Browsing by Author "Shah, Binal N."

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    Biomarkers of Clinical Severity in Treated and Untreated Sickle Cell Disease: A Comparison by Genotypes of a Single Center Cohort and African Americans in the NHANES Study
    (Wiley, 2021) Njoku, Franklin; Zhang, Xu; Shah, Binal N.; Machado, Roberto F.; Han, Jin; Saraf, Santosh L.; Gordeuk, Victor R.; Medicine, School of Medicine
    Haemolysis and vaso-occlusion underlie multi-organ system complications in sickle cell disease (SCD). We assessed real-world biomarkers in University of Illinois adult SCD patients, categorised as severe (HbSS/Sβ0 -thalassaemia; n = 342) or mild (HbSC/Sβ+ -thalassaemia; n = 100) genotypes and stratified according to treatment. African-American controls from the National Health and Nutrition Examination Survey (NHANES) were matched with each genotype category. Most measures of haemolysis, anaemia, inflammation and function of kidneys, liver and lungs differed markedly in untreated severe genotype patients compared to NHANES controls. These same biomarkers were significantly closer to the NHANES control range in untreated mild versus severe genotype patients, but they were not improved in severe genotype patients receiving treatment with hydroxycarbamide or blood transfusions, except that haemoglobin and HbF were higher with hydroxycarbamide. Systolic blood pressures did not differ among the SCD and NHANES groups, but diastolic pressures were higher in mild genotype patients. Ferritin in severe genotype patients on chronic transfusions was 50-fold higher than NHANES controls. The cross-sectional real-world biomarkers of patients on hydroxycarbamide or transfusions were not markedly improved compared to untreated patients. This may be due partly to poor compliance or more severe disease. Our findings highlight the need for more effective treatments.
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    The CYB5R3c.350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease
    (Wiley, 2020-11) Gordeuk, Victor R.; Shah, Binal N.; Zhang, Xu; Thuma, Philip E.; Zulu, Stenford; Moono, Rodgers; Reading, N. Scott; Song, Jihyun; Zhang, Yingze; Nouraie, Mehdi; Campbell, Andrew; Minniti, Caterina P.; Rana, Sohail R.; Darbari, Deepika S.; Kato, Gregory J.; Niu, Mei; Castro, Oswaldo L.; Machado, Roberto; Gladwin, Mark T.; Prchal, Josef T.; Medicine, School of Medicine
    Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (β = 0.29, P = .022 children; β = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.
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    Haptoglobin 1 allele predicts higher serum haptoglobin concentration and lower multiorgan failure risk in sickle cell disease
    (ASH Publications, 2022-12-22) Ruiz, Maria A.; Shah, Binal N.; Ren, Guohui; Hussain, Faiz; Njoku, Franklin; Machado, Roberto F.; Gordeuk, Victor R.; Saraf, Santosh L.; Medicine, School of Medicine
    Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.
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    The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis
    (Public Library of Science, 2020-10-19) Mousa, Andria; Al-Taiar, Abdullah; Anstey, Nicholas M.; Badaut, Cyril; Barber, Bridget E.; Bassat, Quique; Challenger, Joseph D.; Cunnington, Aubrey J.; Datta, Dibyadyuti; Drakeley, Chris; Ghani, Azra C.; Gordeuk, Victor R.; Grigg, Matthew J.; Hugo, Pierre; John, Chandy C.; Mayor, Alfredo; Migot-Nabias, Florence; Opoka, Robert O.; Pasvol, Geoffrey; Rees, Claire; Reyburn, Hugh; Riley, Eleanor M.; Shah, Binal N.; Sitoe, Antonio; Sutherland, Colin J.; Thuma, Philip E.; Unger, Stefan A.; Viwami, Firmine; Walther, Michael; Whitty, Christopher J. M.; William, Timothy; Okell, Lucy C.; Pediatrics, School of Medicine
    Background Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as ‘test-and-treat’ policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. Methods and findings A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case–control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle–Ottawa scale, and all studies were ranked as ‘Good’, scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07–1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92–4.06; p < 0.001) for a delay of 2–3 days and 5.46 (95% CI: 3.49–8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24–4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70–9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. Conclusions Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.