The XN-30 hematology analyzer for rapid sensitive detection of malaria: a diagnostic accuracy study

Annelies Post, Berenger Kaboré, Isaie J Reuling, Joel Bognini, Wouter van der Heijden, Salou Diallo, Palpouguini Lompo, Basile Kam, Natacha Herssens, Kjerstin Lanke, Teun Bousema, Robert W Sauerwein, Halidou Tinto, Jan Jacobs, Quirijn de Mast, Andre J van der Ven, Annelies Post, Berenger Kaboré, Isaie J Reuling, Joel Bognini, Wouter van der Heijden, Salou Diallo, Palpouguini Lompo, Basile Kam, Natacha Herssens, Kjerstin Lanke, Teun Bousema, Robert W Sauerwein, Halidou Tinto, Jan Jacobs, Quirijn de Mast, Andre J van der Ven

Abstract

Background: Accurate and timely diagnosis of malaria is essential for disease management and surveillance. Thin and thick blood smear microscopy and malaria rapid diagnostic tests (RDTs) are standard malaria diagnostics, but both methods have limitations. The novel automated hematology analyzer XN-30 provides standard complete blood counts (CBC) as well as quantification of malaria parasitemia at the price of a CBC. This study assessed the accuracy of XN-30 for malaria detection in a controlled human malaria infection (CHMI) study and a phase 3 diagnostic accuracy study in Burkina Faso.

Methods: Sixteen healthy, malaria-naive CHMI participants were challenged with five Plasmodium falciparum-infected mosquitoes. Blood was sampled daily for XN-30, blood smear microscopy, and malaria qPCR. The accuracy study included patients aged > 3 months presenting with acute febrile illness. XN-30, microscopy, and rapid diagnostic tests (HRP-2/pLDH) were performed on site; qPCR was done in retrospect. The malaria reference standard was microscopy, and results were corrected for sub-microscopic cases.

Results: All CHMI participants became parasitemic by qPCR and XN-30 with a strong correlation for parasite density (R2 = 0.91; p < .0001). The XN-30 accurately monitored treatment and allowed detection of recrudescence. Out of 908 patients in the accuracy study, 241 had microscopic malaria (density 24-491,802 parasites/μL). The sensitivity and specificity of XN-30 compared to microscopy were 98.7% and 99.4% (PPV = 98.7%, NPV = 99.4%). Results were corrected for qPCR-confirmed sub-microscopic cases. Three microscopy-confirmed cases were not detected by XN-30. However, XN-30 detected 19/134 (14.2%) qPCR-confirmed cases missed by microscopy. Among qPCR-confirmed cases, XN-30 had a higher sensitivity (70.9% versus 66.4%; p = .0009) and similar specificity (99.6% versus 100%; p = .5) as microscopy. The accuracy of XN-30 for microscopic malaria was equal to or higher than HRP-2 and pLDH RDTs, respectively.

Conclusions: The XN-30 is a novel, automated hematology analyzer that combines standard hemocytometry with rapid, objective, and robust malaria detection and quantification, ensuring prompt treatment of malaria and malaria anemia and follow-up of treatment response.

Trial registration: Both trials were registered on clinicaltrials.gov with respective identifiers NCT02836002 (CHMI trial) and NCT02669823 (diagnostic accuracy study).

Keywords: Burkina Faso; Diagnosis; Malaria; Sensitivity; Specificity.

Conflict of interest statement

AvV and QdM have a non-restricted research grant from SYSMEX, which funded the current study. None of the other authors had any competing interest.

Figures

Fig. 1
Fig. 1
Forward sideward scatter of patient with and without malaria and gametocytes as recorded by the XN-30
Fig. 2
Fig. 2
Diagnostic performance of XN-30 in CHMI model expressed as (a) line graph and (b) scatterplot
Fig. 3
Fig. 3
Parasite density curves of participants with recrudescent infections. The parasite density treatment threshold of 5 p/uL is indicated with a grey line
Fig. 4
Fig. 4
Patient flow of prospective diagnostic validation study in Nanoro, Burkina Faso, excluding patients with incomplete data
Fig. 5
Fig. 5
ROC curves XN-30 versus malaria microscopy and qPCR
Fig. 6
Fig. 6
Correlation between parasite density of XN-30 and respectively microscopy and qPCR

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