[The effect of glucose-6-phosphate dehydrogenase deficiency on allogeneic hematopoietic stem cell transplantation in patients with hematological disorders].

Objectives: To determine the effect of glucose-6-phosphate-dehydrogenase (G6PD) deficiency on patients' complications and prognosis following allogeneic stem cell hematopoietic transplantation (allo-HSCT) . Methods: 7 patients with G6PD deficiency (study group) who underwent allo-HSCT at Peking University People's Hospital from March 2015 to January 2021 were selected as the study group, and thirty-five patients who underwent allo-HSCT during the same period but did not have G6PD deficiency were randomly selected as the control group in a 1∶5 ratio. Gender, age, underlying diseases, and donors were balanced between the two groups. Collect clinical data from two patient groups and perform a retrospective nested case-control study. Results: The study group consisted of six male patients and one female patient, with a median age of 37 (range, 2-45) years old. The underlying hematologic diseases included acute myeloid leukemia (n=3), acute lymphocytic leukemia (n=2), and severe aplastic anemia (n=2). All 7 G6PD deficiency patients achieved engraftment of neutrophils within 28 days of allo-HSCT, while the engraftment rate of neutrophils was 94.5% in the control group. The median days of platelet engraftment were 21 (6-64) d and 14 (7-70) d (P=0.113). The incidence rates of secondary poor graft function in the study group and control group were 42.9% (3/7) and 8.6% (3/35), respectively (P=0.036). The CMV infection rates were 71.4% (5/7) and 31.4% (11/35), respectively (P=0.049). The incidence rates of hemorrhagic cystitis were 57.1% (4/7) and 8.6% (3/35), respectively (P=0.005), while the bacterial infection rates were 100% (7/7) and 77.1% (27/35), respectively (P=0.070). The infection rates of EBV were 14.3% (1/7) and 14.3% (5/35), respectively (P=1.000), while the incidence of fungal infection was 14.3% (1/7) and 25.7% (9/35), respectively (P=0.497). The rates of post-transplant lymphoproliferative disease (PTLD) were 0% and 5.7%, respectively (P=0.387) . Conclusions: The findings of this study indicate that blood disease patients with G6PD deficiency can tolerate conventional allo-HSCT pretreatment regimens, and granulocytes and platelets can be implanted successfully. However, after transplantation, patients should exercise caution to avoid viral infection, complications of hemorrhagic cystitis, and secondary poor graft function.

Is Glucose-6-Phosphate Dehydrogenase Deficiency a Risk Factor for Autoimmune Thyroid Disease? A Retrospective Case-Control Study.

BACKGROUND: The risk of developing thyroid disorders (TDs) in subjects with inherited glucose-6-phosphate dehydrogenase (G6PD) deficiency is unknown. The aim of this study was to explore the association between autoimmune (AITD) and G6PD deficiency in Northern Sardinia, in a population with a high frequency of these two conditions. METHODS: In this retrospective single-center case-control study, demographic and clinical data were collected from patients examined in a tertiary referral Gastroenterology Section of a teaching hospital. RESULTS: In 8894 subjects examined (64.7% females), 1218 patients were diagnosed with TDs; more specifically, 767 were diagnosed with AITD and 451 were not (non-AITD). Overall, G6PD deficiency was more prevalent in TD patients compared with patients without TD (controls) (16.7% vs. 11.2%; p < 0.0001). Multivariable logistic regression analysis (after adjusting for age, sex, excess weight and smoking habits), confirmed a higher risk of AITD among G6PD deficient patients with an odds ratio (OR) of 1.36 and 95% confidence interval (CI) of 1.11-1.6, female patients (OR 1.33, 95% CI 1.07-1.65) and overweight patients (OR 1.22, 95% CI 1.03-1.44). CONCLUSIONS: The risk of AITD is increased in carriers of G6PD deficiency. A careful assessment of thyroid function is advisable in patients with inherited G6PD defects.

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

INTRODUCTION: Cambodia 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. METHODS: This 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. RESULTS: The 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. CONCLUSION: The 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.

A case of G6PD Utrecht associated with ß-thalassemia responding to splenectomy.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disease caused by a pathogenic G6PD mutation. An 8-year-old Chinese male child was investigated because of chronic nonspherocytic hemolytic anemia (CNSHA) associated with hepatosplenomegaly. Genetic analysis unraveled co-inheritance of a hemizygous mutation c.1225C>T (p.Pro409Ser) in G6PD (G6PD Utrecht, previously reported only in The Netherlands) and heterozygote HBB mutation c.316-197C>T (IVS-Ⅱ-654 C>T). Because IVS-Ⅱ-654 C>T on its own does not cause CNSHA, we believe that the clinical manifestations in this patient are essentially due to the G6PD c.1225C>T mutation. The boy gained transfusion independence after splenectomy.

Mediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness.

RATIONALE: Epidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model. OBJECTIVE: To determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PDS188F) variant and in wild-type (WT) rats. METHODS AND RESULTS: Our findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PDS188F than in WT rats. Additionally, Ang-II induced less glomerular and tubular damage in the kidneys - a consequence of elevated pressure - in G6PDS188F than WT rats. However, Ang-II-induced arterial stiffness increased in G6PDS188F and WT rats, and there were no differences between the groups. Mechanistically, we found aorta of G6PDS188F as compared to WT rats produced less sustained contraction and less inositol-1,2,3-phosphate (IP3) and superoxide in response to Ang-II. Furthermore, aorta of G6PDS188F as compared to WT rats expressed lower levels of phosphorylated extracellular-signal regulated kinase (ERK). Interestingly, the aorta of G6PDS188F as compared to WT rats infused with Ang-II transcribed more (50-fold) myosin heavy chain-11 (MYH11) gene, which encodes contractile protein of smooth muscle cell (SMC), and less (2.3-fold) actin-binding Rho-activating gene, which encodes a protein that enhances SMC proliferation. A corresponding increase in MYH11 and Leiomodin-1 (LMOD1) staining was observed in arteries of Ang-II treated G6PDS188F rats. However, G6PD deficiency did not affect the accumulation of CD45+ cells and transcription of genes encoding interleukin-6 and collagen-1a1 by Ang-II. CONCLUSIONS: The G6PDS188F loss-of-function variant found in humans protected rats from Ang-II-induced HTN and kidney damage, but not from vascular inflammation and arterial stiffness.

Impact of pre-emptive rapid testing for glucose-6-phosphate dehydrogenase deficiency prior to rasburicase administration at a tertiary care centre: A retrospective study.

AIMS: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute haemolysis resulting from exposure to certain medications, chemicals, infections and fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumour lysis syndrome, is one such drug. The US Food and Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency. METHODS: We performed a retrospective chart review of all oncology patients for whom a semi-quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5-year period, in a large academic metropolitan hospital. RESULTS: We identified 16 out of 260 tested individuals as G6PD-deficient (6.1%), including six females. On average, test results were electronically available to health care providers within 4 hours of sample collection, with most results available within 2-3 hours. Four G6PD-deficient patients developed elevated uric acid levels. Two of the G6PD-deficient patients were treated with rasburicase, and subsequently developed haemolysis, which was appropriately managed. CONCLUSION: In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD-deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.

Rasburicase induced methemoglobinemia: A systematic review of descriptive studies.

PURPOSE: There is an increased number of reports being published on rasburicase-induced methemoglobinemia recently. We aimed to identify and critically evaluate all the descriptive studies that described the rasburicase-induced methemoglobinemia, its treatment approach, and their outcomes. METHODOLOGY: PubMed, Scopus and grey literature databases were searched from inception to January 2022 using search terms "rasburicase" and "methemoglobinemia" without any language and date restriction. A bibliographic search was also done to find additional studies. Only descriptive studies on Rasburicase-induced methemoglobinemia were included for our review. Two contributors worked independently on study selection, data abstraction, and quality assessment, and any disagreements were resolved by consensus or discussion with a third reviewer. RESULT: A total of 24 reports including 27 patients (23 male, 3 female patients, and 1 study did not specify the gender of the patient) aged from 5 to 75 years were included in the review. Immediate withdrawal of the drug and administering methylene blue, ascorbic acid, blood transfusion, and supportive oxygen therapy are the cornerstone in the management of rasburicase-induced methemoglobinemia. CONCLUSION: Rasburicase administration should be followed by careful monitoring of patients for any severe complication and treat it as early as possible appropriately. In a patient who presents with rasburicase-induced haemolysis or methemoglobinemia, it is often important to expect a diagnosis of G6PD deficiency unless otherwise confirmed and to avoid administering methylene blue, even though the patient is from a low-risk ethnicity for G6PDD.

Hemolysis After Medication Exposure in Pediatric Patients With G6PD Deficiency.

Hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency varies by mutation status and the oxidative stressor. Although classified by percent of enzymatic deficiency, variability in normal G6PD values clouds assessment of hemolysis risk by level. This was a retrospective, single institution, cohort study assessing risk of postexposure medication-induced hemolysis in G6PD deficient patients. Exposures occurred in 87 of 1415 deficient patients. Only 2 of 87 medication-exposed patients had hemolytic episodes and both had very low enzymatic activity. No hemolytic events occurred with G6PD levels >7 units/g hemoglobin. Correlation of levels with mutation may improve predictive capacity for hemolysis in G6PD deficiency.

Acute Hemolytic Anemia Caused by G6PD Deficiency in Children in Mayotte: A Frequent and Severe Complication.

Severe hemolytic anemia is a rare complication of glucose-6-phosphate dehydrogenase (G6PD) deficiency. It occurs with the Mediterranean (Med) variant corresponding to a class 2 deficiency according to the World Health Organization (WHO) classification, and it correlates with a severe deficiency in G6PD activity. In Mayotte, the majority of patients have the African (A-) variant as a WHO class 3 deficiency. Yet we have observed numerous cases of severe hemolytic anemia defined by a hemoglobin level of <6 g/dL. In this study, we aimed to describe the epidemiological, clinical, and biological features as well as the treatment modalities of children presenting with a severe hemolytic crisis secondary to G6PD deficiency in Mayotte. The secondary objective was to study the disease genotype when this information was available. Between April 2013 and September 2020, 73 children presented with severe anemia because of G6PD deficiency in Mayotte. The median hemoglobin level during the hemolytic crises was 3.9 g/dL. All of the patients underwent a transfusion and hospitalization. Twenty patients had a disease genotype: 11 had the African mutation and 9 had the Med mutation. Although they are among the most common triggers of G6PD acute hemolytic anemia, drugs were found to not be present and fava bean ingestion was found in only 1 child. One of the specific triggers was traditional medicine, including Acalypha indica . Severe hemolytic crisis in children because of G6PD deficiency is a frequent occurrence in Mayotte. The patients had severe disease symptoms, but the severity did not correlate with the genotype: the African (A-) variant and the Med variant resulted in the same level of disease severity.

G6PD: a homozygous deficiency revealed by macrocytosis after acute alcoholism / G6PD : un déficit homozygote révélé par une macrocytose au décours d'un épisode d'éthylisme aigu

G6PD deficiency is one of the most common genetic disorders in the world, affecting more than 400 million people. The large majority of patients do not have anemia of chronic hemolysis but are subject to acute haemolytic anemia after exposure to triggering factor, usually eating fava beans, exposure to oxidative drugs or acidosis. We report the case of a 53-year-old woman that had an acute haemolytic anemia revealed by abnormally rapid increase of MCV that eventually led to discover G6PD deficiency. As investigation did not identify any common triggering factor, we discuss the involvement of the patient's acute alcohol consumption in this haemolytic event.

Le déficit en G6PD est l'une des affections génétiques les plus fréquentes dans le monde, touchant plus de 400 millions de personnes. La majorité des patients n'ont pas d'anémie ni d'hémolyse chronique, mais sont sujets à la survenue d'accès d'hémolyse aigue après exposition à un facteur déclenchant : consommation de fèves, médicaments oxydants, acidose le plus souvent. Nous rapportons ici un cas d'accès d'hémolyse chez une patiente de 53 ans révélé par une augmentation rapide du VGM et qui a permis la mise en évidence d'un déficit en G6PD homozygote. L'enquête étiologique n'ayant pas retrouvé de facteur déclenchant habituel, nous discutons l'implication de la consommation aigue d'alcool de la patiente dans cet accès d'hémolyse.

Advanced germ cell tumors and chemotherapy in G6PD deficient patients: Yes to chemotherapy but no to rasburicase and some premedications.

PURPOSE: Glucose-6 phosphate dehydrogenase (G6PD) deficiency has an estimated prevalence of 5 -7.5% of the global population. Administration of some drugs in G6PD deficient patients may result in clinical conditions of varying severity, including potentially fatal sequels. For these reasons, in case of G6PD deficiency, the use of high dose toxic chemotherapy regimens in potentially curable malignancies with associated risk of tumor lysis syndrome, such as in advanced germ cell tumors, raises both physicians' preoccupations and issues for safeguard patients' health. Nonetheless no systematic information is actually available for safety in premedication to be administered, chemotherapy regimens adopted, and supportive care drugs needed to be provided in some particular situations. METHODS: We present a case of a patient with metastatic testicular cancer and known g6pd deficiency, admitted in our department. We also performed a literature review in tree medical libraries searching for articles addressing the overmentioned security issues. RESULTS: Available literature is particularly scant. nonetheless, there is no evidence contradicting the administration of cytotoxic chemotherapy to G6PD deficient individuals. Our patient was able to complete the preplaned chemotherapy cycles, without any complications. CONCLUSION: Given the absence of data supporting the limitation of chemotherapy to G6PD deficient patients, the latter should not be deprived of the indicated antineoplastic treatment. However, certain premedication agents must be avoided. Continuous patient monitoring during treatment may alleviate physicians' and patients' anxiety and preoccupations.

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-Deficient Mice Are Protected From Experimental Cerebral Malaria and Liver Injury by Suppressing Proinflammatory Response in the Early Stage of Plasmodium berghei Infection.

Epidemiological studies provide compelling evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency individuals are relatively protected against Plasmodium parasite infection. However, the animal model studies on this subject are lacking. Plus, the underlying mechanism in vivo is poorly known. In this study, we used a G6pd-deficient mice infected with the rodent parasite Plasmodium berghei (P.berghei) to set up a malaria model in mice. We analyzed the pathological progression of experimental cerebral malaria (ECM) and acute liver injury in mice with different G6pd activity infected with P.berghei. We performed dual RNA-seq for host-parasite transcriptomics and validated the changes of proinflammatory response in the murine model. G6pd-deficient mice exhibited a survival advantage, less severe ECM and mild liver injury compared to the wild type mice. Analysis based on dual RNA-seq suggests that G6pd-deficient mice are protected from ECM and acute liver injury were related to proinflammatory responses. Th1 differentiation and dendritic cell maturation in the liver and spleen were inhibited in G6pd-deficient mice. The levels of proinflammatory cytokines were reduced, chemokines and vascular adhesion molecules in the brain were significantly down-regulated, these led to decreased cerebral microvascular obstruction in G6pd-deficient mice. We generated the result that G6pd-deficiency mediated protection against ECM and acute liver injury were driven by the regulatory proinflammatory responses. Furthermore, bioinformatics analyses showed that P.berghei might occur ribosome loss in G6pd-deficient mice. Our findings provide a novel perspective of the underlying mechanism of G6PD deficiency mediated protection against malaria in vivo.

COVID-19 may enhance risk of thrombosis and hemolysis in the G6PD deficient patients.

COVID-19 has become a major public health problem since December, 2019 and no highly effective drug has been found until now. Numbers of infected people and deaths by COVID-19 are increasing every day worldwide, therefore self-isolation and protection are highly recommended to prevent the spread of the virus and especially to protect major risk groups such as the elderly population and people with comorbidities including diabetes, hypertension, cancer, cardiovascular diseases and metabolic syndrome. On the other hand, young people without any secondary disease have died by COVID-19 as well. In this study we compared two male patients infected by COVID-19 at the same age and one of them was diagnosed with G6PD deficiency. Both COVID-19 and G6PD deficiency enhance the risk of hemolysis and thrombosis. Serum biochemistry, hemogram and immunological parameters showed that risk of hemolysis and thrombosis may increase in the G6PD deficient patient infected by COVID-19.

Rasburicase-induced haemolysis and methemoglobinemia: an ongoing issue.

We report a case of a 91-year-old Caucasian woman with a history of chronic lymphocytic leukaemia who developed acute hypoxic respiratory failure (AHRF) requiring intubation for less than 24 hours after receiving rasburicase. Laboratory workup was significant for methemoglobinemia and acute anaemia, and blood film demonstrated evidence of oxidative haemolysis with bite cells. The patient was given a presumptive diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency and was managed conservatively with successful resolution of AHRF and stabilisation of haemoglobin level. Seven days after admission, she passed away due to subsequent complications; hence, follow-up G6PD level could not be obtained. Haemolytic anaemia and methemoglobinemia in the setting of recent rasburicase administration should raise clinical suspicion for G6PD deficiency. In non-emergent cases, patients should be screened prior to receiving rasburicase regardless of risk factors. Because rasburicase is often needed emergently, patients at high risk of tumour lysis syndrome should be screened early for G6PD deficiency.