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Neonatal hyperbilirubinemia (NH) is a frequent condition that, if left untreated, can lead to neurological disability and death. We assessed the prevalence of NH and associated neonatal and maternal risk factors in 362 mothers and 365 newborns in a semi-rural area of the Democratic Republic of Congo. In addition, we explored the knowledge and practices of mothers regarding this condition. We collected demographic data, anthropometric data, and obstetric and medical anamneses. We examined newborns at birth and at 24, 48, and 72 hours and measured bilirubin at birth in umbilical cord and capillary blood and thereafter in capillary blood. Hemoglobin, hematocrit, ABO group, Rhesus factor, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemoglobin S (HbS), and malaria were assessed in mothers and newborns. Among 296 newborns (all time points available), 5.7% developed NH (95% CI: 3.4-9.0) between 24 and 72 hours according to National Institute for Health and Care Excellence (NICE) UK guidelines. There was a significantly higher risk in newborns with G6PD deficiency (homo- and hemizygous adjusted Odd Ratio [aOR]: 21.0, 95% CI: 4.1-105.9), preterm births (aOR: 6.1, 95% CI: 1.4-26.9), newborns with excessive birth weight loss (aOR: 5.8, 95% CI: 1.4-23.2), and hyperbilirubinemia at birth (aOR: 14.8, 95% CI: 2.7-79.6). Newborns with feto-maternal ABO incompatibility and G6PD deficiency had significantly higher bilirubin at birth than others. More than 60% of mothers had adequate knowledge of NH, but compliance with phototherapy in the absence of symptoms was low. Although risk factors for NH are common in this area, prevalence was not high, suggesting a need for better case definition. Implementation of point-of-care devices for diagnosis and awareness programs on risk prevention could help reduce neonatal morbidity and mortality associated with hyperbilirubinemia in these areas.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic blood condition, can result in kernicterus at birth, and later in life as severe hemolysis on exposure to certain infections, foods, and drugs. The unavailability of point-of-care tests for G6PD deficiency is a barrier to routine curative treatment of Plasmodium vivax malaria with 8-aminoquinolines, such as primaquine. Two quantitative reference tests (Trinity Biotech, Bray, Ireland and Pointe Scientific, Canton, MI; Cat No. G7583) and the point-of-care STANDARD ™ G6PD test (SD Biosensor, Suwon, South Korea) were evaluated. The STANDARD G6PD test was evaluated at multiple temperatures, in anticoagulated venous and capillary samples, including 79 G6PD-deficient and 66 intermediate samples and across two laboratories, one in the United States and one in Thailand. The STANDARD test performed equivalently to a reference assay for its ability to diagnose G6PD deficiency (< 30% normal) with a sensitivity of 100% (0.95 confidence interval [CI]: 95.7-100) and specificity of 97% (0.95 CI: 94.5-98.5), and could reliably identify females with less than 70% normal G6PD activity with a sensitivity of 95.5% (0.95 CI: 89.7-98.5) and specificity of 97% (0.95 CI: 94.5-98.6). The STANDARD G6PD product represents an opportunity to diagnose G6PD deficiency equally for males and females in basic clinical laboratories in high- and low-resource settings. This quantitative point-of-care diagnostic test for G6PD deficiency can provide equal access to safe radical cure of P. vivax cases in high- and low-resource settings, for males and females and may support malaria elimination, in countries where P. vivax is endemic.

Afghanistan's national guidelines recommend primaquine (PQ) for radical treatment of Plasmodium vivax malaria, but this is rarely implemented because of concerns over potential hemolysis in patients who have G6PD deficiency. Between August 2009 and February 2014, we conducted an open-label, randomized controlled trial of chloroquine (CQ) alone versus chloroquine plus primaquine (0.25 mg base/kg/day for 14 days) (CQ+PQ) in patients aged 6 months and older with microscopy confirmed P. vivax infection. In the CQ+PQ group, G6PD deficiency was excluded by fluorescent spot testing. The primary outcome was P. vivax recurrence assessed by survival analysis over one year follow-up. Of 593 patients enrolled, 570 attended at or after 14 days of follow-up. Plasmodium vivax recurrences occurred in 37 (13.1%) of 282 patients in the CQ+PQ arm versus 86 (29.9%) of 288 in the CQ arm (Cox proportional hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.25-0.54) (intention-to-treat analysis). Protection against recurrence was greater in the first 6 months of follow-up (HR 0.082; 95% CI 0.029-0.23) than later (HR 0.65, 95% CI 0.41-1.03). Five of seven patients requiring hospital admission were considered possible cases of PQ-related hemolysis, and PQ was stopped in a further six; however, in none of these cases did hemoglobin fall by ≥ 2 g/dL or to below 7 g/dL, and genotyping did not detect any cases of Mediterranean variant G6PD deficiency. PQ 0.25 mg/kg/day for 14 days prevents relapse of P. vivax in Afghanistan. Patient visits during the first week may improve adherence. Implementation will require deployment of point-of-care phenotypic tests for G6PD deficiency.

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol 487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects ( N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [ N = 3]) and primaquine (-1.25 to -3.0 g/dL [ N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% ( N = 2) and > 80% ( N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

The use of primaquine and other 8-aminoquinolines for malaria elimination is hampered by, among other factors, the limited availability of point-of-care tests for the diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Historically, the most used source of blood for G6PD analyses is venous blood, whereas diagnostic devices used in the field require the use of capillary blood; data have shown that the two sources of blood often differ with respect to hemoglobin concentration and number of red blood cells. Therefore, we have analyzed, in both capillary and venous blood drawn from the same healthy donors, the correlation of G6PD activity assessed by two qualitative tests (the Fluorescent Spot test and the CareStart test) with the gold standard quantitative spectrophotometric assay. Results obtained on 150 subjects with normal, intermediate, and deficient G6PD phenotypes show that, although differences exist between the aforementioned characteristics in capillary and venous blood, these do not impact on the quantitative assessment of G6PD activity after corrected for hemoglobin concentration or red blood cell count. Furthermore, we have assessed the sensitivity and specificity of the two qualitative tests against the gold standard spectrophotometric assay at different activity thresholds of residual enzymatic activity in both blood sources., (© The American Society of Tropical Medicine and Hygiene.)

Accurate diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is required to avoid the risk of acute hemolysis associated with 8-aminoquinoline treatment. The performance of the BinaxNOW G6PD test compared with the quantitative spectrophotometric analysis of G6PD activity was assessed in 356 Plasmodium vivax-infected subjects in Brazil, Peru, Thailand, and India. In the quantitative assay, the median G6PD activity was 8.81 U/g hemoglobin (range = 0.05-20.19), with 11 (3%) subjects identified as deficient. Sensitivity of the BinaxNOW G6PD to detect deficient subjects was 54.5% (6 of 11), and specificity was 100% (345 of 345). Room temperatures inadvertently falling outside the range required to perform the rapid test (18-25°C) together with subtlety of color change and insufficient training could partially explain the low sensitivity found. Ensuring safe use of 8-aminoquinolines depends on additional development of simple, highly sensitive G6PD deficiency diagnostic tests suitable for routine use in malaria-endemic areas., (© The American Society of Tropical Medicine and Hygiene.)