaction tests to screen returnees from high malaria risk destinations.
This case report illustrates the importance of effective blood donor screening for malaria during the POR phase of malaria using more sensitive and objective methods than microscopy, such as antigen and antibody detecting immunochemical methods. It also reaffirms the importance of proactive case detection and follow-up, particularly in armed forces personnel returning from high malaria risk destinations, here too, using molecularly methods rather than microscopy, and emphasizes the need for stringent implementation of the strategies that are in place including reactive entomological surveillance and vector control.
Acknowledgements
The authors wish to acknowledge the staff of the Regional Malaria Office of the Polonnaruwa district, clinical staff of the Polonnaruwa Hospital who detected, investigated and managed the malaria patients and performed the surveillance operations. The authors also acknowledge the Mr. S Hettigedara, Senior Nutritionist, Police Hospital, Colombo, Dr. E.A.L.C.K. Edirisinghe, Director, National Blood Transfusion Service and Dr. Jagath Amarasekara, Consultant Community Physician, Anti malaria Campaign for their support and advice.
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