In 2017, the Food and Drug Administration approved 2 medications for sickle cell anemia (SCA): hydroxyurea for children and l-glutamine for children and adults. The approval of hydroxyurea was long overdue, but the approval of l-glutamine was a surprise to many. Any effective new treatment for SCA is a welcome advance, but there are few published studies of l-glutamine as a specific treatment for SCA. Accordingly, there are many unanswered questions about its efficacy, safety, and role in current therapy. Abstract source Full text

Background: Children with sickle cell anemia and sickle cell trait are at an increased risk of invasive pneumococcal disease compared to children with normal hemoglobin. We assessed and compared pneumococcal vaccination status among these three groups. Procedure: Children with sickle cell anemia and sickle cell trait were identified using Michigan newborn screening records (1997-2014); each child was matched to four children with normal hemoglobin based on age, Medicaid enrollment (at least 1 year from 2012-2014), race, and census tract. Vaccination records were obtained from the state's immunization system. Pneumococcal vaccine coverage (PCV7 or PCV13 depending on date of administration) was assessed at milestone ages of 3, 5, 7, and 16 months. The proportion of children with vaccine coverage at each milestone was calculated overall and compared among children with sickle cell anemia, sickle cell trait, and normal hemoglobin using chi-square tests. Results: The study population consisted of 355 children with sickle cell anemia, 17,319 with sickle cell trait, and 70,757 with normal hemoglobin. The proportion of children with age-appropriate pneumococcal vaccination coverage was low at each milestone and generally decreased over time. Children with sickle cell anemia were more likely to be covered compared to children with sickle cell trait or normal hemoglobin. Conclusions: Despite higher pneumococcal vaccination coverage among children with sickle cell anemia, opportunities for improvement exist among all children. Targeted interventions will benefit from mechanisms to identify children with increased risks such as sickle cell anemia or trait to improve pneumococcal vaccination coverage among these groups. Abstract source Full text

Despite its rarity in the United States, sickle cell disease accounts for a disproportionate amount of healthcare utilization and costs. The majority of this is due to acute care for painful crises. A small subpopulation of patients accounts for most these costs due to frequent visits to emergency departments and acute care facilities. Previous investigations have found that these high utilizing patients are distinguished by both a more severe disease course and certain non-hematologic characteristics, which may include higher socioeconomic status and some psychiatric and psychological characteristics. This prospective observational cohort study was undertaken to test the ability of these characteristics to prospectively predict acute pain care outcomes, including visit frequency, total opioid doses, and pain improvement at the Johns Hopkins Sickle Cell Infusion Center (SCIC). Seventy-three participants were followed for 12 months and SCIC utilization and treatment outcomes were tabulated for 378 visits. Participants who visited the SCIC most frequently had markedly worse pain improvement despite higher within-visit opioid doses. Higher utilization was associated with indicators of greater illness severity, more aggressive treatment for sickle cell disease, higher baseline opioid doses, higher socioeconomic status, greater pain-related anxiety, and a history of psychiatric treatment. Overall, poor acute pain treatment response was associated with higher utilization and higher baseline opioid doses. The pattern of association between high utilization, poor acute care outcomes, and higher baseline opioid doses is discussed in terms of prior research and future directions. Abstract source Full text

Background: Globally, sickle cell disease (SCD) is one of the commonest severe monogenic disorders, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Red blood cell (RBC) transfusions are used to treat complications of SCD, e.g. acute chest syndrome (ACS) (this often involves a single transfusion episode), or they can be part of a regular long-term transfusion programme to prevent SCD complications. Objectives: To summarize the evidence in Cochrane Reviews of the effectiveness and safety of RBC transfusions versus no transfusion, or restrictive (to increase the total haemoglobin) versus liberal (to decrease the haemoglobin S level below a specified percentage) transfusion, for treating or preventing complications experienced by people with SCD. Methods: We included Cochrane Reviews of randomised or quasi-randomised controlled trials published in the Cochrane Database of Systematic Reviews, that addressed various SCD complications and had RBC transfusion as an intervention or comparator. We assessed the methodological quality of included reviews according to the AMSTAR quality assessment. Main Results: We included 15 Cochrane Reviews, 10 of which had no included studies with an RBC transfusion intervention (five reported RCTs with other interventions; and five contained no studies). Five of the 15 reviews included participants randomised to RBC transfusion, but in one of these reviews only 10 participants were randomised with no usable data. Four reviews (nine trials with 1502 participants) reported data comparing short- or long-term RBC transfusions versus standard care, disease-modifying agents, a restrictive versus a liberal transfusion strategy and long-term RBC transfusions versus transfusions to treat complications. All reviews were of high quality according to AMSTAR quality assessment, however, the quality of the included trials was highly variable across outcomes. Trials were downgraded according to GRADE methodology for risk of bias, indirectness (most trials were conducted in children with HbSS), and imprecision (outcomes had wide confidence intervals). Authors' Conclusions: This overview provides support from two high-quality Cochrane Reviews for the use of RBC transfusions in preventing stroke in children and adolescents at high risk of stroke (abnormal TCDs or SCI) and evidence that it may decrease the risk of SCI in children with abnormal TCD velocities. In addition RBC transfusions may reduce the risk of ACS and painful crisis in this population. This overview highlights the lack of high-quality evidence in adults with SCD and the number of reviews that have no evidence for the use of RBC transfusions across a spectrum of SCD complications. Also of concern is the variable and often incomplete reporting of patient-relevant outcomes in the included trials such as SCD-related serious adverse events and quality of life. Abstract source Full text

In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi-center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sβ°) during the first 2 years of life (ClinicalTrials.gov: NCT01207037). Time to first occurrence of a severe clinical event-acute splenic sequestration (ASS), vaso-occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death-was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ±1 months. Median follow-up was 19.4 months. During the study period, 38.6% of infants experienced >=1 severe event: 14% ASS, 22.8% >= 1 VOC (median age: 13.4 and 12.8 months, respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or ϒ-globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43), respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for subsequent severe complications, who might maximally benefit from early disease modifying treatments. Abstract source Full text

Sickle cell disease (SCD) pain associates with cold temperature and touch. Patients and murine models with SCD have baseline thermal and mechanical pain. In SCD mice, the baseline hypersensitivity is exacerbated by experimental vaso-occlusive crises. We hypothesized that patients with SCD will similarly experience increased hypersensitivity to thermal and mechanical stimuli during acute painful events compared with baseline health. We conducted a prospective study of 24 patients with SCD aged 7 to 19 years. Patients underwent quantitative sensory testing to thermal (cold/heat) and mechanical stimuli on the thenar eminence of the nondominant hand (glabrous skin) and the lateral dorsum of the foot (hairy skin) during baseline health and within 48 hours of hospitalization for acute pain. Primary outcomes were changes in: (1) cold pain threshold (°C), (2) heat pain threshold (°C), and (3) mechanical pain threshold (g). Median age was 10.5 (interquartile range [IQR] 9-14.8) years, 67% were females, and 92% were on hydroxyurea. Patients with SCD had increased cold pain sensitivity in the hand during hospitalization compared with baseline (25.2°C [IQR 18.4-27.5°C] vs 21.3°C [IQR 4.9-26.2°C]; P = 0.011) and increased mechanical pain sensitivity in the foot during hospitalization (0.32 g [IQR 0.09-1.1 g] vs 1.7 g [IQR 0.4-8.3 g]; P = 0.003). There were no differences in heat pain sensitivity. The increased cold (P = 0.02) and mechanical (P = 0.0016) pain sensitivity during hospitalization persisted after adjusting for age, sex, hydroxyurea use, opioid consumption, and numeric pain score. Thus, cold and mechanical pain is significantly worse during an acute SCD painful event as compared to baseline health in patients with SCD. Abstract source Full text

Objective: To evaluate the impact of an initiative to increase hydroxyurea use among children with sickle cell anemia (SCA) who presented to the emergency department (ED). Study Design: This observational cohort study included children with SCA not taking hydroxyurea who presented to the ED with pain or acute chest syndrome and then attended a Quick-Start Hydroxyurea Initiation Project (Q-SHIP) session. A Q-SHIP session includes a hematologist-led discussion on hydroxyurea, a video of patients talking about hydroxyurea, and a direct offer to start hydroxyurea. Results: Over 64 weeks, 112 eligible patients presented to the ED and 59% (n = 66) participated in a Q-SHIP session a median of 6 days (IQR 2, 20 days) after ED or hospital discharge; 55% of participants (n = 36) started hydroxyurea. After a median follow-up of 49 weeks, 83% (n = 30) of these participants continued hydroxyurea. Laboratory markers of hydroxyurea adherence were significantly increased from baseline: median mean corpuscular volume +8.6 fL (IQR 5.0, 17.7, P < .0001) and median hemoglobin F +5.7% (IQR 2.5, 9.8, P = .0001). Comparing Q-SHIP participants to nonparticipants, 12 weeks after ED visit, participants were more likely to have started hydroxyurea than nonparticipants (53% vs 20%, P = .0004) and to be taking hydroxyurea at last follow-up (50% vs 20%, P = .001). Two years after the implementation of Q-SHIP the overall proportion of eligible patients on hydroxyurea presenting to our ED increased from 56% to 80%, P = .0069. Conclusions: Participation in a clinic to specifically address starting hydroxyurea after a SCA complication increases hydroxyurea use. Abstract source Full text

The ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs Day Hospital) trial is an ongoing prospective study comparing outcomes of people with sickle cell disease (SCD) seeking care for acute pain management in either an emergency department or specialty infusion clinic. The objective of this paper is to describe the baseline characteristics and health care utilization of patients in the trial. This is a multicenter study across 4 US cities that enrolled all adults with SCD living within 60 miles (96.6 km) of a study site who were expected to have acute care utilization over the study period. Twenty-one percent of participants had no acute care visits in the first 12 months of follow-up. Using negative binomial regression, we describe subject characteristics that predict acute care utilization. Three hundred ninety-one subjects have completed 12 months of follow-up with a mean age of 34.5 years (standard deviation, 11.4), 60% are female. Fifty-four percent of subjects with hemoglobin SS disease and 46% with hemoglobin SC disease had 3 or more acute visits over the study period. The prevalence of chronic pain in this cohort was 68%. Predictors of higher rates of acute care utilization included being unemployed, having chronic pain, being on chronic transfusion therapy, having a history of stroke, and being on disability or on Medicaid. This is the first prospective cohort in the modern era, and it demonstrates much higher rates of acute care utilization than reported in the Cooperative Study of Sickle Cell Disease. Abstract source Full text

Sickle cell disease (SCD) is a common, life-threatening genetic disorder that is best managed when diagnosed early by newborn screening. However, SCD is most prevalent in low-resource regions of the world where newborn screening is rare and diagnosis at the point-of-care is challenging. In many such regions, the majority of affected children die, undiagnosed, before the age of 5 years. A rapid and affordable point-of-care test for SCD is needed. The diagnostic accuracy of HemoTypeSC, a point-of-care immunoassay, for SCD was evaluated in individuals who had SCD, hemoglobin C disease, the related carrier (trait) states, or a normal hemoglobin phenotype. Children and adults participated in low-, medium- and high-resource environments (Ghana [n = 383], Martinique [n = 46], and USA [n = 158]). Paired blood specimens were obtained for HemoTypeSC and a reference diagnostic assay. HemoTypeSC testing was performed at the site of blood collection, and the reference test was performed in a laboratory at each site. In 587 participants, across all study sites, HemoTypeSC had an overall sensitivity of 99.5% and specificity of 99.9% across all hemoglobin phenotypes. The test had 100% sensitivity and specificity for sickle cell anemia. Sensitivity and specificity for detection of normal and trait states were >99%. HemoTypeSC is an inexpensive (<$2 per test), accurate, and rapid point-of-care test that can be used in resource-limited regions with a high prevalence of SCD to provide timely diagnosis and support newborn screening programs. Abstract source Full text

Background: Globally, sickle cell disease (SCD) is one of the most common haemoglobinopathy. Considered a public health problem, it leads to vessel occlusion, blood stasis and chronic activation of the coagulation system responsible for vaso-occlussive crises and venous thromboembolism (VTE) which may be fatal. Although contemporary observational studies suggest a relationship between SCD or sickle trait (SCT) and VTE, there is lack of a summary or meta-analysis data on this possible correlation. Hence, we propose to summarize the available evidence on the association between SCD, SCT and VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE). Methods: We searched PubMed and Scopus to identify all cross-sectional, cohort and case-control studies reporting on the association between SCD or SCT and VTE, DVT or PE in adults or children from inception to April 25, 2017. For measuring association between SCD or SCT and VTE, DVT, or PE, a meta-analysis using the random-effects method was performed to pool weighted odds ratios (OR) of risk estimates. Results: From 313 records initially identified from bibliographic databases, 10 studies were eligible and therefore included the meta-analysis. SCD patients had significantly higher risk for VTE (pooled OR 4.4, 95%CI 2.6-7.5, p < 0.001), DVT (OR 1.1, 95% CI 1.1-1.2, p < 0.001) and PE (pooled OR 3.7, 95% CI 3.6-3.8, p < 0.001) as compared to non SCD-adults. A higher risk of VTE (OR 33.2, 95% CI 9.7-113.4, p < 0.001) and DVT (OR 30.7, 95% CI 1.6-578.2, p = 0.02) was found in pregnant or postpartum women with SCD as compared to their counterparts without SCD. Compared to adults with SCT, the risk of VTE was higher in adults with SCD (pooled OR 3.1, 95% CI 1.8-5.3, p < 0.001), and specifically in SCD pregnant or postpartum women (OR 20.3, 95% CI 4.1-102, p = 0.0003). The risk of PE was also higher in adults with SCD (OR 3.1, 95% CCI 1.7-5.9, p = 0.0004) as compared to those with SCT. The risk of VTE was higher in individuals with SCT compared to controls (pooled OR 1.7, 95% CI 1.3-2.2, p < 0.0001), but not in pregnant or postpartum women (OR 0.9, 95% CI 0.3-2.9, p = 0.863). Compared to controls, SCT was associated with a higher risk of PE (pooled OR 2.1, 95% CI 1.2-3.8, p = 0.012) but not of DVT (pooled OR 1.2, 95% CI 0.9-1.7, p = 0.157). Conclusion: Individuals with SCD, especially pregnant or postpartum women, might have a higher risk of VTE compared to the general population. SCT might also increases the risk of VTE. However, currently available data are not sufficient to allow a definite conclusion. Further larger studies are needed to provide a definitive conclusion on the association between SCD, SCT and VTE. Abstract source Full text