Malaria rapid diagnostic tests (RDTs) are instrument-free tests that provide results within 20 min and can be used by community health workers. RDTs detect antigens produced by the Plasmodium parasite such as Plasmodium falciparum histidine-rich protein-2 (PfHPR2) and Plasmodium lactate dehydrogenase (pLDH). The accuracy of RDTs for the diagnosis of uncomplicated P. falciparum infection is equal or superior to routine microscopy (but inferior to expert microscopy). Sensitivity for Plasmodium vivax is 75-100%; for Plasmodium ovale and Plasmodium malariae, diagnostic performance is poor. Design limitations of RDTs include poor sensitivity at low parasite densities, susceptibility to the prozone effect (PfHRP2-detecting RDTs), false-negative results due to PfHRP2 deficiency in the case of pfhrp2 gene deletions (PfHRP2-detecting RDTs), cross-reactions between Plasmodium antigens and detection antibodies, false-positive results by other infections and susceptibility to heat and humidity. End-user's errors relate to safety, procedure (delayed reading, incorrect sample and buffer volumes) and interpretation (not recognizing invalid test results, disregarding faint test lines). Withholding antimalarial treatment in the case of negative RDT results tends to be infrequent and tendencies towards over-prescription of antibiotics have been noted. Numerous shortcomings in RDT kits' labelling, instructions for use (correctness and readability) and contents have been observed. The World Health Organization and partners actively address quality assurance of RDTs by comparative testing of RDTs, inspections of manufacturing sites, lot testing and training tools but no formal external quality assessment programme of end-user performance exists. Elimination of malaria requires RDTs with lower detection limits, for which nucleic acid amplification tests are under development.
BackgroundMalaria Rapid Diagnostic Tests (RDTs) are widely used for diagnosing malaria. The present retrospective study evaluated the CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test targeting the Plasmodium falciparum specific antigen histidine-rich protein (HRP-2) and the pan-Plasmodium antigen lactate dehydrogenase (pLDH) in a reference setting.MethodsThe CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test was evaluated on a collection of samples obtained in returned international travellers using microscopy corrected by PCR as the reference method. Included were P. falciparum (n = 320), Plasmodium vivax (n = 76), Plasmodium ovale (n = 76), Plasmodium malariae (n = 23) and Plasmodium negative samples (n = 95).ResultsOverall sensitivity for the detection of P. falciparum was 88.8%, increasing to 94.3% and 99.3% at parasite densities above 100 and 1,000/μl respectively. For P. vivax, P. ovale and P. malariae, overall sensitivities were 77.6%, 18.4% and 30.4% respectively. For P. vivax sensitivity reached 90.2% for parasite densities above 500/μl. Incorrect species identification occurred in 11/495 samples (2.2%), including 8/320 (2.5%) P. falciparum samples which generated only the pan-pLDH line. For P. falciparum samples, 205/284 (72.2%) HRP-2 test lines had strong or medium line intensities, while for all species the pan-pLDH lines were less intense, especially in the case of P. ovale. Agreement between observers was excellent (kappa values > 0.81 for positive and negative readings) and test results were reproducible. The test was easy to perform with good clearing of the background.ConclusionThe CareStart™ Malaria HRP-2/pLDH (Pf/pan) Combo Test performed well for the detection of P. falciparum and P. vivax, but sensitivities for P. ovale and P. malariae were poor.
BackgroundIn the Peruvian Amazon, Plasmodium falciparum and Plasmodium vivax malaria are endemic in rural areas, where microscopy is not available. Malaria rapid diagnostic tests (RDTs) provide quick and accurate diagnosis. However, pfhrp2 gene deletions may limit the use of histidine-rich protein-2 (PfHRP2) detecting RDTs. Further, cross-reactions of P. falciparum with P. vivax-specific test lines and vice versa may impair diagnostic specificity.MethodsThirteen RDT products were evaluated on 179 prospectively collected malaria positive samples. Species diagnosis was performed by microscopy and confirmed by PCR. Pfhrp2 gene deletions were assessed by PCR.ResultsSensitivity for P. falciparum diagnosis was lower for PfHRP2 compared to P. falciparum-specific Plasmodium lactate dehydrogenase (Pf-pLDH)- detecting RDTs (71.6% vs. 98.7%, p<0.001). Most (19/21) false negative PfHRP2 results were associated with pfhrp2 gene deletions (25.7% of 74 P. falciparum samples). Diagnostic sensitivity for P. vivax (101 samples) was excellent, except for two products. In 10/12 P. vivax-detecting RDT products, cross-reactions with the PfHRP2 or Pf-pLDH line occurred at a median frequency of 2.5% (range 0%–10.9%) of P. vivax samples assessed. In two RDT products, two and one P. falciparum samples respectively cross-reacted with the Pv-pLDH line. Two Pf-pLDH/pan-pLDH-detecting RDTs showed excellent sensitivity with few (1.0%) cross-reactions but showed faint Pf-pLDH lines in 24.7% and 38.9% of P. falciparum samples.ConclusionPfHRP2-detecting RDTs are not suitable in the Peruvian Amazon due to pfhrp2 gene deletions. Two Pf-pLDH-detecting RDTs performed excellently and are promising RDTs for this region although faint test lines are of concern.
BackgroundAlthough severe malaria is an important cause of mortality among children in Burkina Faso, data on community-acquired invasive bacterial infections (IBI, bacteremia and meningitis) are lacking, as well as data on the involved pathogens and their antibiotic resistance rates.MethodsThe present study was conducted in a rural hospital and health center in Burkina Faso, in a seasonal malaria transmission area. Hospitalized children (<15 years) presenting with T≥38.0°C and/or signs of severe illness were enrolled upon admission. Malaria diagnosis and blood culture were performed for all participants, lumbar puncture when clinically indicated. We assessed the frequency of severe malaria (microscopically confirmed, according to World Health Organization definitions) and IBI, and the species distribution and antibiotic resistance of the bacterial pathogens causing IBI.ResultsFrom July 2012 to July 2013, a total of 711 patients were included. Severe malaria was diagnosed in 292 (41.1%) children, including 8 (2.7%) with IBI co-infection. IBI was demonstrated in 67 (9.7%) children (bacteremia, n = 63; meningitis, n = 6), 8 (11.8%) were co-infected with malaria. Non-Typhoid Salmonella spp. (NTS) was the predominant isolate from blood culture (32.8%), followed by Salmonella Typhi (18.8%), Streptococcus pneumoniae (18.8%) and Escherichia coli (12.5%). High antibiotic resistance rates to first line antibiotics were observed, particularly among Gram-negative pathogens. In addition, decreased ciprofloxacin susceptibility and extended-spectrum beta lactamase (ESBL) production was reported for one NTS isolate each. ESBL production was observed in 3/8 E. coli isolates. In-hospital mortality was 8.2% and case-fatality rates for IBI (23.4%) were significantly higher compared to severe malaria (6.8%, p<0.001).ConclusionsAlthough severe malaria was the main cause of illness, IBI were not uncommon and had higher case-fatality rates. The high frequency, antibiotic resistance rates and mortality rates of community acquired IBI require improvement in hygiene, better diagnostic methods and revision of current treatment guidelines.
Malaria is a serious condition in the non-immune traveller, and prognosis depends on timely diagnosis. Although microscopy remains the cornerstone of diagnosis, malaria rapid diagnostic tests (RDTs) are increasingly used in non-endemic settings. They are easy to use, provide results rapidly and require no specific training and equipment. Reported sensitivities vary between different RDT products but are generally good for Plasmodium falciparum, with RDTs detecting the P. falciparum antigen histidine-rich protein-2 (PfHRP2) scoring slightly better than P. falciparum-lactate dehydrogenase (Pf-pLDH)-detecting RDTs. Sensitivity is lower for Plasmodium vivax (66.0 - 88.0%) and poor for Plasmodium ovale (5.5 - 86.7%) and Plasmodium malariae (21.4 - 45.2%). Rapid diagnostic tests have several other limitations, including persistence of the PfHRP2 antigen, cross-reactions of P. falciparum with the non-falciparum test line and vice versa and (rare) false-positive reactions due to other infectious agents or immunological factors. False-negative results occur in the case of low parasite densities, prozone effect or pfhrp2 gene deletions. In addition, errors in interpretation occur, partly due to inadequacies in the instructions for use. Finally, RDTs do not give information about parasite density. In the diagnostic laboratory, RDTs are a valuable adjunct to (but not a replacement for) microscopy for the diagnosis of malaria in the returned traveller.In malaria endemic settings, special groups of travellers (those travelling for long periods, expatriates and short-stay frequent travellers) who are remote from qualified medical services may benefit from self-diagnosis by RDTs, provided they use correctly stored RDT products of proven accuracy, with comprehensive instructions for use and appropriate hands-on training.
BackgroundIn most sub-Saharan African countries malaria rapid diagnostic tests (RDTs) are now used for the diagnosis of malaria. Most RDTs used detect Plasmodium falciparum histidine-rich protein-2 (PfHRP2), though P. falciparum-specific parasite lactate dehydrogenase (Pf-pLDH)-detecting RDTs may have advantages over PfHRP2-detecting RDTs. Only few data are available on the use of RDTs in severe illness and the present study compared Pf-pLDH to PfHRP2-detection.MethodsHospitalized children aged one month to 14 years presenting with fever or severe illness were included over one year. Venous blood samples were drawn for malaria diagnosis (microscopy and RDT), culture and complete blood count. Leftovers were stored at −80 °C and used for additional RDT analysis and PCR. An RDT targeting both PfHRP2 and Pf-pLDH was performed on all samples for direct comparison of diagnostic accuracy with microscopy as reference method. PCR was performed to explore false-positive RDT results.ResultsIn 376 of 694 (54.2%) included children, malaria was microscopically confirmed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value were 100.0, 70.9, 69.4 and 100.0%, respectively for PfHRP2-detection and 98.7, 94.0, 91.6 and 99.1%, respectively for Pf-pLDH-detection. Specificity and PPV were significantly lower for PfHRP2-detection (p <0.001). For both detection antigens, specificity was lowest for children one to five years and in the rainy season. PPV for both antigens was highest in the rainy season, because of higher malaria prevalence. False positive PfHRP2 results were associated with prior anti-malarial treatment and positive PCR results (98/114 (86.0%) samples tested).ConclusionAmong children presenting with severe febrile illness in a seasonal hyperendemic malaria transmission area, the present study observed similar sensitivity but lower specificity and PPV of PfHRP2 compared to Pf-pLDH-detection. Further studies should assess the diagnostic accuracy and safety of an appropriate Pf-pLDH-detecting RDT in field settings and if satisfying, replacement of PfHRP2 by Pf-pLDH-detecting RDTs should be considered.
BackgroundThe present study evaluated the SD Bioline Malaria Ag 05FK40 (SDFK40), a three-band RDT detecting Plasmodium falciparum-specific parasite lactate dehydrogenase (Pf-pLDH) and pan Plasmodium-specific pLDH (pan-pLDH), in a reference setting.MethodsThe SDFK40 was retrospectively and prospectively tested against a panel of stored (n = 341) and fresh (n = 181) whole blood samples obtained in international travelers suspected of malaria, representing the four Plasmodium species as well as Plasmodium negative samples, and compared to microscopy and PCR results. The prospective panel was run together with OptiMAL (Pf-pLDH/pan-pLDH) and SDFK60 (histidine-rich protein-2 (HRP-2)/pan-pLDH).ResultsOverall sensitivities for P. falciparum tested retrospectively and prospectively were 67.9% and 78.8%, reaching 100% and 94.6% at parasite densities >1,000/μl. Sensitivity at parasite densities ≤ 100/μl was 9.1%. Overall sensitivities for Plasmodium vivax and Plasmodium ovale were 86.7% and 80.0% (retrospectively) and 92.9% and 76.9% (prospectively), reaching 94.7% for both species (retrospective panel) at parasite densities >500/μl. Sensitivity for Plasmodium malariae was 21.4%. Species mismatch occurred in 0.7% of samples (3/411) and was limited to non-falciparum species erroneously identified as P. falciparum. None of the Plasmodium negative samples in the retrospective panel reacted positive. Compared to OptiMAL and SDFK60, SDFK40 showed lower sensitivities for P. falciparum, but better detection of P. ovale. Inter-observer agreement and test reproducibility were excellent, but lot-to-lot variability was observed for pan-pLDH results in case of P. falciparum.ConclusionSDFK40 performance was poor at low (≤ 100/μl) parasite densities, precluding its use as the only diagnostic tool for malaria diagnosis. SDFK40 performed excellent for P. falciparum samples at high (>1,000/μl) parasite densities as well as for detection of P. vivax and P. ovale at parasite densities >500/μl.
BackgroundThe present study assessed malaria RDT kits for adequate and correct packaging, design and labelling of boxes and components. Information inserts were studied for readability and accuracy of information.MethodsCriteria for packaging, design, labelling and information were compiled from Directive 98/79 of the European Community (EC), relevant World Health Organization (WHO) documents and studies on end-users' performance of RDTs. Typography and readability level (Flesch-Kincaid grade level) were assessed.ResultsForty-two RDT kits from 22 manufacturers were assessed, 35 of which had evidence of good manufacturing practice according to available information (i.e. CE-label affixed or inclusion in the WHO list of ISO13485:2003 certified manufacturers). Shortcomings in devices were (i) insufficient place for writing sample identification (n = 40) and (ii) ambiguous labelling of the reading window (n = 6). Buffer vial labels were lacking essential information (n = 24) or were of poor quality (n = 16). Information inserts had elevated readability levels (median Flesch Kincaid grade 8.9, range 7.1 - 12.9) and user-unfriendly typography (median font size 8, range 5 - 10). Inadequacies included (i) no referral to biosafety (n = 18), (ii) critical differences between depicted and real devices (n = 8), (iii) figures with unrealistic colours (n = 4), (iv) incomplete information about RDT line interpretations (n = 31) and no data on test characteristics (n = 8). Other problems included (i) kit names that referred to Plasmodium vivax although targeting a pan-species Plasmodium antigen (n = 4), (ii) not stating the identity of the pan-species antigen (n = 2) and (iii) slight but numerous differences in names displayed on boxes, device packages and information inserts. Three CE labelled RDT kits produced outside the EC had no authorized representative affixed and the shape and relative dimensions of the CE symbol affixed did not comply with the Directive 98/79/EC. Overall, RDTs with evidence of GMP scored better compared to those without but inadequacies were observed in both groups.ConclusionOverall, malaria RDTs showed shortcomings in quality of construction, design and labelling of boxes, device packages, devices and buffers. Information inserts were difficult to read and lacked relevant information.
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