Pain Frequency and Health Care Utilization Patterns in Women with Sickle Cell Disease Experiencing Menstruation-Associated Pain Crises.

Background: Pain crises in sickle cell disease (SCD) lead to high rates of health care utilization. Historically, women have reported higher pain burdens than men, with recent studies showing a temporal association between pain crisis and menstruation. However, health care utilization patterns of SCD women with menstruation-associated pain crises have not been reported. We studied the frequency, severity, and health care utilization of menstruation-associated pain crises in SCD women. Materials and Methods: A multinational, cross-sectional cohort study of the SCD phenotype was executed using a validated questionnaire and medical chart review from the Consortium for the Advancement of Sickle Cell Research (CASiRe) cohort. Total number of pain crises, emergency room/day hospital visits, and hospitalizations were collected from a subcohort of 178 SCD women within the past 6 months and previous year. Results: Thirty-nine percent of women reported menstruation-associated pain crises in their lifetime. These women were significantly more likely to be hospitalized compared with those who did not (mean 1.70 vs. 0.67, p = 0.0005). Women reporting menstruation-associated pain crises in the past 6 months also experienced increased hospitalizations compared with those who did not (mean 1.71 vs. 0.75, p = 0.0016). Forty percent of women reported at least four menstruation-associated pain crises in the past 6 months. Conclusions: Nearly 40% of SCD women have menstruation-associated pain crises. Menstruation-associated pain crises are associated with high pain burden and increased rates of hospitalization. Strategies are needed to address health care disparities within gynecologic care in SCD.

Sense of mastery and attitude towards illness: Examining longitudinal benefits of a medical specialty camp for youth with sickle cell disease.

Medical specialty camps can play an important role in the positive development of psychosocial outcomes for children and youth with sickle cell disease (SCD). This study examined how sense of mastery and attitude towards illness outcomes changed over 6 months for 100 campers aged 8-16 years with SCD. The outcomes were measured twice before and twice after camp. Latent growth curve modeling was used to analyze data. Results showed no changes in the outcomes for this study population. Implications for future research designs, populations, and outcomes are discussed, as are implications for communications about camp, and policy and practice.

Pain Burden in the CASiRe International Cohort of Sickle Cell Patients: United States and Ghana.

OBJECTIVES: Sickle Cell Disease (SCD) is a genetic blood disorder affecting over 1 million people globally. The aim of this analysis is to explore the pain burden of patients with SCD in two countries: the United States and Ghana. METHODS: The Consortium for the Advancement of Sickle Cell Research (CASiRe) was created to better understand the clinical severity of patients with SCD worldwide. Data regarding gender, SCD genotype, prior medical diagnoses, and validated pain burden measures were analyzed from the CASiRe database. The Sickle Cell Pain Burden Interview (SCPBI) was used to assess pain burden, the impact of pain on physical, emotional, and social function. RESULTS: Most subjects identified as Black/African American (n = 298, 97.0%). Patient ages ranged from 6 to 73 years. 35.9% resided in the United States, 64.1% resided in Ghana, 40.9% were men, and 58.7% were women. The mean SCPBI score for US SCD patients was 6.53(±5.89) vs 4.04(±5.10) for Ghanaian patients, P <0.001. Pain burden was higher in US men vs Ghanaian men (6.74(±5.68) vs 3.54(±4.46), P = .003) and in US women vs Ghanaian women (6.37 ± 6.06 vs 4.44(±5.54), P = .032). Pain burden was higher in US patients than Ghanaian patients for both the Hb SC/SBeta+ genotype (5.40(±5.29) vs 2.82(±4.86), P = .054) and Hb SS/SBeta0 genotype (6.79(±6.01) vs 4.49(±5.13), P = .003). Pain burden was significantly higher in SCD patients with comorbid conditions independent of geographic origin including stroke, cholecystectomy, gallstones, depression, and headache. DISCUSSION: US patients with SCD have a higher pain burden than Ghanaian patients. Further studies should investigate underlying contributors to pain burden in these populations and further explore the etiology of geographic differences in pain.

Global geographic differences in healthcare utilization for sickle cell disease pain crises in the CASiRe cohort.

BACKGROUND: Sickle cell disease (SCD) is characterized by frequent, unpredictable pain episodes and other vaso-occlusive crises (VOCs) leading to significant healthcare utilization. VOC frequency is often an endpoint in clinical trials investigating novel therapies for this devastating disease. PROCEDURE: The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaboration investigating clinical severity in SCD using a validated questionnaire and medical chart review standardized across four countries (United States, United Kingdom, Italy and Ghana). RESULTS: This study, focused on pain crisis incidence and healthcare utilization, included 868 patients, equally represented according to age and gender. HgbSS was the most common genotype. Patients from Ghana used the Emergency Room/Day Hospital for pain more frequently (annualized mean 2.01) than patients from other regions (annualized mean 1.56 U.S.; 1.09 U.K.; 0.02 Italy), while U.K. patients were hospitalized for pain more often (annualized mean: U.K. 2.98) than patients in other regions (annualized mean 1.98 U.S.; 1.18 Ghana; Italy 0.54). Italy's hospitalization rate for pain (annualized mean: 0.57) was nearly 20 times greater than its emergency room/day hospital only visits for pain (annualized mean: 0.03). When categorized by genotype and age, similar results were seen. CONCLUSIONS: Geographic differences in pain crisis frequency and healthcare utilization may correlate with variable organization of healthcare systems among countries and should be considered regarding trial design, endpoints, and analysis of results when investigating novel agents for clinical benefit.

Age of first pain crisis and associated complications in the CASiRe international sickle cell disease cohort.

Pain is a hallmark of Sickle Cell Disease (SCD) affecting patients throughout their life; the first pain crisis may occur at any age and is often the first presentation of the disease. Universal newborn screening identifies children with SCD at birth, significantly improving morbidity and mortality. Without early screening, diagnosis is generally made after disease manifestations appear. The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaborative group evaluating the clinical severity of subjects with SCD using a validated questionnaire and medical chart review, standardized across 4 countries (United States, United Kingdom, Italy and Ghana). We investigated the age of first pain crisis in 555 sickle cell subjects, 344 adults and 211 children. Median age of the first crisis in the whole group was 4 years old, 5 years old among adults and 2 years old among children. Patients from the United States generally reported the first crisis earlier than Ghanaians. Experiencing the first pain crisis early in life correlated with the genotype and disease severity. Early recognition of the first pain crisis could be useful to guide counseling and management of the disease.

An Analysis of Racial and Ethnic Backgrounds Within the CASiRe International Cohort of Sickle Cell Disease Patients: Implications for Disease Phenotype and Clinical Research.

Millions are affected by sickle cell disease (SCD) worldwide with the greatest burden in sub-Saharan Africa. While its origin lies historically within the malaria belt, ongoing changes in migration patterns have shifted the burden of disease resulting in a global public health concern. We created the Consortium for the Advancement of Sickle Cell Research (CASiRe) to understand the different phenotypes of SCD across 4 countries (USA, UK, Italy, and Ghana). Here, we report the multi-generational ethnic and racial background of 877 SCD patients recruited in Ghana (n = 365, 41.6%), the USA (n = 254, 29%), Italy (n = 81, 9.2%), and the UK (n = 177, 20.2%). West Africa (including Benin Gulf) (N = 556, 63.4%) was the most common geographic region of origin, followed by North America (N = 184, 21%), Caribbean (N = 51, 5.8%), Europe (N = 27, 3.1%), Central Africa (N = 24, 2.7%), and West Africa (excluding Benin Gulf) (N = 21, 2.4%). SCD patients in Europe were primarily West African (73%), European (10%), Caribbean (8%), and Central African (8%). In the USA, patients were largely African American (71%), Caribbean (13%), or West African (10%). Most subjects identified themselves as Black or African American; the European cohort had the largest group of Caucasian SCD patients (8%), including 21% of the Italian patients. This is the first report of a comprehensive analysis of ethnicity within an international, transcontinental group of SCD patients. The diverse ethnic backgrounds observed in our cohort raises the possibility that genetic and environmental heterogeneity within each SCD population subgroup can affect the clinical phenotype and research outcomes.

Hemoglobin S/Hemoglobin Quebec-Chori Presenting as Sickle Cell Disease: A Case Report.

BACKGROUND: Sickle cell disease is a homozygous hemoglobinopathy with vaso-occlusive complications secondary to abnormal sickling of red blood cells under stressful conditions such as hypoxia. Children with sickle cell trait have a heterozygous genetic state, typically without symptoms. OBSERVATION: An 8-year-old boy diagnosed with sickle cell trait was found to have multiple complications consistent with sickle cell disease, including pain crises, osteomyelitis, and priapism. Over a 6-year period, he underwent routine laboratory evaluations without a definitive diagnosis. The diagnosis of a compound heterozygous state of hemoglobin S/hemoglobin Quebec-Chori was eventually made on the basis of mass spectrometry and confirmed with hemoglobin subunit beta gene sequencing. CONCLUSION: Expanding diagnostic evaluation in patients with abnormal clinical presentations is vital to making the correct diagnosis and hence earlier institution of appropriate management of rare hemoglobinopathies.

A study of the geographic distribution and associated risk factors of leg ulcers within an international cohort of sickle cell disease patients: the CASiRe group analysis.

Vasculopathy is a hallmark of sickle cell disease ultimately resulting in chronic end organ damage. Leg ulcer is one of its sequelae, occurring in ~ 5-10% of adult sickle cell patients. The majority of leg ulcer publications to date have emanated from single center cohort studies. As such, there are limited studies on the geographic distribution of leg ulcers and associated risk factors worldwide. The Consortium for the Advancement of Sickle Cell Research (CASiRe) was formed to improve the understanding of the different phenotypes of sickle cell disease patients living in different geographic locations around the world (USA, UK, Italy, Ghana). This cross-sectional cohort sub-study of 659 sickle cell patients aimed to determine the geographic distribution and risk factors associated with leg ulcers. The prevalence of leg ulcers was 10.3% and was associated with older age, SS genotype, male gender, and Ghanaian origin. In fact, the highest prevalence (18.6%) was observed in Ghana. Albuminuria, proteinuria, increased markers of hemolysis (lower hemoglobin, higher total bilirubin), lower oxygen saturation, and lower body mass index were also associated with leg ulceration. Overall, our study identified a predominance of leg ulcers within male hemoglobin SS patients living in sub-Saharan Africa with renal dysfunction and increased hemolysis.

Identification of risk factors for an unsuccessful transition from pediatric to adult sickle cell disease care.

BACKGROUND: A successful transition from pediatric to adult sickle cell disease (SCD) care is paramount to continued improvements in survival. In order to enhance transition success, our pediatric SCD transition process was modified to include combined adult and pediatric provider clinics that incorporated participation by our local SCD community-based organization. All children ages 16 and over participated in this newly-formed transition program. PROCEDURE: After 5 years of implementation of the modified SCD transition program, we retrospectively studied clinical and non-clinical risk factors for an unsuccessful transition. Risk factor categories studied included patient demographics, transition clinic attendance, and disease severity. RESULTS: Thirty-two percent of patients did not transition successfully. Demographic factors such as gender, race, and type of insurance did not influence transition outcome, although travel distance to the adult SCD center was an identifiable risk factor for an unsuccessful transition. While transition clinic attendance rate did not affect transition outcomes, older age at first modified combined transition clinic visit was a significant risk factor for lack of transition. Patients with clinical markers of milder disease severity (SC and Sß(+) genotypes and no chronic transfusion therapy) were at higher risk for an unsuccessful transition than patients with severe disease. CONCLUSIONS: We have identified several risk factors for lack of transition success which will allow us to modify our transition efforts going forward to capture this highest risk subset.

Severe methemoglobinemia linked to gel-type topical benzocaine use: a case report.

BACKGROUND: Methemoglobinemia is an uncommon cause of tissue hypoxia, but it can be life threatening if it is not identified and treated promptly. OBJECTIVES: To highlight the importance of understanding the potential risks of over-the-counter medications, especially in unsupervised use. Topical benzocaine must be used with caution, even in the healthy population. CASE REPORT: We report a case of methemoglobinemia secondary to topical benzocaine gel. A 6-year-old boy presented to our Pediatric Emergency Department with cyanosis, vomiting, and lethargy after using a gel-type, 7.5% benzocaine (Baby Orajel) for a toothache. Physical examination revealed dusky blue skin, tachycardia, tachypnea, and a normal neurologic examination. His percutaneous oxygen saturation remained 77-83% despite the administration of 100% oxygen. His arterial blood sample had a dark chocolate color appearance, and methemoglobinemia was suspected. His methemoglobin level was 69.9%, which is considered a lethal level. After a single dose of methylene blue (1 mg/kg/dose), cyanosis was reduced and oxygenation improved. CONCLUSION: Over-the-counter topical benzocaine should be used with caution, and the presence of methemoglobinemia must be promptly identified and treated.

Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP).

Patients with severe immune thrombocytopenic purpura (ITP) may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long-term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin (IVIG), and splenectomy. Therefore, acute platelet increases were studied in 35 patients completely unresponsive to IVIG or high-dose steroid treatment. Because of their lack of response to either or both single agents, these patients were administered a 3- or 4-drug combination including IVIG 1 g/kg, intravenous methylprednisolone 30 mg/kg, Vinca alkaloids (VCR 0.03 mg/kg), and/or intravenous anti-D (50-75 microg/kg). Subsequent maintenance therapy with the oral combination of danazol (10-15 mg/kg) and azathioprine (2 mg/kg) was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments. One patient developed an ileus, but otherwise there was little toxicity of combination treatment. Combination chemotherapy is a useful approach for patients with ITP refractory to conventional treatments both for acute induction and for long-term maintenance therapy.

Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with alphabeta-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the role of variants of caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type caspase-10 in a co-transfection assay. Other variants in caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Americans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in caspase-10 can produce contrasting phenotypic effects.