An International Survey of Glucose-6-Phosphate Dehydrogenase Laboratory Reporting Practices: Implications for Tafenoquine Eligibility Assessment

Abstract

Context.— Glucose-6-phosphate dehydrogenase (G6PD) activity is used in the evaluation of hemolysis risk in patients being assessed for G6PD deficiency. A long-acting 8-aminoquinoline drug (tafenoquine) used in malaria treatment is contraindicated in patients with G6PD deficiency (<70% normal G6PD activity). The current state of G6PD reporting practices to support clinical eligibility assessment is poorly understood. Objective.— To assess clinical laboratory reporting practices for G6PD testing. Design.— In October 2019 and October 2020, voluntary questionnaires were distributed to 327 and 324 laboratories participating in the College of American Pathologists G6PD proficiency testing (PT). Results.— Two hundred fifty-seven and 119 laboratories responded to the 2019 and 2020 questionnaires, respectively. Few laboratories have received clinical questions about average normal G6PD activity (US/Canada, 2.0% [3 of 149]; international, 8.4% [9 of 107]), whereas slightly more have determined the average normal G6PD activity for their own assay and patient populations (US/Canada, 6.7% [10 of 149]; international, 19.4% [21 of 108]). Few laboratories report G6PD activity in percent of normal format (US/Canada, 2.7% [4 of 149]; international, 8.3% [9 of 108]). The most common unit of measurement in use for quantitative G6PD reporting is unit per gram of hemoglobin. Reference intervals vary based on assay, reaction temperature, and participant laboratory and demonstrate moderate correlation (r = .46–.51) to G6PD activity measured from a “normal” PT challenge specimen. Nearly half of participants (47.8% [85 of 178]) categorized a quantitatively “intermediate” G6PD PT challenge as “normal” when using qualitative assays. Conclusions.— Percent of normal G6PD activity reporting would facilitate patient eligibility assessment for drugs, such as tafenoquine. Quantitative assays are better able to differentiate “intermediate” specimens than qualitative assays.

Clinical performance validation of the STANDARD G6PD test: A multi-country pooled analysis

“…Of note, challenges associated with false normal G6PD results are not limited to POC tests. For context, a recent report from the College of American Pathologists (CAP) highlights challenges with the accurate diagnosis of specimens with intermediate G6PD activity in current reference clinical laboratory testing [ 11 ]. Among laboratories participating in the CAP proficiency testing, 12.5% of those conducting quantitative reference testing misclassified an intermediate specimen as normal, and 47.8% of those conducting qualitative testing misclassified it as normal [ 11 ].…”

“…Until recently, diagnosis of G6PD deficiency has primarily relied on moderate to high complexity laboratory assays. In practice, the implementation of such tests has been challenging as described in a recent publication from the College of American Pathologists as well as meta-analysis spectrophotometry-based quantification of G6PD activity [ 11 , 12 ]. More recently, point-of-care (POC) tests for G6PD deficiency are emerging, providing opportunities to expand testing to populations without access to laboratory-based assays [ 13 ].…”

Clinical performance validation of the STANDARD G6PD Test: A multi-country pooled analysis

“…Due to the observed inter-laboratory variability of the G6PD reference assay, 11,22 absolute G6PD values were normalized for each laboratory conducting the reference assay in each study. [24][25][26] Reference G6PD activity values were expressed as the percentage of each site's adjusted male median (AMM).…”

“…11 Among laboratories participating in the CAP proficiency testing, 12.5% of those conducting quantitative reference testing misclassified an intermediate specimen as normal, and 47.8% of those conducting qualitative testing misclassified it as normal. 11 These findings suggest that misclassifications of G6PD intermediate specimens are not unique to POC tests and that accurate classification of this group is a challenge in clinical laboratory testing.…”

“…In practice, the implementation of such tests has been challenging as described in recent publications from the College of American Pathologists. 11,12 More recently, point-of-care (POC) tests for G6PD deficiency are emerging, providing opportunities to expand testing to populations without access to laboratory-based assays. 13 Such tests are particularly important in the context of malaria case management, given the limited infrastructure in settings where malaria patients typically seek care.…”