Najat Mahdi

The relation of C-reactive protein to vasoocclusive crisis in children with sickle cell disease

In view of evidence linking sickle cell anemia (SCA) with chronic inflammation, and given the role of high sensitivity C-reactive protein (hs-CRP) as inflammatory mediator, we hypothesized that SCA vasoocclusive crisis (VOC) is associated with heightened hs-CRP levels. Study subjects comprised 104 SCA patients who experienced VOC event during the study period (VOC group), and 40 SCA patients who did not develop VOC for at least 9 months prior to blood collection (Steady-state group). hs-CRP determination was done by latex-enhanced nephelometry. Higher hs-CRP levels were seen in VOC [median(range)=31.3(1.14-363.0)] than steady-state [median(range)=5(0.16-185.0)] groups (P<0.001), with enrichment in high hs-CRP percentiles in VOC cases, which translated into step-wise increased VOC risk. Receiver-operating characteristic (ROC) analysis was employed in assessing the usefulness of hs-CRP as predictor of the frequency and severity of VOC. Spearmans correlation coefficient between hs-CRP and VOC was 0.65 (P<0.001) among unselected patients (0.71 in males and 0.59 in females). hs-CRP area under ROC curves was 0.90 (95% CI=0.85-0.94) among unselected patients, 0.94 (95% CI=0.89-0.98) for males, and 0.85 (95% CI=0.77-0.93) for females. Logistic regression analysis confirmed the positive association of increased hs-CRP levels with VOC, which correlated positively with VOC frequency (P<0.001), type (P<0.001), pain (P<0.001), and need for hospitalization (P=0.024). These data support strong association of increased hs-CRP levels with VOC, which impacts VOC-related parameters, and support a role for hs-CRP in VOC follow-up.

Serum IL-6, IL-10, and TNFα levels in pediatric sickle cell disease patients during vasoocclusive crisis and steady state condition

Vaso-occlusive crisis (VOC) is a significant complication of sickle cell disease (SCD), and altered production of pro-inflammatory and anti-inflammatory molecules contributed to its pathogenesis. In view of the association of chronic inflammation with VOC onset, and given the capacity of interleukin (IL)-10 as anti-inflammatory, and IL-6, and TNFα as pro-inflammatory cytokines, we tested the association of altered IL-10, IL-6, and TNFα secretion with VOC pathogenesis and its severity. Study subjects comprised 147 SCD patients with active VOC (VOC Group), and 63 pain-free SCD patients for at least 9 months before blood collection (Steady-state Group). Serum cytokine concentrations were determined by ELISA. IL-10 levels were significantly reduced, while IL-6 levels were increased in VOC compared to Steady-state groups; serum TNFα levels were comparable between both groups. There was enrichment of low IL-10, but high IL-6 and TNFα quartiles in VOC Group, which translated into increased VOC risk. In contrast, high IL-10, but low IL-6 and TNFα quartiles were seen in Steady-state Group. Correlation analysis demonstrated significant association between reduced IL-10 levels and the frequency, type, severity, and duration of VOC and requirement for hydroxyurea treatment, while IL-6 correlated with duration of VOC episodes. Our data support strong association of reduced IL-10 and increased IL-6 levels with VOC, and their modulation of VOC-related parameters.

The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease

The association of vascular endothelial growth factor (VEGFA) variants and VEGF secretion with sickle cell disease (SCD) vasoocclusive crisis (VOC) was investigated in 210 VOC patients and 114 pain‐free control patients.

Depression, anxiety, and stress comorbidities in sickle cell anemia patients with vaso-occlusive crisis.

We investigated the association of sickle cell anemia (SCA) vaso-occlusive crisis (VOC) with depression, anxiety, and stress disorders among Bahraini patients and controls. This was a cross-sectional study that involved administering Depression Anxiety Stress Scales (DASS-21) consisting of structured depression, anxiety, and stress scales to SCA patients with (n=138) and without (n=105) VOC. Multinomial regression and correlation analysis were used in assessing the association of VOC with depression and/or anxiety and/or stress, after adjusting for other covariates. Significantly higher proportion of VOC patients was found among the severe-extremely severe anxiety (P<0.002) and stress (P=0.001) groups; the frequency of depressed patients was comparable between the 2 groups. Adjusting for age, sex, income, number of affected individuals per family, and HbS levels, mild-moderate (P=0.042; odds ratio=2.00; 95% confidence interval=1.03-3.91) and severe-extremely severe (P=0.004; odds ratio=4.43; 95% confidence interval=1.59-12.34) anxiety were independently associated with VOC. Both depression and stress were not associated with VOC after adjusting for these covariates. These results suggest a positive contribution of VOC to the increased rates of anxiety disorders among SCA patients, thereby recommending counseling SCA patients with repeated VOC for these psychologic comorbidities, in particular anxiety.

QTc Interval and QT Dispersion in patients with Thalassemia Major: electrocardiographic (eKG) and echocardiographic evaluation

Background Doppler echocardiographic studies in patients with β-Thalassemia Major (β-TM) had shown different patterns of left ventricle (LV) systolic and diastolic dysfunctions. Aim This cross-sectional study was designed to study the LV systolic and diastolic function in patients with β-TM using Pulsed Doppler (PD) Echocardiogram and assess the QTc interval and QT dispersion (QTd) on 12 leads ECG. Method All patients were evaluated clinically as well as by echocardiography and 12 leads ECG. The study included patients with β-TM (n = 38, age 15.7 ± 8.9 years), compared with an age-matched healthy control group (n = 38, age 15.9 ± 8.9 years). Results In 38 patients with β-TM Compared with healthy control group, The QTc interval and the QTd dispersion on ECG were increased with no significant difference mode echo showed that β-TM patients have thicker LV septal wall index (0.659 ± 0.23 vs. 0.446 ± 0.219 cm/M2, P < 0.001), posterior wall index (0.659 ± 0.235 vs. 0.437 ± 0.214 cm/M2, P < 0.01), and larger LVEDD index is (3.99 ± 0.48 vs. 2.170 ± 0.57 cm/M2. P < 0.05). Pulsed Doppler showed high LV trans-mitral E wave velocity index (70.818 ± 10.139 vs. 57.532 ± 10.139, P < 0.05) and E/A ratio (1.54 vs.1.23, P < 0.01). The duration of deceleration time index (DT) and isovolumic relaxation time index (IVRT) were significantly shorter in patients with β-TM (150.234 ± 20.0.23 vs. 167.123 ± 167.123 ± 19.143 msec/M2, P < 0.01) and (60.647 ± 6.77 vs. 75.474 ± 5.83 msec/M2, P < 0.001), respectively. The tricuspid valve velocity in patients with β-TM was significantly higher than controls (2.993 ± 0.569 vs. 1.93 ± 0.471 m/sec, respectively, P < 0.01), with calculated pulmonary artery pressure of 2.4 times the control (36.0 vs. 14.8 mmHg). However, the LVEF% or fractional shortening were not significantly different. Conclusion In this study, β-thalassemia major patients compared with controls have differences of QT dispersion and corrected QT interval that is of no statistical significance. A significantly thicker LV wall and LV diastolic filling indices are suggestive of restrictive diastolic pattern. These data indicate that LV diastolic abnormalities compromised initially in patients with β-thalassemia major.

Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso-occlusive crisis

Objectives:  Vaso‐occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients. Insofar as polymorphism in human platelet alloantigen (HPA) exhibit a prothrombotic nature, we hypothesized that specific HPA polymorphic variants are associated with VOC. We investigated the distribution of HPA1, HPA2, HPA3, HPA4, and HPA5 alleles genotypes among VOC and non‐VOC control SCA patients.

Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia

We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.

Pulsed and Tissue Doppler Echocardiographic Changes in Patients with Thalassemia Major

Background Doppler echocardiographic studies of left ventricle (LV) systolic and diastolic function in patients with β-Thalassemia Major (β-TM) had shown different patterns of systolic and diastolic dysfunction. Aim This cross-sectional study was designed to study the LV systolic and diastolic function in patients with β-TM using Pulsed Doppler (PD) and Tissue Doppler (TD) echocardiography. Methods All patients were evaluated clinically and by echocardiography, The study included patients with β-TM (n = 38, age 15.7 ± 8.9 years) compared with an age-matched control group (n = 38, age 15.9 ± 8.9 years). The pulse Doppler indices were normalized for age and heart rate. Results Compared with control patients, M-Mode showed that patients with β-TM have thicker LV septal wall index (0.659 ± 0.23 vs. 0.446 ± 0.219 cm, P ≤ 0.001), posterior wall index (0.659 ± 0.235 vs. 0.437 ± 0.214 cm, P ≤ 0.01), and larger LVEDD index is (3.99 ± 0.48 vs. 2.170 ± 0.57 mm. P = 0.035). Pulsed Doppler showed high LV trans-mitral E wave velocity (70.818 ± 10.139 vs. 57.532 ± 10.139, p = 0.027) and E/A ratio (1.54 vs. 1.23, P ≤ 0.01). The duration of Deceleration time (DT) and isovolumic relaxation time (IVRT) were significantly shorter in patients with β-TM (150.234 ± 20.0.23 vs. 167.123 ± 19.143 msec, P ≤ 0.01) and (60.647 ± 6.77 vs. 75.474 ± 5.83 msec, P ≤ 0.001), respectively. The ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus E/Em– was significantly higher in β-TM group (14.024 ± 2.29 vs. 12.132 ± 1.82, P ≤ 0.01). The Tissue Doppler systolic velocity (Sm) and the early diastolic velocity (Em) were significantly lower in β-TM group compared to control (4.31 ± 1.2 cm/s vs. 6.95 ± 2.1, P ≤ 0.01 and 4.31 ± 2.7 cm/s vs. 5.82 ± 2.5, P ≤ 0.01) respectively. The tricuspid valve velocity was significantly higher than controls (2.993 ± 0.569 vs. 1.93 ± 0.471 m/sec, respectively, P ≤ 0.01). However, the LVEF% and fractional shortening were normal with no significant difference in both groups. Conclusion In this study, patients with β-thalassemia major compared with controls, have significantly thicker LV wall, and larger LV cavity and LV diastolic filling indices suggestive of restrictive pattern with a higher tricuspid valve velocity. These data showed that left ventricle diastolic indices are compromised initially in patients with β-thalassemia major.

The impact of two different doses of chelating therapy (deferasirox) on echocardiographic tissue Doppler indices in patients with thalassemia major

Background:  Chelating therapy in transfusion‐dependent patients with β‐thalassemia major (β‐TM) is mandatory to reduce the toxic effect of iron on the myocardium.

The pro-BNP Serum Level and Echocardiographic Tissue Doppler Abnormalities in Patients with Beta Thalassemia Major

Background Doppler echocardiographic studies of the left ventricle (LV) function in patients with β-Thalassemia Major (β-TM) had shown different patterns of systolic and diastolic dysfunctions associated with abnormal serum brain natriuretic peptide (BNP). Aim This cross-sectional study was designed to study the LV systolic and diastolic functions and correlate that with serum level of N-terminal pro brain natriuretic hormone (NT- pro BNP) in patients with β-TM using Pulsed Doppler (PD) and Tissue Doppler (TD) echocardiography. Methods The study was conducted on patients with β-TM (n = 38, age 15.7 ± 8.9 years) and compared with an age-matched controls (n = 38, age 15.9 ± 8.9 years). In all participants, PD and TD echocardiography were performed and blood samples were withdrawn for measuring the serum level of NT-pro BNP, ferritin, and alanine transaminase. Results Patients with β-TM compared with controls, have thicker LV septal wall index (0.65 ± 0.26 vs. 0.44 ± 0.21 cm, P < 0.001), posterior wall index (0.65 ± 0.23 vs. 0.43 ± 0.21 cm, P < 0.01), and larger LVEDD index (4.35 ± 0.69 vs.3.88 ± 0.153 mm, P < 0.001). In addition, β-TM patients have higher transmitral E wave velocity (E) (70.818 ± 10.139 vs. 57.532 ± 10.139, p = 0.027) and E/A ratio (1.54 ± 0.17 vs. 1.23 ± 0.19, P < 0.01) and shorter deceleration time (DT) (160.13 ± 13.3 vs. 170.50 ± 19.20 m sec, P < 0.01). Furthermore, the ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em–) was significantly higher in β-TM group (19.6 ± 2.81 vs. 13.868 ± 1.41, P < 0.05). The tissue doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in β-TM group compared to controls (Sm: 4.82 ± 1.2 vs. 6.22 ± 2.1 mm/sec, P < 0.05; Em: 3.51 ± 2.7 vs. 4.12 ± 2.5 mm/sec P < 0.05, respectively). The tricuspid valve velocity was significantly higher in β-TM patients compared with controls (2.993 ± 0.569 vs. 1.93 ± 0.471 m/sec, respectively, P < 0.01). The mean serum NT pro-BNP in β-TM was significantly higher compared with controls (37.6 ± 14.73 vs. 5.5 ± 5.4pg/ml, P < 0.05). The left ventricle ejection fraction (EF%) and fractional shortening (FS%) were not significantly different between both groups. Conclusion We conclude that patients with β-TM had a significantly higher serum level of NT-pro BNP that is positively correlated with the E/Em ratio on tissue Doppler. Furthermore, we confirm our previous findings that patients with β-TM exhibit LV diastolic pattern on echocardiogram suggestive of restrictive type with well preserved left ventricle systolic function.