Testing For Glucose-6-phosphate Dehydrogenase Deficiency Research Articles

Radical cure for Plasmodium vivax malaria after G6PD qualitative testing in four provinces in Cambodia, results from Phase I implementation

BackgroundCambodia aims to eliminate all forms of malaria by 2025. In 2020, 90% of all malaria cases were Plasmodium vivax. Thus, preventing P. vivax and relapse malaria is a top priority for elimination. 14-day primaquine, a World Health Organization-recommended radical cure treatment regimen, specifically targets dormant hypnozoites in the liver to prevent relapse. Cambodia introduced P. vivax radical cure with primaquine after glucose-6-phosphate dehydrogenase (G6PD) qualitative testing in 2019. This paper presents Cambodia’s radical cure Phase I implementation results and assesses the safety, effectiveness, and feasibility of the programme prior to nationwide scale up.MethodsPhase I implementation was carried out in 88 select health facilities (HFs) across four provinces. Males over 20kgs with confirmed P. vivax or mixed (P. vivax and Plasmodium falciparum) infections were enrolled. A descriptive analysis evaluated the following: successful referral to health facilities, G6PD testing results, and self-reported 14-day treatment adherence. P. vivax incidence was compared before and after radical cure rollout and a controlled interrupted time series analysis compared the estimated relapse rate between implementation and non-implementation provinces before and after radical cure.ResultsIn the 4 provinces from November 2019 to December 2020, 3,239 P. vivax/mixed infections were reported, 1,282 patients underwent G6PD deficiency testing, and 959 patients received radical cure, achieving 29.6% radical cure coverage among all P. vivax/mixed cases and 98.8% coverage among G6PD normal patients. Among those who initiated radical cure, 747 patients (78%) completed treatment. Six patients reported side effects. In implementation provinces, an average 31.8 relapse cases per month were estimated signaling a 90% (286 cases) reduction in relapse compared to what would be expected if radical cure was not implemented.ConclusionsPlasmodium vivax radical cure is a crucial tool for malaria elimination in Cambodia. The high coverage of radical cure initiation and adherence among G6PD normal patients demonstrated the high feasibility of providing radical cure at point of care in Cambodia. Incomplete referral from community to HFs and limited capacity of HF staff to conduct G6PD testing in high burden areas led to lower coverage of G6PD testing. Phase I implementation informed approaches to improve referral completion and patient adherence during the nationwide expansion of radical cure in 2021.

Prevalence of Mediterranean Mutation of Glucose 6 Phosphate Dehydrogenase in Children of Malak Din Khel Subtribe of Afridi

Objective: To determine the prevalence of Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency in the Malak Din Khel subtribe, the biggest subtribe of Afridi, with expectations of newer findings in the area of medicine and research.Study Design: Cross-sectional study.Place and Duration of Study: This study was conducted in District Khyber from March 2018 to August 2018.Materials and Methods: The sample size of this study was 177 preschool-going children of 4-5 years of age. Multistage cluster sampling was done. Only resident families of Khyber Agency were selected. Children of age 04 to 05 years were enrolled in the study after consent from a parent/ guardian. Children with major comorbidities, non-consenting parents/ guardians, and children transfused in the last 24-48 hours were excluded from the study. 05 ml of blood was collected from each child. G6PD qualitative tests were performed in the field; rest of the tests were carried out later at Dabgari Garden “”in lab. PCR was processed according to protocol. Data were analyzed by SPSS 26.0.Results: A total sample size of 177 respondents were initially investigated through a qualitative test for G6PD deficiency. Among these, only 4 (2.3%) respondents were found to be G6PD deficient, The PCR analysis depicted that among 177 respondents, 31 (17.5%) were found to be mutant. Among these, 26(84%) were heterozygous, while 5 (16%) respondents were found to be homozygous. The PCR analysis further revealed that among the 5 homozygous respondents, 3 were found to be G6PD deficient, as also depicted by the qualitative test. One of the homozygous respondents, although found deficient by qualitative test, showed no Mediterranean mutation.Conclusion: Most studies done in Pakistan are hospital-based and the method for diagnosing is a qualitative test, but if the G6PD enzyme activity level is more than 30% qualitative test cannot pick the respondent as deficient. In our study, we ran qualitative tests on all respondents and only 4/177(2.3%), followed by PCR analysis for Mediterranean mutation of all samples, which showed that 31/177 (17.5%) were G6PD deficient. Further studies need to be conducted in the same manner to know the exact prevalence of G6PD. Detailed studies in other ethnic groups of the country must also be conducted to highlight the actual position of this threat.

Prevalence and molecular analysis of glucose-6-phosphate dehydrogenase deficiency in Chin State, Myanmar.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is caused by X-linked recessive disorderliness. It induces severe anemia when a patient with G6PD deficiency is exposed to oxidative stress that occurs with administration of an antimalarial drug, primaquine. The distribution of G6PD deficiency remains unknown while primaquine has been used for malaria treatment in Myanmar. This study aimed to investigate the prevalence of G6PD deficiency and its variants in Chin State, Myanmar. Among 322 participants, 18 (11 males and 7 females) demonstrated a G6PD deficiency. Orissa variant was dominant in the molecular analysis. This would be related to neighboring Indian and Bangladeshi population, in which Orissa variant was also reported as the main mutation type. The screening test for G6PD deficiency before primaquine treatment appears to be important in Myanmar.

A Review of the Current Status of G6PD Deficiency Testing to Guide Radical Cure Treatment for Vivax Malaria.

Plasmodium vivax malaria continues to cause a significant burden of disease in the Asia-Pacific, the Horn of Africa, and the Americas. In addition to schizontocidal treatment, the 8-aminoquinoline drugs are crucial for the complete removal of the parasite from the human host (radical cure). While well tolerated in most recipients, 8-aminoquinolines can cause severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. G6PD deficiency is one of the most common enzymopathies worldwide; therefore, the WHO recommends routine testing to guide 8-aminoquinoline based treatment for vivax malaria whenever possible. In practice, this is not yet implemented in most malaria endemic countries. This review provides an update of the characteristics of the most used G6PD diagnostics. We describe the current state of policy and implementation of routine point-of-care G6PD testing in malaria endemic countries and highlight key knowledge gaps that hinder broader implementation. Identified challenges include optimal training of health facility staff on point-of-care diagnostics, quality control of novel G6PD diagnostics, and culturally appropriate information and communication with affected communities around G6PD deficiency and implications for treatment.

G6PD testing and radical cure for Plasmodium vivax in Cambodia: A mixed methods implementation study.

IntroductionCambodia aims to eliminate malaria by 2025, however tackling Plasmodium vivax (P.v) presents multiple challenges. The prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency has prevented the deployment of 8-aminoquinolones for “radical cure”, due to the risk of severe haemolysis. Patients with P. vivax have therefore continued to experience recurrent relapses leading to cumulative health and socioeconomic burden. The recent advent of point of care testing for G6PD deficiency has made radical cure a possibility, however at the time of the study lack of operational experience and guidance meant that they had not been introduced. This study therefore aimed to design, implement and evaluate a new care pathway for the radical cure of P.vivax.MethodsThis implementation study took place in Pursat province, Western Cambodia. The interventions were co-developed with key stakeholders at the national, district, and local level, through a continuous process of consultations as well as formal meetings. Mixed methods were used to evaluate the feasibility of the intervention including its uptake (G6PD testing rate and the initiation of primaquine treatment according to G6PD status); adherence (self-reported); and acceptability, using quantitative analysis of primary and secondary data as well as focus group discussions and key informant interviews.ResultsThe co-development process resulted in the design of a new care pathway with supporting interventions, and a phased approach to their implementation. Patients diagnosed with P.v infection by Village Malaria Workers (VMWs) were referred to local health centres for point-of-care G6PD testing and initiation of radical cure treatment with 14-day or 8-week primaquine regimens depending on G6PD status. VMWs carried out follow-up in the community on days 3, 7 and 14. Supporting interventions included training, community sensitisation, and the development of a smartphone and tablet application to aid referral, follow-up and surveillance. The testing rate was low initially but increased rapidly over time, reflecting the deliberately cautious phased approach to implementation. In total 626 adults received G6PD testing, for a total of 675 episodes. Of these 555 occurred in patients with normal G6PD activity and nearly all (549/555, 98.8%) were initiated on PQ14. Of the 120 with deficient/intermediate G6PD activity 61 (50.8%) were initiated on PQ8W. Self-reported adherence was high (100% and 95.1% respectively). No severe adverse events were reported. The pathway was found to be highly acceptable by both staff and patients. The supporting interventions and gradual introduction were critical to success. Challenges included travel to remote areas and mobility of P.v patients.ConclusionThe new care pathway with supporting interventions was highly feasible with high levels of uptake, adherence and acceptability in this setting where high prevalence of G6PD deficiency is high and there is a well-established network of VMWs. Scaling up of the P.v radical cure programme is currently underway in Cambodia and a decline in reduction in the burden of malaria is being seen, bringing Cambodia a step closer to elimination.

An Evaluation of a New Quantitative Point-of Care Diagnostic to Measure Glucose-6-phosphate Dehydrogenase Activity

Malaria continues to be one of the most crucial infectious burdens in endemic areas worldwide, as well as for travelers visiting malaria transmission regions. It has been reported that 8-aminoquinolines are effective against the Plasmodium species, particularly primaquine, for anti-hypnozoite therapy in P. vivax malaria. However, primaquine causes acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, G6PD deficiency testing should precede hypnozoite elimination with 8-aminoquinoline. Several point-of-care devices have been developed to detect G6PD deficiency. The aim of the present study was to evaluate the performance of a novel, quantitative G6PD diagnostics based on a metagenomic blue fluorescent protein (mBFP). We comparatively evaluated the sensitivity and specificity of the G6PD diagnostic modality with standard methods using 120 human whole blood samples. The G6PD deficiency was spectrophotometrically confirmed. The performance of the G6PD quantitative test kit was compared with that of a licensed control medical device, the G6PD strip. The G6PD quantitative test kit had a sensitivity of 95% (95% confidence interval (CI): 89.3–100%) and a specificity of 100% (95% CI: 94.3–100%). This study shows that the novel diagnostic G6PD quantitative test kit could be a cost-effective and time-efficient, and universally mandated screening tool for G6PD deficiency.

Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.

Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3–100.0)/97 (95.2–98.2) and 100 (95.7–100.0)/97.4 (95.7–98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3–99.9)/88.2 (83.9–91.7) and 82.4 (56.6–96.2)/87.6(83.3–91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.

G6PD diaxBox: Digital image-based quantification of G6PD deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. More than 400 million people worldwide are affected by this genetic condition. Testing for G6PD deficiency before drug administration is essential for patient safety. Rapidly ascertaining the G6PD status of a person is desirable for proper treatment. The device described in this study, the G6PD diaxBOX, was developed to quantify G6PD deficiency using paper-based analytical devices (PADs) and a colorimetric assay. The G6PD diaxBOX is a straightforward, affordable, portable, and instrument-free analytical system. The major components of the G6PD diaxBox are a banknote-checking UV fluorescent lamp and camera that are easy to access and analysis software. When NADPH is generated, it absorbs at UV 340 nm and emits colored light that is detected with the camera. The determined Pearson's coefficient shows that the color intensity measured from the G6PD diaxBOX correlated with G6PD activity level. Also, a Bland-Altman analysis indicated that more than 95% of the measurement error was in the upper and lower boundaries (±2 SD) and the error from the severe and moderate deficiency group was less than ± 1 SD. Therefore, the error from G6PD diaxBOX was within the limit boundary and the overall accuracy was more than 80%. The G6PD diaxBOX facilitates the effective and efficient quantification of G6PD deficiency and as such represents a clinically well-suited, rapid point-of-care test.

Investigation of glucose-6-phosphate dehydrogenase (G6PD) deficiency prevalence in a Plasmodium vivax-endemic area in the Republic of Korea (ROK)

BackgroundGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent inborn disorder. This X-chromosome-linked recessive disease affects more than 400 million people globally, and is associated with haemolytic anaemia after medication with the anti-latent malaria drug, primaquine. To prevent malaria, the Republic of Korea (ROK) Army administers malaria chemoprophylaxis. Due to the previously low G6PD deficiency prevalence in the ROK, prior to primaquine administration, testing for G6PD deficiency was not mandatory. In this study, to evaluate the risk from malaria chemoprophylaxis in the ROK, G6PD deficiency prevalence was investigated.MethodsBlood specimens from 1632 soldiers entering training camp for the 3rd Infantry of the ROK Army were collected. CareStart™ Biosensor for G6PD and haemoglobin (Hb) was used to detect G6PD levels. G6PD variants using the DiaPlexC G6PD Genotyping kit (Asian type) and full-length sequencing were examined.ResultsOf 1632 blood specimens tested, none was observed to be G6PD deficient. The median value of all tested samples was 7.582 U/g Hb. An investigation of 170 G6PD DNA variants was analysed and categorized as partially low normal [n = 131, 30–80% (2.27–6.05 U/g Hb) of the median value], high [n = 3, > 150% (> 11.373 U/g Hb) of the median value], or normal [n = 36, 80–150% (6.05–11.373 U/g Hb) of the median value], and none was amplified by the DiaPlexC kit. Five silent mutations (C→T) in 131 partially low normal specimens were found at the 1311th nucleotide position by sequence analysis. Another 8 silent mutations (T93C) were also detected in 131 partially low normal specimens. Thus, it is inferred that these silent mutations could be related to G6PD activity.ConclusionsThis G6PD deficiency prevalence study, conducted among participants from the 3rd Infantry of the ROK Army, provided crucial evidence for the safety of malaria chemoprophylaxis. This study showed that the prevalence of G6PD deficiency among 1632 young soldiers was wholly absent. Although G6PD phenotypic mutations were not detected, many silent mutations (C1311T and T93C) were observed. Thus, it is inferred that malaria chemoprophylaxis is relatively safe against G6PD deficiency-mediated haemolytic anaemia. However, given the number of individuals whose G6PD were at the partially low normal range and the frequent detection of G6PD deficiency-related mutations, consistent monitoring of G6PD deficiency is needed.

Optimizing G6PD testing for Plasmodium vivax case management and beyond: why sex, counseling, and community engagement matter.

Safe access to the most effective treatment options for Plasmodium vivaxmalaria are limited by the absence of accurate point-of-care testingto detect glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human genetic disorder. G6PD-deficient patients are at risk of life-threatening hemolysis when exposed to 8-aminoquinolines, the only class of drugs efficacious against P. vivaxhypnozoites. Until recently, only qualitative tests were available in most settings. These can identify patients with severe G6PD deficiency (mostly male) but not patients with intermediate G6PD deficiency (always female).This has led to and reinforced a gap in awareness in clinical practice of the risks and implications of G6PD deficiency in females-who, unlike males, can have a heterozygous genotype for G6PD.Increasing recognition of the need for radical cure of P. vivax, first for patients' health and then for malaria elimination, is driving the development of new point-of-care tests for G6PD deficiency and their accessibility to populations in low-resource settings. The availability of user-friendly, affordable, and accurate quantitative point-of-care diagnostics for the precise classification of the three G6PD phenotypes can reduce sex-linked disparities by ensuring safe and effective malaria treatment, providing opportunities to develop supportive counseling to enhance understanding of genetic test results, and improving the detection of all G6PD deficiency phenotypes in newborns and their family members.

Geographical Accessibility to Glucose-6-Phosphate Dioxygenase Deficiency Point-of-Care Testing for Antenatal Care in Ghana.

Background: Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency screening test is essential for malaria treatment, control, and elimination programs. G6PD deficient individuals are at high risk of severe hemolysis when given anti-malarial drugs such as primaquine, quinine, other sulphonamide-containing medicines, and chloroquine, which has recently been shown to be potent for the treatment of coronavirus disease (COVID-19). We evaluated the geographical accessibility to POC testing for G6PD deficiency in Ghana, a malaria-endemic country. Methods: We obtained the geographic information of 100 randomly sampled clinics previously included in a cross-sectional survey. We also obtained the geolocated data of all public hospitals providing G6PD deficiency testing services in the region. Using ArcGIS 10.5, we quantified geographical access to G6PD deficiency screening test and identified clinics as well as visualize locations with poor access for targeted improvement. The travel time was estimated using an assumed speed of 20 km per hour. Findings: Of the 100 clinics, 58% were Community-based Health Planning and Services facilities, and 42% were sub-district health centers. The majority (92%) were Ghana Health Service facilities, and the remaining 8% were Christian Health Association of Ghana facilities. Access to G6PD deficiency screening test was varied across the districts, and G6PD deficiency screening test was available in all eight public hospitals. This implies that the health facility-to-population ratio for G6PD deficiency testing service was approximately 1:159,210 (8/1,273,677) population. The spatial analysis quantified the current mean distance to a G6PD deficiency testing service from all locations in the region to be 34 ± 14 km, and travel time (68 ± 27 min). The estimated mean distance from a clinic to a district hospital for G6PD deficiency testing services was 15 ± 11 km, and travel time (46 ± 33 min). Conclusion: Access to POC testing for G6PD deficiency in Ghana was poor. Given the challenges associated with G6PD deficiency, it would be essential to improve access to G6PD deficiency POC testing to facilitate administration of sulphadoxine-pyrimethamine to pregnant women, full implementation of the malaria control program in Ghana, and treatment of COVID-19 patients with chloroquine in malaria-endemic countries. To enable the World Health Organization include appropriate G6PD POC diagnostic tests in its list of essential in-vitro diagnostics for use in resource-limited settings, we recommend a wider evaluation of available POC diagnostic tests for G6PD deficiency, particularly in malaria-endemic countries.

Optimizing G6PD testing for Plasmodium vivax case management: why sex, counseling, and community engagement matter.

Safe access to the most effective treatment options for Plasmodium vivaxmalaria are limited by the absence of accurate point-of-care testingto detect glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human genetic disorder. G6PD-deficient patients are at risk of life-threatening hemolysis when exposed to 8-aminoquinolines, the only class of drugs efficacious against P. vivaxhypnozoites. Until recently, only qualitative tests were available in most settings. These accurately identify patients with severe G6PD deficiency (mostly male) but not patients with intermediate G6PD deficiency (always female).This has led to and reinforced a gap in awareness in clinical practice of the risks and implications of G6PD deficiency in females-who, unlike males, can have a heterozygous genotype for G6PD.Increasing recognition of the need for radical cure of P. vivax, first for patients' health and then for malaria elimination, is driving the development of new point-of-care tests for G6PD deficiency and their accessibility to populations in low-resource settings. The availability of simple, affordable, and accurate point-of-care diagnostics for the precise classification of the three G6PD phenotypes can reduce sex-linked disparities by ensuring safe and effective malaria treatment, providing opportunities to develop supportive counseling to enhance understanding of genetic test results, and improving the detection of all G6PD deficiency phenotypes in newborns and their family members.

Ispitivanje i upoređivanje troškova G6PD enzimskog skrining testa za novorođenu decu u odnosu na troškove lečenja pacijenata sa favizmom hospitalizovanih usled hemolize

Objective. We compared the glucose-6-phosphate dehydrogenase (G6PD) deficiency screening costs in neonates and treatment costs for patients with favism who were referred to the government hospitals of Isfahan with acute hemolysis. Methods. In this retrospective study, 116 patients with favism were selected, and their clinical data and treatment costs were recorded in Iranian Rials (IRR) and United States Dollars (USD). The costs of neonatal G6PD screening tests were estimated based on quantitative and qualitative screening kits by referring to each hospital's laboratories. Approximately 84760 births occurred in Isfahan province from October 2014 to October 2015. Results. Based on our results, 73 patients (62.9%) were males, and 43 of them (37.1%) were females. The causes for hemolysis were the consumption of broad beans in 78.4%, infection in 19.8%, and drugs (erythromycin and sodium cephalothin) in 1.7% of patients. The majority of patients (46.6%) received a single blood transfusion, and 18.9% received two or more transfusions, while 34.5% had received no blood transfusions. The mean and standard deviation of patients' medical expenses were 7,472,005±7,329,847 IRR (276.74±271.47 USD). The total cost of treatment for patients was 869,162,324 IRR (32,191.19 USD). The screening cost for all newborns from October 2014 to October 2015 with qualitative kits was 754,364,000 IRR (27,939.40 USD) and with the quantitative kits was 960,330,800 IRR (35,567.80 USD). Conclusion. The costs of the qualitative screening test for G6PD deficiency are lower than the costs of treatments of favism patients in Isfahan.

Methemoglobinemia Secondary to Herbal Products.

Dear Editor, We read with interest the recent article by Al-Qahtani et al. regarding methemoglobinemia in a young boy.[1] We would like to discuss few other essential points that we believe to be important for Saudi J Med Med Sci readers to have a comprehensive understanding of this topic.[23] While there seems to be a good temporal correlation between Ferula asafoetida ingestion and the development of methemoglobinemia in the case reported, we still strongly recommend that in such cases, a comprehensive workup should be performed to rule out congenital methemoglobinemia. In young patients, we should be very cautious and always consider congenital methemoglobinemia before labeling them as a case of acquired methemoglobinemia. We recommend genetic testing for cytochrome b5 reductase deficiency and hemoglobin (Hb) M to ensure that in such cases, the child is free from any genetic perturbations that can put him/her at risk for the recurrence of methemoglobinemia in future.[4] Hb M is a special variant in which heme iron can undergo auto-oxidation, resulting in methemoglobinemia. The common Hb M variants are Hb M-Boston, Hb M-Iwate, Hb Auckland, Hb Chile, Hb M-Saskatoon and Hb M-Milwaukee. Food products such as frozen items may have high nitrate content, and there have been reports of clusters of cases with many family members developing methemoglobinemia because of frozen food consumption.[5] In addition, it should be noted that rarely used topical agents such as eutectic mixture of local anesthetic cream, e-cigarettes, contaminated water and other herbal medicines such as choy sum can lead to methemoglobinemia.[6] In the case reported by Al-Qahtani et al., it is unclear why the patient had anemia of 10.4 g/dl and leukocytosis of 24,000/mm. Did the authors look for hemolysis in this case and what was the likely explanation of the high white blood cell count? Getting a serum lactate dehydrogenase and other hemolytic panel such as serum haptoglobin, direct antiglobulin test and peripheral blood smear would be beneficial to rule out concomitant hemolysis that can be associated with methemoglobinemia.[7] The family history is very relevant in this case, as rightly explained by Al-Qahtani et al.[1] As per the history provided, both the brothers of the infant had glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, we recommend that the parents should also be checked for this deficiency. In case of a male boy, there is a 50% chance of having a G6PD deficiency if the mother is a carrier. Therefore, genetic testing of parents is mandatory to predict the likelihood of transmitting the condition to children. Methylene blue (MB) is the drug of choice in the management of methemoglobinemia. In the case reported by Al-Qahtani et al., MB was not given for the fear that he may be positive for G6PD deficiency given the strong family history. This patient was critically sick and mechanically ventilated. We are not sure about the logistic resources at the author’s medical center, but a rapid fluorescent spot test for G6PD deficiency is now readily available, which can confirm G6PD deficiency in as early as a few minutes.[8] This patient was not given either MB or vitamin C and instead was successfully treated with hyperoxic ventilation. This is a great learning case, but we wish to reinforce the fact to the readers that MB should be the first choice and all efforts should be made to check the G6PD status so that patients are not denied the standard of care. It should also be noted that in addition to MB and ascorbic acid, other drugs such as riboflavin and cimetidine can be used to treat methemoglobinemia with variable outcomes.[3] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

A cross-sectional study on parental awareness for newborn screening and assessment of the burden of congenital hypothyroidism and glucose 6-phosphate dehydrogenase deficiency

Introduction: Newborn Screening (NBS) has been one of the most successful health programs and of most paramount importance worldwide but not so in India. Due to the lack of awareness and paucity of laboratory facilities, the disease burden in our population has not yet been established. Aim and Objective: The aim and objective of the study was to assess the burden of Congenital Hypothyroidism (CH) and Glucose 6-Phosphate Dehydrogenase (G6PD) deficiency in this area by NBS tests and to assess the impact of awareness sessions on the response rate of parents for NBS. Material and Methods: The screening was conducted in 474 babies of age 48 h up to 8 weeks. The dried blood spots collected were subjected to the following analytical protocol. Thyroid-stimulating hormone (TSH) level and G6PD enzyme activity were analyzed by immunofluorescence method-based neonatal kits. All babies with a positive screening test for G6PD deficiency and CH were asked for venous confirmatory testing after 7 days. Results: The efficiency of the program for all live birth babies delivered in the institute was 92% (n = 410/445). It was 82% in the first phase of the study period and 98.5% in the second phase. Repeated training of nursing professional reduced the sampling errors from 14.7% in the first phase to 6.1% in the second phase. A total of 11 samples reflected high TSH values, of which one baby confirmed for CH. Of the 24 babies who screened positive for G6PD, four were confirmed for the same. The prevalence for CH and G6PD deficiency was, respectively, 1 in 462 (2/1000) and 4 in 462 (8.7/1000). Conclusion: Development of expansion of NBS program in the state should be made mandatory for all newborns. The recommendations include awareness among parents, during antenatal and postnatal period and also to health professionals and provision for laboratory facilities for NBS testing at low cost.

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

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.

PIN21 COST-EFFECTIVENESS ANALYSIS OF TAFENOQUINE WITH A RAPID DIAGNOSTIC TEST FOR G6PD DEFICIENCY IN PATIENTS WITH PLASMODIUM VIVAX INFECTIONS IN BRAZIL

Plasmodium vivax causes 89% of malaria cases in Brazil. P. vivax is a debilitating and deadly disease with significant economic impact. The introduction of the recently FDA-approved one-dose treatment with tafenoquine (TQ) faces a challenge: as is the case with primaquine (PQ), patients with a glucose-6-phosphate dehydrogenase deficiency (G6PDd) can suffer potentially serious complications, including hemolytic anemia. To mitigate this risk, PATH-Mologic are developing a point-of-care diagnostic test to identify patients’ G6PD status to safely administer TQ or PQ. We performed a cost-effectiveness analysis (CEA) of P. vivax control comparing two strategies: Gold standard G6PDd testing (GS) with PQ vs. PATH-Mologic RDT with TQ. The analysis was performed from the perspective of the Brazil’s public health system. We used a decision tree model parametrized using data from the literature and predictions for the costs of the RDT and tafenoquine. The outcomes of the analysis were cost per adequately diagnosed case, cost per hospitalization averted, and cost per relapse prevented. The cost of GS-PQ was $46 compared to $110 for RDT-TQ. The sensitivity of GS was 0.98 compared to 1 for RDT and the relapse-free efficacy at six months was 0.9 with TQ compared to 0.77 with PQ. Our model indicates that the RDT-TQ was dominant for cost per adequately diagnosed case. The ICERs comparing RDT-TQ to GS-PQ were $1,776 per hospitalization averted and $14,141 per relapse prevented. The PATH-Mologic RDT and TQ combination is cost-effective in terms of cost per adequate diagnosis. The cost-effectiveness with regard to cost per hospitalization averted and cost per relapse prevented depends on the willingness to pay of Brazil’s public health system for these outcomes. These findings can help the Brazilian government in considering the implementation of the intervention in malaria-endemic areas.

Tafenoquine and G6PD: a primer for clinicians.

Tafenoquine, an 8-aminoquinoline, is now indicated for causal prophylaxis against all human malarias and as radical curative (anti-relapse) treatment against Plasmodium vivax and Plasmodium ovale. As with other 8-aminoquinolines, tafenoquine causes hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (hemizygous males and homozygous females) and is contraindicated in this population. Those with intermediate G6PD activity (heterozygous females) are also at risk for hemolysis. Awareness of how to prescribe tafenoquine in relation to G6PD status is needed so it can be used safely. A standard literature search was performed on varying combinations of the terms tafenoquine, Arakoda, Kodatef, Krintafel, Kozenis, primaquine, G6PD deficiency, malaria prophylaxis and radical cure. The data were gathered and interpreted to review how tafenoquine should be prescribed in consideration of the G6PD status of an individual and traveller. Tafenoquine should only be given to those with G6PD activity >70% of the local population median. Qualitative G6PD tests are sufficient for diagnosing G6PD deficiency in males. However, in females quantitative G6PD testing is necessary to differentiate deficient, intermediate and normal G6PD statuses. Testing for G6PD deficiency is mandatory before tafenoquine prescription. Measures can be taken to avoid tafenoquine administration to ineligible individuals (i.e. due to G6PD status, age, pregnancy and lactation). Primaquine is still necessary for some of these cases. This review provides actions that can be taken to diagnose and manage hemolysis when tafenoquine is given inadvertently to ineligible individuals. Attention to G6PD status is required for safe prescription of tafenoquine. A high index of suspicion is needed if hemolysis occurs. Clinicians should seek evidence-based information for the management and treatment of iatrogenicy hemolysis caused by 8-aminoquinolines.

Point-of-Care Testing for G6PD Deficiency: Opportunities for Screening.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked genetic disorder, is associated with increased risk of jaundice and kernicterus at birth. G6PD deficiency can manifest later in life as severe hemolysis, when the individual is exposed to oxidative agents that range from foods such as fava beans, to diseases such as typhoid, to medications such as dapsone, to the curative drugs for Plasmodium (P.) vivax malaria, primaquine and tafenoquine. While routine testing at birth for G6PD deficiency is recommended by the World Health Organization for populations with greater than 5% prevalence of G6PD deficiency and to inform P. vivax case management using primaquine, testing coverage is extremely low. Test coverage is low due to the need to prioritize newborn interventions and the complexity of currently available G6PD tests, especially those used to inform malaria case management. More affordable, accurate, point-of-care (POC) tests for G6PD deficiency are emerging that create an opportunity to extend testing to populations that do not have access to high throughput screening services. Some of these tests are quantitative, which provides an opportunity to address the gender disparity created by the currently available POC qualitative tests that misclassify females with intermediate G6PD activity as normal. In populations where the epidemiology for G6PD deficiency and P. vivax overlap, screening for G6PD deficiency at birth to inform care of the newborn can also be used to inform malaria case management over their lifetime.

Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries.

Primaquine is the only available antimalarial drug that kills dormant liver stages of Plasmodium vivax and Plasmodium ovale malarias and therefore prevents their relapse (‘radical cure’). It is also the only generally available antimalarial that rapidly sterilises mature P. falciparum gametocytes. Radical cure requires extended courses of primaquine (usually 14 days; total dose 3.5–7 mg/kg), whereas transmissibility reduction in falciparum malaria requires a single dose (formerly 0.75 mg/kg, now a single low dose [SLD] of 0.25 mg/kg is recommended). The main adverse effect of primaquine is dose-dependent haemolysis in glucose 6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy. X-linked mutations conferring varying degrees of G6PD deficiency are prevalent throughout malaria-endemic regions. Phenotypic screening tests usually detect <30% of normal G6PD activity, identifying nearly all male hemizygotes and female homozygotes and some heterozygotes. Unfortunately, G6PD deficiency screening is usually unavailable at point of care, and, as a consequence, radical cure is greatly underused. Both haemolytic risk (determined by the prevalence and severity of G6PD deficiency polymorphisms) and relapse rates vary, so there has been considerable uncertainty in both policies and practices related to G6PD deficiency testing and use of primaquine for radical cure. Review of available information on the prevalence and severity of G6PD variants together with countries’ policies for the use of primaquine and G6PD deficiency testing confirms a wide range of practices. There remains lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens. Despite substantially lower haemolytic risks, implementation of SLD primaquine as a P. falciparum gametocytocide also varies. In Africa, a few countries have recently adopted SLD primaquine, yet many with areas of low seasonal transmission do not use primaquine as an antimalarial at all. Most countries that recommended the higher 0.75 mg/kg single primaquine dose for falciparum malaria (e.g., most countries in the Americas) have not changed their recommendation. Some vivax malaria–endemic countries where G6PD deficiency testing is generally unavailable have adopted the once-weekly radical cure regimen (0.75 mg/kg/week for 8 weeks), known to be safer in less severe G6PD deficiency variants. There is substantial room for improvement in radical cure policies and practices.