Classification of induced malaria case in an elimination setting: investigation of transfusion-transmitted malaria cases

Despite being preventable and treatable, malaria continues to have a devastating impact on the health and livelihood of people around the world. According to the World Health Organization (WHO), about 228 million malaria cases and an estimated 405,000 deaths occurred worldwide in 2018 [1].

The WHO launched the Global technical strategy for malaria 2016–2030 in 2015, aiming to reduce global malaria mortality rates and malaria case incidence by at least 90% by 2030, and to eliminate malaria for at least 35 countries [2]. WHO certification of malaria elimination in a particular country requires evidence that local transmission of human malaria parasites has ceased, resulting in zero incidence of indigenous cases for at least three consecutive years [3].

China has made remarkable achievements in malaria control over the past decades. In 2010 it launched the National Malaria Elimination Programme, with the goal of achieving malaria elimination by 2020 [4]. Local malaria transmission has been significantly reduced, leading to the proportion of imported cases increasing from 45.7% in 2010 to 99.9% in 2016, with nearly all provinces reporting imported cases in the past few years [5]. No indigenous case has been reported since 2017 [6, 7]. However, occasionally, few cases are reported in which the patient had never been to any malaria endemic areas, which necessitates a search for other modes of transmission.

According to WHO guidelines, an introduced malaria case refers to a case contracted locally, with strong epidemiological evidence linking it directly to a known imported case (first-generation local transmission). An induced case refers to a case for which the origin can be traced to blood transfusion or other form of parenteral inoculation of the parasite but not to transmission by a natural mosquito-borne inoculation [3]. A clear distinction between induced and indigenous (or introduced) malaria cases has become especially important so as to provide sufficient evidence to exclude the possibility of the re-establishment of malaria transmission. This study reports the identification of three transfusion-transmitted malaria cases via imported cases to China in 2016 and 2017, which can provide a reference for the investigation and analysis of other cases of a similar nature.

In Jiangsu Province, malaria caused by P. falciparum was eliminated in the 1990s, and no indigenous Plasmodium vivax malaria cases have been reported since 2011 [8]. In 2016 and 2017, however, three cases of P. falciparum were reported from three different laboratories. None of the three patients had a history of travel to a malaria endemic country, and none had a past history of infection.

Certification of malaria elimination in a country requires proof that local transmission of all human malaria parasites has been interrupted, resulting in zero incidence of indigenous cases for at least the past three consecutive years [3]. Evidence-based classification of all malaria cases is important for verification of countries and/or regions within countries approaching malaria elimination or maintaining malaria free status. However, classification of cases as imported, introduced, locally acquired, relapsing, recrudescent or induced is often difficult [3]. Sufficient information should be collected for identification of induced cases. For example, the three blood transfusion malaria cases described in this study, included epidemiological and parasitological data from the donors and the recipients, in addition to the relationships of molecular markers used for genotyping parasites from donors and recipients.

Three transfusion-transmitted induced malaria cases via imported cases to China have been reported, and an evidence-based approach is provided for investigation and analysis of other cases of a similar nature. Usually, a combination of epidemiological and parasitological evidence is enough to prove blood-transfusion transmission, however, further evidence of a link between donor and recipient provided by the molecular typing of parasite microsatellite markers as used in this study adds a further layer of certainty regarding the provenance of infection.

In regions entering malaria elimination phases, clinicians and laboratory staff may not consider malaria as a cause of febrile illness. All the three cases in this study were considered and confirmed as malaria at least 2 weeks subsequent to the onset of symptoms. This length of delay in diagnosis may lead to serious consequences for the patient, such as severe malaria and death [11]. In addition, if the patient recovers without treatment for malaria, they may continue to harbour the parasite and may act as a reservoir for further infections in regions that are still receptive to malaria transmission [12].

Furthermore, if malaria is not identified in the patient, then the donor would also remain undiagnosed and could also be a source of infection to malaria vectors leading to the re-introduction of malaria transmission. It is, therefore, necessary for clinicians and laboratory staff to maintain a high level of awareness and expertise regarding malaria case detection and treatment.

Due to social and economic development and the “Belt and Road Initiative”, the population has rapidly become more mobile, leading to increased threats for the maintenance of the malaria-free status of China [13, 14]. In this study, RDT tests were negative for malaria from two foreign students, which may be due to the low parasitaemia in the asymptomatic donors. Other countries where malaria incidence is very low may encounter similar situations in which malaria cases may not be identified by RDT tests or microscopical examination. Therefore, more stringent screening policies should be considered during blood donation in such settings [15]. Standard screening with more sensitive detection technologies such as PCR should be developed for the screening of blood from at-risk donors such as overseas students and migrant workers. In addition, the potential treatment of whole blood with parasite killing processes, such as UV light and riboflavin before storage in blood banks should be considered [16].

Three transfusion-transmitted malaria cases were identified in China in 2016 and 2017. All cases were due to the donation of malaria parasite infected blood by individuals who had been infected outside China. These cases highlight a threat to the maintenance of China’s malaria-free status, and can provide a reference for those faced with similar challenges in malaria case identification and classification. In addition, a stricter screening policy including the use of appropriate detection methods for malaria parasites should be developed and adopted during blood donation in malaria elimination settings.