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13 pages, 763 KiB

Open AccessArticle

Primary Hyperparathyroidism in Sickle Cell Disease: An Unknown Complication of the Disease in Adulthood

by Elsa Denoix, Charlène Bomahou, Lorraine Clavier, Jean-Antoine Ribeil, François Lionnet, Pablo Bartolucci, Marie Courbebaisse, Jacques Pouchot and Jean-Benoît Arlet

J. Clin. Med. 2020, 9(2), 308; https://doi.org/10.3390/jcm9020308 - 22 Jan 2020

Cited by 4 | Viewed by 2483

Abstract

Primary hyperparathyroidism (pHPT) is the third most common endocrine disorder and usually affects patients between 60 and 70 years of age. To our knowledge, this condition has never been studied in young patients with sickle cell disease (SCD). Our objective was to describe [...] Read more.

Primary hyperparathyroidism (pHPT) is the third most common endocrine disorder and usually affects patients between 60 and 70 years of age. To our knowledge, this condition has never been studied in young patients with sickle cell disease (SCD). Our objective was to describe the clinical and biological characteristics of pHPT in adult patients with SCD and its management. We conducted a retrospective study that included SCD patients who were diagnosed with pHPT in four SCD referral centers. pHPT was defined by the presence of elevated serum calcium levels with inappropriate normal or increased parathyroid hormone (PTH) serum levels or histopathological evidence of parathyroid adenoma or hyperplasia. Patients with severe renal impairment (GFR <30 mL/min) were excluded. Twenty-eight patients (18 women, 64%; 22 homozygous genotype, 79%) were included. The median age at pHPT diagnosis was 41 years (interquartile range –IQR- 31.5–49.5). The median serum calcium and PTH concentration were, respectively, 2.62 mmol/L (IQR 2.60–2.78) and 105 pg/mL (IQR 69–137). Bone mineral density (BMD) revealed very low BMD (≤−2.5 SD) in 44% of patients explored (vs. 12.5% among 32 SCD patients matched for SCD genotype, sex, age, and BMI, p = 0.03). Fourteen patients (50%) received surgical treatment, which was successful in all cases, but four of these patients (29%) presented with pHPT recurrence after a median time of 6.5 years. Three of these patients underwent a second cervical surgery that confirmed the presence of a new parathyroid adenoma. These results suggest that SCD is a condition associated with pHPT in young subjects. SCD patients with pHPT have a high risk of very low BMD. A diagnosis of pHPT should be suspected in the presence of mild hypercalcemia or low BMD in SCD patients. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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9 pages, 245 KiB

Open AccessArticle

One-Fifth of Children with Sickle Cell Anemia Show Exercise-Induced Hemoglobin Desaturation: Rate of Perceived Exertion and Role of Blood Rheology

by Valentine Brousse, Corinne Pondarre, Cecile Arnaud, Annie Kamden, Mariane de Montalembert, Benedicte Boutonnat-Faucher, Hélène Bourdeau, Keyne Charlot, David Grévent, Suzanne Verlhac, Lydie da Costa and Philippe Connes

J. Clin. Med. 2020, 9(1), 133; https://doi.org/10.3390/jcm9010133 - 3 Jan 2020

Cited by 6 | Viewed by 2759

Abstract

Perceived exertion is an important self-limiting factor influencing functional capacity in patients with sickle cell anemia (SCA). Exercise-related hemoglobin desaturation (EHD) may occur during a six-minute walking test (6MWT) and could influence the perceived rate of exertion. The aims of this study were [...] Read more.

Perceived exertion is an important self-limiting factor influencing functional capacity in patients with sickle cell anemia (SCA). Exercise-related hemoglobin desaturation (EHD) may occur during a six-minute walking test (6MWT) and could influence the perceived rate of exertion. The aims of this study were (1) to compare the 6MWT responses (heart rate, perceived rate of exertion, and distance covered) between SCA children with and without EHD, and (2) to test the associations between EHD and several biological/physiological parameters. Nine of 51 SCA children (18%) at steady state (mean age 11.9 ± 3.8 years) exhibited EHD at the end of the 6MWT. The rate of perceived exertion increased with exercise in the two groups, but reached higher values in the EHD group. Heart rate and performance during the 6MWT did not differ between the two groups. The magnitude of change in SpO2 during the 6MWT was independently associated with the red blood cell (RBC) deformability and RBC aggregates strength. This study demonstrates that SCA children with EHD during a 6MWT have a higher rate of perceived exertion than non-EHD children despite a similar physiological demand, and that abnormal RBC rheology determinants appear to be significant contributors. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

12 pages, 1667 KiB

Open AccessArticle

World Health Organization’s Growth Reference Overestimates the Prevalence of Severe Malnutrition in Children with Sickle Cell Anemia in Africa

by Djamila L. Ghafuri, Shehu U. Abdullahi, Binta W. Jibir, Safiya Gambo, Halima Bello-Manga, Lawal Haliru, Khadija Bulama, Fahd M. Usman, Awwal Gambo, Muktar H. Aliyu, Brittany C. Greene, Adetola A. Kassim, Chris Slaughter, Mark Rodeghier and Michael R. DeBaun

J. Clin. Med. 2020, 9(1), 119; https://doi.org/10.3390/jcm9010119 - 2 Jan 2020

Cited by 8 | Viewed by 4428

Abstract

Anthropometric indices are widely used to assess the health and nutritional status of children. We tested the hypothesis that the 2007 World Health Organization (WHO) reference for assessment of malnutrition in children with sickle cell anemia (SCA) overestimates the prevalence of severe malnutrition [...] Read more.

Anthropometric indices are widely used to assess the health and nutritional status of children. We tested the hypothesis that the 2007 World Health Organization (WHO) reference for assessment of malnutrition in children with sickle cell anemia (SCA) overestimates the prevalence of severe malnutrition when compared to a previously constructed SCA-specific reference. We applied the WHO and SCA-specific references to children with SCA aged 5–12 years living in northern Nigeria (Primary Prevention of Stroke in Children with SCA in sub-Saharan Africa (SPRING) trial) to determine the difference in prevalence of severe malnutrition defined as body mass index (BMI) Z-score <−3 and whether severe malnutrition was associated with lower mean hemoglobin levels or abnormal transcranial Doppler measurements (>200 cm/s). A total of 799 children were included in the final analysis (median age 8.2 years (interquartile range (IQR) 6.4–10.4)). The application of the WHO reference resulted in lower mean BMI than the SCA-specific reference (−2.3 versus −1.2; p < 0.001, respectively). The use of the WHO reference when compared to the SCA-specific reference population also resulted in a higher prevalence of severe malnutrition (28.6% vs. 6.4%; p < 0.001). The WHO reference significantly overestimates the prevalence of severe malnutrition in children with SCA when compared to an SCA-specific reference. Regardless of the reference population, severe malnutrition was not associated with lower mean hemoglobin levels or abnormal transcranial Doppler (TCD) measurements. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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12 pages, 233 KiB

Open AccessArticle

An Educational Study Promoting the Delivery of Transcranial Doppler Ultrasound Screening in Paediatric Sickle Cell Disease: A European Multi-Centre Perspective

by Baba P. D. Inusa, Laura Sainati, Corrina MacMahon, Raffaella Colombatti, Maddalena Casale, Silverio Perrotta, Paola Rampazzo, Claire Hemmaway and Soundrie T. Padayachee

J. Clin. Med. 2020, 9(1), 44; https://doi.org/10.3390/jcm9010044 - 24 Dec 2019

Cited by 10 | Viewed by 2706

Abstract

Background: Effective stroke prevention in sickle cell disease (SCD) is recommended for children with sickle cell anaemia. Effective implementation relies on the correct stratification of stroke risk using Transcranial Doppler Ultrasound (TCD), prior to committing children to long-term treatment with transfusion. Nevertheless, less [...] Read more.

Background: Effective stroke prevention in sickle cell disease (SCD) is recommended for children with sickle cell anaemia. Effective implementation relies on the correct stratification of stroke risk using Transcranial Doppler Ultrasound (TCD), prior to committing children to long-term treatment with transfusion. Nevertheless, less than 50% of children with SCD in Europe receive annual TCD—one of the reasons being a lack of trained personnel. The present European multi-centre study was designed to promote the standardisation and delivery of effective screening. Methods: Fifty-five practitioners from differing professional backgrounds were recruited to the TCD training program. The impact of the training programme was evaluated in three European haematology clinics by comparing stroke risk classification and middle cerebral artery time-averaged maximum velocity (TAMMV) obtained from a cohort of 555 patients, before and after training. Results: 42% (23/55) of trainees successfully completed the program. The TAMMV, used to predict stroke risk at each Centre, demonstrated the highest values in Centre 3 (p < 0.0001) before training. The imaging-TCD TAMMV was also higher in Centre 3 (p < 0.001). Following training, the TAMMV showed closer agreement between centres for both imaging-TCD and non-imaging TCD. The stroke risk distribution of children at each centre varied significantly before training (p < 0.001), but improved after training (Fisher’s Exact: no treatment = 5.6, p = 0.41, treatment = 13.8, p < 0.01). The same consistency in stroke risk distribution following training was demonstrated with both non-imaging and imaging-TCD data. Conclusion: The attainment of competency in stroke screening using transcranial Doppler scanning (TCD) in sickle cell disease is more feasible for professionals with an ultrasound imaging background. A quality assurance (QA) system is required to ensure that standards are maintained. Further work is in progress to develop an achievable and reproducible QA program. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

15 pages, 23794 KiB

Open AccessArticle

Comparison between Adult Patients with Sickle Cell Disease of Sub-Saharan African Origin Born in Metropolitan France and in Sub-Saharan Africa

by Vasco Honsel, Djamal Khimoud, Brigitte Ranque, Lucile Offredo, Laure Joseph, Jacques Pouchot and Jean-Benoît Arlet

J. Clin. Med. 2019, 8(12), 2173; https://doi.org/10.3390/jcm8122173 - 9 Dec 2019

Cited by 8 | Viewed by 3592

Abstract

Sickle cell disease (SCD) prevalence has increased rapidly in Europe as a result of an increase in the life expectancy of these patients and the arrival of SCD migrants from Africa. The aim of our study was to compare the phenotypes of adult [...] Read more.

Sickle cell disease (SCD) prevalence has increased rapidly in Europe as a result of an increase in the life expectancy of these patients and the arrival of SCD migrants from Africa. The aim of our study was to compare the phenotypes of adult patients born in Sub-Saharan Africa (SSA) who migrated to France with those of patients with the same origin who were born in France. This single-center observational study compared the demographic, clinical and biological characteristics of SCD adult patients of SSA origin who were born in France or SSA. Data were collected from computerized medical charts. Groups were compared using multivariate logistic regression with adjustment for age, gender and type of SCD. Of the 323 SCD patients followed in our center, 235 were enrolled, including 111 patients born in France and 124 patients born in SSA. SCD genotypes were balanced between groups. Patients born in Africa were older (median age 32.1 (24.4–39) vs. 25.6 (22.1–30.5) years, p < 0.001) and more often women (n = 75 (60.5%) vs. 48 (43.2%), p = 0.008). The median age at arrival in France was 18 years (13–23). The median height was lower among patients born in SSA (169 (163–175) vs. 174.5 cm (168–179), p < 0.001). Over their lifetimes, patients born in France had more acute chest syndromes (median number 2 (1–4) vs. 1 (0–3), p = 0.002), with the first episode occurring earlier (19 (11.6–22.3) vs. 24 (18.4–29.5) years, p < 0.007), and were admitted to intensive care units more often (53.3% vs. 34.9%, p = 0.006). This difference was more pronounced in the SS/Sβ0 population. Conversely, patients born in SSA had more skin ulcers (19.4% vs. 6.3%, p = 0.03). No significant differences were found in social and occupational insertion or other complications between the two groups. Patients born in SSA had a less severe disease phenotype regardless of their age than those born in France. This difference could be related to a survival bias occurring in Africa during childhood and migration to Europe that selected the least severe phenotypes. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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16 pages, 1786 KiB

Open AccessArticle

Impact of A Six Week Training Program on Ventilatory Efficiency, Red Blood Cell Rheological Parameters and Red Blood Cell Nitric Oxide Signaling in Young Sickle Cell Anemia Patients: A Pilot Study

by Marijke Grau, Elie Nader, Max Jerke, Alexander Schenk, Celine Renoux, Thomas Dietz, Bianca Collins, Daniel Alexander Bizjak, Philippe Joly, Wilhelm Bloch, Aram Prokop and Philippe Connes

J. Clin. Med. 2019, 8(12), 2155; https://doi.org/10.3390/jcm8122155 - 5 Dec 2019

Cited by 11 | Viewed by 3454

Abstract

Patients with sickle cell anemia (SCA) show impaired ventilatory efficiency, altered blood rheology, high levels of oxidative/nitrosative stress and enhanced hemolysis with large amounts of circulating free hemoglobin, which reduces nitric oxide (NO) bioavailability. The aim of the study was to investigate whether [...] Read more.

Patients with sickle cell anemia (SCA) show impaired ventilatory efficiency, altered blood rheology, high levels of oxidative/nitrosative stress and enhanced hemolysis with large amounts of circulating free hemoglobin, which reduces nitric oxide (NO) bioavailability. The aim of the study was to investigate whether physical exercise could improve these physiological and biological markers described to contribute to SCA pathophysiology. Twelve SCA patients participated in a controlled six weeks training program with moderate volume (two sessions per week with 15–30 min duration per session) and intensity (70% of the first ventilatory threshold). Parameters were compared before (T0) and after (T1) training. Daily activities were examined by a questionnaire at T0 and one year after the end of T1. Results revealed improved ventilatory efficiency, reduced nitrosative stress, reduced plasma free hemoglobin concentration, increased plasma nitrite levels and altered rheology at T1 while no effect was observed for exercise performance parameters or hematological profile. Red blood cell (RBC) NO parameters indicate increased NO bioavailability which did not affect RBC deformability. Participants increased their daily life activity level. The data from this pilot study concludes that even low intensity activities are feasible and could be beneficial for the health of SCA patients. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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10 pages, 750 KiB

Open AccessArticle

International Differences in Outpatient Pain Management: A Survey of Sickle Cell Disease

by Nadirah El-Amin, Paul Nietert and Julie Kanter

J. Clin. Med. 2019, 8(12), 2136; https://doi.org/10.3390/jcm8122136 - 3 Dec 2019

Cited by 6 | Viewed by 3333

Abstract

Vaso-occlusive pain crises are the hallmark of sickle cell disease (SCD) and the primary reason for health care utilization. Both national and international guidelines recommend aggressive intravenous opioids, intravenous fluids and anti-inflammatory therapy as the mainstay of treatment for acute SCD pain. However, [...] Read more.

Vaso-occlusive pain crises are the hallmark of sickle cell disease (SCD) and the primary reason for health care utilization. Both national and international guidelines recommend aggressive intravenous opioids, intravenous fluids and anti-inflammatory therapy as the mainstay of treatment for acute SCD pain. However, many vaso-occlusive crises are managed at home with oral medication and supportive care. There are no guidelines on home medication management of SCD-related pain, likely due to the lack of well-defined endpoints for acute events and the lack of funding for already approved pain medications. Amplifying this issue is the growing concern for opioid abuse and misuse in the United States (US) and internationally. This study aimed to evaluate differences in opioid prescribing practices among providers treating SCD in the US and internationally. A survey was disseminated electronically to known providers using a combination of purposive and snowball sampling strategy. There were 127 responses and 17 countries represented. US providers were more likely to prescribe opioids (p < 0.001) and were more likely to be “very comfortable” prescribing opioids than non-US prescribers (p < 0.001). US providers also tended to prescribe more tablets per patient of stronger opioids than non-US physicians. US physicians were more likely to be concerned that patients were abusing opioids than non-US physicians (32% vs. 27%, p < 0.05). There are significant variations in how different parts of the world manage pain in the outpatient setting for SCD. Identifying optimal home pain management strategies is necessary to improve care and long-term outcomes in SCD. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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11 pages, 1060 KiB

Open AccessArticle

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

by Baba Psalm Duniya Inusa, Raffaella Colombatti, David C. Rees, Matthew M. Heeney, Carolyn C. Hoppe, Bernhards Ogutu, Hoda M. Hassab, Chunmei Zhou, Suqin Yao, Patricia B. Brown, Lori E. Heath, Joseph A. Jakubowski and Miguel R. Abboud

J. Clin. Med. 2019, 8(11), 2009; https://doi.org/10.3390/jcm8112009 - 17 Nov 2019

Cited by 10 | Viewed by 3465

Abstract

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences [...] Read more.

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS)), serious adverse events (SAEs), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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10 pages, 482 KiB

Open AccessArticle

GSTM1 and Liver Iron Content in Children with Sickle Cell Anemia and Iron Overload

by Latika Puri, Jonathan M. Flanagan, Guolian Kang, Juan Ding, Wenjian Bi, Beth M. McCarville, Ralf B. Loeffler, Aaryani Tipirneni-Sajja, Martha Villavicencio, Kristine R. Crews, Claudia M. Hillenbrand and Jane S. Hankins

J. Clin. Med. 2019, 8(11), 1878; https://doi.org/10.3390/jcm8111878 - 5 Nov 2019

Cited by 4 | Viewed by 2423

Abstract

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate [...] Read more.

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 (GSTM1) gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by GSTM1 genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: GSTM1 wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous GSTM1 deletion (GSTM1-null; 7.8, SD±6.9, p = 0.09). However, after >12 months of chelation, GSTM1-null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for GSTM1-null = 0.1 (SD±3.3); versus −0.3 (SD±3.0) and −1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, p = 0.047). GSTM1 homozygous deletion may prevent effective chelation in children with SCA and iron overload. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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16 pages, 1925 KiB

Open AccessArticle

Identification of Clinical and Laboratory Parameters Associated with the Development of Acute Chest Syndrome during Vaso-Occlusive Episodes in Children with Sickle Cell Disease: A Preliminary Step before Assessing Specific and Early Treatment Strategies

by Fouad Madhi, Annie Kamdem, Camille Jung, Adele Carlier-Gonod, Sandra Biscardi, Jeremy Busca, Cecile Arnaud, Isabelle Hau, David Narbey, Ralph Epaud and Corinne Pondarre

J. Clin. Med. 2019, 8(11), 1839; https://doi.org/10.3390/jcm8111839 - 1 Nov 2019

Cited by 7 | Viewed by 2877

Abstract

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil [...] Read more.

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (±2.3) vs. 3.3 (±1.8) days, p < 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion (p < 0.0001). The multivariate model retained pain score (≥9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (≥260 × 10⁹/L) and neutrophil (>10 × 10⁹/L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74–0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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10 pages, 617 KiB

Open AccessArticle

Is There Any Improvement of the Coagulation Imbalance in Sickle Cell Disease after Hematopoietic Stem Cell Transplantation?

by Laurence Rozen, Denis F. Noubouossie, Laurence Dedeken, Phu Quoc Lê, Alina Ferster and Anne Demulder

J. Clin. Med. 2019, 8(11), 1796; https://doi.org/10.3390/jcm8111796 - 26 Oct 2019

Cited by 2 | Viewed by 2722

Abstract

Several components of the clotting system are modified towards hypercoagulability in sickle cell disease (SCD). To date, hematopoietic stem cell transplantation (HSCT) is the only validated curative treatment of SCD. Here, we investigated the changes in the hemostatic potential of SCD children who’ve [...] Read more.

Several components of the clotting system are modified towards hypercoagulability in sickle cell disease (SCD). To date, hematopoietic stem cell transplantation (HSCT) is the only validated curative treatment of SCD. Here, we investigated the changes in the hemostatic potential of SCD children who’ve received a successful HSCT. Seventeen children with severe SCD were enrolled in the study. Thrombin generation (TG) was performed on citrated platelet-poor plasma, obtained before and 3, 6, 9, 12 and 15 months after HSCT. TG was triggered using 1 pM tissue factor and 4 µM phospholipids with or without thrombomodulin (TM). Before the HSCT, SCD children showed a higher endogenous thrombin potential (ETP), higher peak, higher velocity and shorter time-to-peak of TG than the normal controls (NC). ETP did not significantly change following the HSCT. However, the peak, velocity and time-to-peak of TG reversed to normal ranges from 3 months post-HSCT and remained so up to 15 months post-HSCT. The reduction of ETP after the addition of thrombomodulin (RETP) was dramatically reduced in SCD children before HSCT as compared with the NC. A partial reversal of RETP was observed from 3 months through 15 months post-HSCT. No statistical difference was observed for patient age or donor hemoglobinopathy status. In summary, successful HSCT improves the kinetics of TG but not the total thrombin capacity in SCD children. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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7 pages, 502 KiB

Open AccessArticle

Evaluation of a Non-Parenteral Opioid Analgesia Protocol for Acute Sickle Cell Pain Episodes in Children

by Paul Telfer, Filipa Barroso, Kim Newell, Jo Challands and Banu Kaya

J. Clin. Med. 2019, 8(10), 1728; https://doi.org/10.3390/jcm8101728 - 18 Oct 2019

Cited by 5 | Viewed by 3030

Abstract

We evaluated a protocol comprising intranasal diamorphine (IND) combined with oral short and modified-release morphine for children at the emergency department (ED) with acute painful episodes of sickle cell disease (SCD). In a retrospective audit of 83 episodes in 38 children, the mean [...] Read more.

We evaluated a protocol comprising intranasal diamorphine (IND) combined with oral short and modified-release morphine for children at the emergency department (ED) with acute painful episodes of sickle cell disease (SCD). In a retrospective audit of 83 episodes in 38 children, the mean time between arrival in the treatment area and the administration of IND was 10 min (range <5 min to 1.39 h). IND was administered in <5 min in 43 (51.6%), and in <20 min in 75 (90.4%) episodes. Persisting pain, requiring background analgesia with modified-release oral morphine, was required in 25 (30.1%) episodes. Inadequate control of pain requiring a switch to intravenous morphine PCA was required in eight episodes in four patients. Acute chest syndrome (ACS) developed in four of 83 episodes (4.8%, 95% CI 0.2–9.4%) and in four of 38 children (10.5%, 95% CI 0.7–20.5%). In conclusion, this protocol enabled the rapid administration of strong opioid analgesia in an ED setting, and may reduce the short and long-term adverse effects associated with parenteral opioids in children. There was no evidence of an increased incidence of ACS associated with use of oral morphine. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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10 pages, 746 KiB

Open AccessArticle

Optimizing Hydroxyurea Treatment for Sickle Cell Disease Patients: The Pharmacokinetic Approach

by Charlotte Nazon, Amelia-Naomi Sabo, Guillaume Becker, Jean-Marc Lessinger, Véronique Kemmel and Catherine Paillard

J. Clin. Med. 2019, 8(10), 1701; https://doi.org/10.3390/jcm8101701 - 16 Oct 2019

Cited by 7 | Viewed by 3905

Abstract

Background: Hydroxyurea (HU) is a FDA- and EMA-approved drug that earned an important place in the treatment of patients with severe sickle cell anemia (SCA) by showing its efficacy in many studies. This medication is still underused due to fears of physicians and [...] Read more.

Background: Hydroxyurea (HU) is a FDA- and EMA-approved drug that earned an important place in the treatment of patients with severe sickle cell anemia (SCA) by showing its efficacy in many studies. This medication is still underused due to fears of physicians and families and must be optimized. Methods: We analyzed our population and identified HU pharmacokinetic (PK) parameters in order to adapt treatment in the future. Working with a pediatric population, we searched for the most indicative sampling time to reduce the number of samples needed. Results: Nine children treated by HU for severe SCA were included for this PK study. HU quantification was made using a validated gas chromatography/mass spectrometry (GC/MS) method. Biological parameters (of effectiveness and compliance) and clinical data were collected. None of the nine children reached the therapeutic target defined by Dong et al. as an area under the curve (AUC) = 115 h.mg/L; four patients were suspected to be non-compliant. Only two patients had an HbF over 20%. The 2 h sample was predictive of the medication exposure (r² = 0.887). Conclusions: It is urgent to be more efficient in the treatment of SCA, and pharmacokinetics can be an important asset in SCA patients. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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8 pages, 603 KiB

Open AccessArticle

Serum Immunoglobulin Levels in Children with Sickle Cell Disease: A Large Prospective Study

by Sophia Cherif-Alami, Isabelle Hau, Cécile Arnaud, Annie Kamdem, Basil Coulon, Elodie Idoux, Stéphane Bechet, Rita Creidy, Françoise Bernaudin, Ralph Epaud and Corinne Pondarré

J. Clin. Med. 2019, 8(10), 1688; https://doi.org/10.3390/jcm8101688 - 15 Oct 2019

Cited by 6 | Viewed by 2962

Abstract

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS [...] Read more.

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSβ⁰ thalassemia) and 157 with milder genotypes (HbSC and HbSβ⁺ thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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16 pages, 1650 KiB

Open AccessArticle

Trajectories of Biological Values and Vital Parameters: An Observational Cohort Study of Adult Patients with Sickle Cell Disease Hospitalized for a Non-Complicated Vaso-Occlusive Crisis

by Raphael Veil, Simon Bussy, Vincent Looten, Jean-Benoît Arlet, Jacques Pouchot, Anne-Sophie Jannot and Brigitte Ranque

J. Clin. Med. 2019, 8(9), 1502; https://doi.org/10.3390/jcm8091502 - 19 Sep 2019

Cited by 2 | Viewed by 2947

Abstract

Hospital admission of patients with sickle-cell disease (SCD) presenting with a vaso-occlusive crisis (VOC) can be justified by pain refractory to usual outpatient care and/or the occurrence of a complication. Yet, the trajectories of vital parameters and standard biomarkers throughout a non-complicated VOC [...] Read more.

Hospital admission of patients with sickle-cell disease (SCD) presenting with a vaso-occlusive crisis (VOC) can be justified by pain refractory to usual outpatient care and/or the occurrence of a complication. Yet, the trajectories of vital parameters and standard biomarkers throughout a non-complicated VOC has not been established. In this observational cohort study, we describe the course of routine parameters throughout 329 hospital stays for non-complicated VOC. We used a new spline-based approach to study and visualize non-specific time-dependent variables extracted from the hospital clinical data warehouse. We identified distinct trends during the VOC for hemoglobin level, leukocytes count, C-Reactive Protein (CRP) level and temperature. Hemoglobin decreased after admission and rarely returned to steady state levels before discharge. White blood cell counts were elevated at admission before immediately decreasing, whereas eosinophils increased slowly throughout the first five days of the stay. In over 95% of non-complicated VOC-related stays, the CRP value was below 100 mg/L within the first day following admission and above normal after 48 hours, and the temperature was below 38 °C throughout the entire stay. Knowing the typical trajectories of these routine parameters during non-complicated VOC may urge the clinicians to be more vigilant in case of deviation from these patterns. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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15 pages, 1588 KiB

Open AccessArticle

Hepatobiliary Complications in Children with Sickle Cell Disease: A Retrospective Review of Medical Records from 616 Patients

by Slimane Allali, Mariane de Montalembert, Valentine Brousse, Claire Heilbronner, Melissa Taylor, Josephine Brice, Elisabetta Manzali, Nicolas Garcelon and Florence Lacaille

J. Clin. Med. 2019, 8(9), 1481; https://doi.org/10.3390/jcm8091481 - 18 Sep 2019

Cited by 31 | Viewed by 6315

Abstract

Hepatobiliary complications in children with sickle cell disease (SCD) are rarely reported but can be life-threatening. We retrospectively assessed their prevalence in a cohort of 616 children followed in a French university-hospital SCD reference center. Eligibility criteria were the following: age <18 years, [...] Read more.

Hepatobiliary complications in children with sickle cell disease (SCD) are rarely reported but can be life-threatening. We retrospectively assessed their prevalence in a cohort of 616 children followed in a French university-hospital SCD reference center. Eligibility criteria were the following: age <18 years, seen at least twice with an interval of more than 6 months from January 2008 to December 2017, with all genotypes of SCD. Patients with hepatobiliary complications were identified via the local data warehouse and medical files were thoroughly reviewed. At least one hepatobiliary complication was reported in 37% of the children. The most frequent was cholelithiasis, in 25% of cases, which led to systematic screening and elective cholecystectomy in the case of gallstones. Overall, 6% of the children experienced acute sickle cell hepatic crisis, sickle cell intra-hepatic cholestasis, or acute hepatic sequestration, with severity ranging from mild liver pain and increased jaundice to multiple organ failure and death. Emergency treatment was exchange transfusion, which led to normalization of liver tests in most cases. Five children had chronic cholangiopathy, associated with auto-immune hepatitis in two cases. One needed liver transplantation, having a good outcome but with many complications. Transfusion iron load and infectious hepatitis cases were mild. Hepatotoxicity of an iron chelator was suspected to contribute to abnormal liver test results in five patients. We propose recommendations to prevent, explore, and treat hepatobiliary complications in SCD children. We underline the need for emergency exchange transfusion when acute liver failure develops and warn against liver biopsy and transplantation in this condition. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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7 pages, 180 KiB

Open AccessArticle

Shared Care for Adults with Sickle Cell Disease: An Analysis of Care from Eight Health Systems

by Arch G. Mainous III, Benjamin Rooks, Rebecca J. Tanner, Peter J. Carek, Vandy Black and Thomas D. Coates

J. Clin. Med. 2019, 8(8), 1154; https://doi.org/10.3390/jcm8081154 - 2 Aug 2019

Cited by 7 | Viewed by 3658

Abstract

Adult sickle cell disease (SCD) patients frequently transition from pediatric hematology to adult primary care. We examined healthcare utilization for adult patients with SCD with shared care between hematologists and primary care providers (PCP). We analyzed the OneFlorida Data Trust, a centralized data [...] Read more.

Adult sickle cell disease (SCD) patients frequently transition from pediatric hematology to adult primary care. We examined healthcare utilization for adult patients with SCD with shared care between hematologists and primary care providers (PCP). We analyzed the OneFlorida Data Trust, a centralized data repository of electronic medical record (EMR) data from eight different health systems in Florida. The number of included adults with SCD was 1147. We examined frequent hospitalizations and emergency department (ED) visits by whether the patient had shared care or single specialty care alone. Most patients were seen by a PCP only (30.4%), followed by both PCP and hematologist (27.5%), neither PCP nor hematologist (23.3%), and hematologist only (18.7%). For patients with shared care versus single specialist care other than hematologist, the shared care group had a lower likelihood of frequent hospitalizations (OR 0.63; 95% CI 0.43–0.90). Similarly, when compared to care from a hematologist only, the shared care group had a lower likelihood of frequent hospitalizations (OR 0.67; 95% CI 0.47–0.95). There was no significant relationship between shared care and ED use. When patients with SCD have both a PCP and hematologist involved in their care there is a benefit in decreased hospitalizations. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

Review

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19 pages, 646 KiB

Open AccessReview

Choice of Donor Source and Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Sickle Cell Disease

by Emily Limerick and Courtney Fitzhugh

J. Clin. Med. 2019, 8(11), 1997; https://doi.org/10.3390/jcm8111997 - 15 Nov 2019

Cited by 8 | Viewed by 4892

Abstract

In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with [...] Read more.

In the United States, one out of every 500 African American children have sickle cell disease (SCD), and SCD affects approximately 100,000 Americans. Significant advances in the treatment of this monogenetic disorder have failed to substantially extend the life expectancy of adults with SCD over the past two decades. Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with SCD. While human leukocyte antigen (HLA) matched sibling HSCT has been successful, its availability is extremely limited. This review summarizes various conditioning regimens that are currently available. We explore recent efforts to expand the availability of allogeneic HSCT, including matched unrelated, umbilical cord blood, and haploidentical stem cell sources. We consider the use of nonmyeloablative conditioning and haploidentical donor sources as emerging strategies to expand transplant availability, particularly for SCD patients with complications and comorbidities who can undergo neither matched related transplant nor myeloablative conditioning. Finally, we show that improved conditioning agents have improved success rates not only in the HLA-matched sibling setting but also alternative donor settings. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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13 pages, 3151 KiB

Open AccessReview

Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

by Saranya Veluswamy, Payal Shah, Christopher C. Denton, Patjanaporn Chalacheva, Michael C. K. Khoo and Thomas D. Coates

J. Clin. Med. 2019, 8(10), 1690; https://doi.org/10.3390/jcm8101690 - 15 Oct 2019

Cited by 23 | Viewed by 10168

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive [...] Read more.

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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17 pages, 760 KiB

Open AccessReview

Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease

by Santosh L. Saraf and Damiano Rondelli

J. Clin. Med. 2019, 8(10), 1565; https://doi.org/10.3390/jcm8101565 - 1 Oct 2019

Cited by 9 | Viewed by 5099

Abstract

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is [...] Read more.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but has been used less frequently in adults compared to children. This is, in part, due to (1) greater chronic organ damage, limiting tolerability to myeloablative conditioning regimens, (2) a higher rate of HSCT-related complications in adults versus children with SCD, and (3) limited coverage by public and private health insurance. Newer approaches using nonmyeloablative and reduced-intensity conditioning HSCT regimens have demonstrated better safety and tolerability, with high rates of stable engraftment in SCD adults. This review will focus on the impacts of HSCT, using more contemporary approaches to SCD-related complications in adults. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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21 pages, 953 KiB

Open AccessReview

Why, Who, When, and How? Rationale for Considering Allogeneic Stem Cell Transplantation in Children with Sickle Cell Disease

by Françoise Bernaudin

J. Clin. Med. 2019, 8(10), 1523; https://doi.org/10.3390/jcm8101523 - 22 Sep 2019

Cited by 8 | Viewed by 5084

Abstract

Considering the progress made in the management of sickle cell disease during the past 30 years, along with the excellent results obtained with hematopoietic stem cell transplantation (SCT), it is important to reexamine why, who, when and how to recommend allogeneic SCT in [...] Read more.

Considering the progress made in the management of sickle cell disease during the past 30 years, along with the excellent results obtained with hematopoietic stem cell transplantation (SCT), it is important to reexamine why, who, when and how to recommend allogeneic SCT in children with sickle cell disease. While sickle cell disease has a low risk of death in children and a high risk for morbidity during aging, SCT carries an early risk of death, graft-vs-host disease and infertility. Nevertheless, SCT offers at least 95% chance of cure with low risk of chronic graft-vs-host disease when a matched-sibling donor is available and the risks of infertility can be reduced by ovarian, sperm or testis cryopreservation. Thus, all available therapies such as hydroxyurea, transfusions and SCT should be presented to the parents, providers, and affected children and discussed with them from infancy. Furthermore, the use of these therapies should be adjusted to the severity of the disease and to local availabilities in order to choose the treatment offering the best benefit/risk ratio. Full article

(This article belongs to the Special Issue Sickle Cell Anemia: From Genetic Epidemiology to New Therapeutic Strategies)

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