Malaria parasites ‘invisible’ to rapid tests: A conversation with Selam Mihreteab (Eritrea)
The vast majority of malaria rapid diagnostic tests (RDTs) used around the world are based on the detection of P. falciparum histidine-rich protein 2 (HRP2), alone or in combination with other antigens. The WHO has recently warned of a serious threat related to the emergence of parasites not expressing the HRP2 protein which are, therefore, ‘invisible’ to this type of rapid tests (Ref).
Eritrea, in the Horn of Africa, introduced the use of malaria RDTs at the community level and primary health facilities in 2006. However, in 2015 this strategy encountered a turning point. Selam Mihreteab, manager of the National Malaria Control Programme (NMCP – Ministry of Health, Eritrea) was one of the focal persons involved in the national response to this new challenge.
Q: When did you first suspect there was a problem with the performance of HRP2-RDTs in your country?
SM: The problem with the performance of HRP2-RDTs was first detected in 2015 from health facility reports informing on the occurence of false negative RDT results. When the HRP2-based RDTs were constantly giving negative results for a fever case with strong clinical suspicion for malaria, they took blood film slides for microscopic confirmation and found positive results.
Q: What actions did your programme take to investigate the claims of false negative RDTs?
SM: The health facilities reported these cases as a product quality defect issue and hence the Programme initially focused on confirming or ruling out the quality of the SD Bioline Pf/Pv HRP2/pLDH kits being used at the moment. Therefore, we carried out a rapid survey in 11 health facilities where blood was sampled from suspected malaria patients and tested with the RDTs and microscopy. The RDTs showed over 80% false negative results when compared with the microscopic results. In addition, we contacted the RDT manufacturer and they responded positively by sending a team to Eritrea for joint investigation. Additional blood samples from malaria patients were taken for simultaneous testing with the SD Bioline Pf/Pv RDT and microscopic examination, confirming again the occurence of false negative results by RDT (positive for P.falciparum species by microscopy). The manufacturer also sent samples to South Korea for PCR-testing and confirmed the malaria infection caused by P. falciparum.
We also informed WHO by completing a complaint form after which a team from WHO/AFRO and WHO/HQs visited the country and did a preliminary assessment of the filed complaint. Finally, 2 hospitals were selected for additional assessment and a new set of samples was taken for RDT, microscopy and PCR testing. WHO coordinated the molecular analysis of pfhrp2/3-deletions through their reference lab network and this work was carried out by the Australian Defence Force Malaria and Infectious Disease Institute. Out of 50 P. falciparum specimens, 62% were found to have their HRP2 gene deleted. This evidence confirmed the need to switch from HRP2-based RDTs to pLDH-based RDTs for the detection of P. falciparum infections in Eritrea.
Q: Once you realized that a change in the national diagnostic strategy was going to be needed, how did you foster the required collaboration and advocacy at multiple levels? How did you manage to engage all the relevant stakeholders?
SM: The first step taken was to communicate the case with different director-generals, directors, managers and the general health staff through meetings and orientation seminars. We included the issue in the annual Ministry of Health report for 2016, and published an article in Malaria Journal. We also updated the Global Fund on the matter so that the change in RDT type and subsequent re-training and procurement related budget implications could be supported.
Q: What main difficulties and hurdles have you encountered in managing this challenge?
SM: The main challenge encountered was the lack of pLDH-based RDTs that could fully substitute the HRP2-RDT that we had been using for 10 years. Our health personnel and community health agents were used to seeing RDTs with strong bands, while the pLDH detecting RDTs had weaker bands. Moreover, no specific pLDH-RDT could detect both P. falciparum and P. vivax infection, an important feature of RDTs for Eritrea where nearly 30% of infections are due to P. vivax malaria. Another challenge was the issue of re-training health workers on the new RDT.
Q: What lessons would you like to pass on to other countries that need to make a change in their RDT policy due to high prevalence of pfhrp2/3 deletions? What would have made the transition easier for your programme?
SM: Countries that need to make a change in their RDT policy need to select and test alternative RDTs at field conditions immediately after detection of the deletions. Avoid as much as possible the use of two types of RDTs as it may confuse health workers and create inconveniencies to the Programme.
Q: Finally, what would be your message to other NMCPs that are unaware of this emerging threat, or that may not be considering this as a problem that requires urgent attention?
SM: Malaria RDTs are critical for malaria diagnosis in areas lacking microscopy services and any threat concerning these RDTs may jeopardize malaria diagnosis at large, including active case detection and outbreak investigation activities. All NMCPs need to be vigilant on pfhrp2/3 deletions as they are becoming a threat to malaria case management. Regular quality control and quality assurance of RDTs is required to ensure an adequate delivery of diagnostic services, but any reports of product quality issues must also be investigated thoroughly for possible deletion of pfhrp2/3 genes.
In addition, it is very important that malaria-endemic countries implement continuous surveillance activities to detect on time the emergence of deletions, before they reach very high levels as it happened in Eritrea.
