Performance of the Access Bio/CareStart rapid diagnostic test for the detection of glucose-6-phosphate dehydrogenase deficiency: Asystematic review and meta-analysis.

Benedikt Ley,Daniel A Pfeffer,Lorenz Von Seidlein,Didier Menard,Ari Winasti Satyagraha,Germana Bancone,Fe Espino,Hisni Rahmat,Amalia Karahalios,Michael E Von Fricken,Sunil Parikh,Nwe Nwe Oo,Ric N Price,Gisela Henriques,Nicholas M Douglas

doi:10.1371/journal.pmed.1002992

Abstract

To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994). Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90-0.99) and a specificity of 0.95 (95% CI 0.92-0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94-1.00), with an LR+ and an LR- of 18.23 (95% CI 13.04-25.48) and 0.05 (95% CI 0.02-0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings. The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR- render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings.

Highlights

Radical cure of Plasmodium vivax and P. ovale malaria requires killing of both the blood and liver stages of the parasite to prevent relapsing malaria and reduce ongoing transmission [1]
Its high negative predictive value (NPV) suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR− render the test suitable to confirm and exclude glucose-6-phosphate dehydrogenase deficiency (G6PDd)
While PQ is tolerated in most patients, it can cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd), the severity of which is dependent on the underlying genetic variant, the dose of PQ administered, and the age of the patient’s red blood cell (RBC) population [7,8]

Summary

Introduction

Radical cure of Plasmodium vivax and P. ovale malaria requires killing of both the blood and liver stages of the parasite to prevent relapsing malaria and reduce ongoing transmission [1]. While PQ is tolerated in most patients, it can cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd), the severity of which is dependent on the underlying genetic variant, the dose of PQ administered, and the age of the patient’s red blood cell (RBC) population [7,8]. Depending on the ratio of G6PD-normal to G6PD-deficient RBCs, heterozygous females may be at a risk of severe drug-induced haemolysis [13,14]. To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994)

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Conclusion