Review/overview of pain in sickle cell disease

Sickle cell disease (SCD) is a highly complex inherited disorder of hemoglobin structure. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Its manifestations could be acute, chronic, nociceptive, neuropathic that could occur singly or in various combinations. Pain continues to be the major factor of SCD phenotypic complications and the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing curative therapies such as hematopoietic stem cell transplantation and gene therapy, effective pain management continues to lag behind. Palliative therapies continue to be the major approach to the management of SCD and its complications. The advent of hydroxyurea made partial success in preventing the frequency of vaso-occlusive crises and l-glutamine awaits post-trial confirmation of benefits. The search for additional pharmacotherapeutic agents that could be used singly or in combination with hydroxyurea and/or l-glutamine awaits their dawn hopefully in the near future. The purpose of this review is to describe the various manifestations of SCD, their pathophysiology and their current management. Recent impressive advances in understanding the pathophysiology of pain promise the determination of agents that could replace or minimize the use of opioids.     

Vein of Galen and sinus thrombosis with bilateral thalamic infarcts in sickle cell anaemia: CT follow-up and angiographic demonstration

A 2-year-old boy with known sickle cell disease presented in acute coma. CT revealed bilateral thalamic infarcts and incomplete sinus thrombosis. Angiography confirmed thrombosis of the straight sinus and vein of Galen.     

Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.     

Influenza immunization coverage of children with sickle cell disease

ObjectivesTo assess receipt of annual flu immunization among children living with sickle cell disease (SCD).MethodsReceipt of flu immunization (2014–2019) by SCD status was assessed among all Michigan children <18 years of age using the statewide immunization registry. Logistic regression was used to estimate the odds of annual flu immunization by SCD status and age.ResultsAnnual flu immunization coverage was higher among children with SCD (46.9%; n = 751) than without (23.2%; n = 2,012,846). The annual adjusted odds of flu immunization for those with SCD were 2.8 (95% CI: 2.5–3.1) times higher than for those without SCD; there were no significant differences by age among children with SCD. Among those without SCD, adolescents aged 13–17 were 2.2 (95% CI: 2.2–2.2) times less likely to receive annual flu immunization than children 6–35 months.ConclusionsChildren with SCD had higher annual flu immunization rates than those without SCD, but >50% remain unimmunized.     

Pharmacokinetics of arginine butyrate in patients with hemoglobinopathy

Recent reports have demonstrated improvement in the clinical status and hemoglobin levels with use of intravenous arginine butyrate in patients with homozygous β-thalassemia and sickle cell disease.

To allow optimalization of therapy, we conducted pharmacokinetic studies in nine patients, five with sickle cell disease and four with β-thalassemia, treated with continuous intravenous infusion of arginine butyrate.

The disappearance of the drug after discontinuation was characterized by a biphasic elimination with an initial rapid phase followed by a slower phase. Redistribution was noted in five of the patients after 11.2 ± 4.0 min. The short half life was the result of both rapid clearance rate of 93.6 ± 31.9 ml/kg/min and small Vc (0.21 ± 0.26 l/kg) and Vss (0.31 ± 0.37 l/kg).

While preliminary results of the effectiveness of arginine butyrate are encouraging with a rise of γ-globin mRNA and F reticulocytes in some patients, the rapid elimination of this agent will probably limit its current use to administration by continuous infusion.     

Septic complications after splenectomy for sickle cell sequestration crisis

Patients with sickle cell disease (SCD) are predisposed to infections. There is a paucity of recent information on the incidence of post-splenectomy infectious complications in these patients. The purpose of this study was to determine whether splenectomy increases infectious complications in SCD. Twenty-nine patients with SCD had splenectomy for sequestration crises at our hospital between 1988 and 1992; 16 of them received all of their follow-up care at our institution. These 16 charts were reviewed for infectious-related admissions, hospital days, days of IV antibiotics, positive cultures, and episodes of sepsis. For each patient, these parameters in the pre- and postoperative period were compared and expressed as number per year. The mean age at time of splenectomy was 2.5 ± 0.4 years and the mean follow-up was 4.5 ± 0.4 years. There was no significant difference in the pre- and postoperative periods for admissions, hospital days, days of IV antibiotics, positive cultures, or episodes of sepsis per year. There were also no operative deaths. The incidence of pre-splenectomy sepsis was 0.04 ± 0.03 episodes per year compared to 0.09 ± 0.04 (P = ns) episodes/year after splenectomy. Sepsis occurred at an average of 20.8 (range 2–30) months postoperatively; Streptococcus pneumoniae was the most common causative organism. The total mortality after splenectomy in SCD patients was 3.4% (1/29) over a nearly 5-year period. Although infections are common in children with SCD, there was no increase in infections or episodes of sepsis in SCD patients who underwent splenectomy. Accepted: 6 March 1997     

Sickle cell disease in pregnancy

With advances in management, many women with sickle cell disease now survive to have children. The high risk of fetal and maternal sequelae mandates multidisciplinary management involving an obstetrician, a haematologist, an anaesthetist and a haemoglobinopathy specialist nurse. Hydroxyurea, a new treatment for sickle cell disease, is contraindicated in pregnancy. Exchange transfusion may be indicated in women with a serious obstetric or haematological complications. In those with sickle cell disease, the entire pregnancy is a high-risk period that warrants close monitoring. It is thus important for every obstetrician to be familiar with the condition.