Clinical epidemiology of individuals with Sickle cell anemia using Hydroxyurea at Muhimbili National Hospital, Dar Es Salaam, Tanzania

2020 ◽  
Vol 31 (1) ◽  
pp. 106-119
Author(s):  
Elisha Osati ◽  
Edward Kija ◽  
Florence Urio ◽  
Magdalena Lyimo ◽  
Siana Nkya ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Severe Pain ◽  
Clinical Epidemiology ◽  
Fetal Hemoglobin ◽  
Dar Es Salaam ◽  
Acute Chest Syndrome ◽  
Muhimbili National Hospital ◽  
National Hospital

Background: The pathophysiology of sickle cell disease (SCD) is complex and involves nitric oxide depletion, increased inflammation/adhesion molecules and vaso-occlusion in addition to the chronic hemolytic anemia. This pathophysiology results in systemic clinical complications including recurrent episodes of severe pain, stroke, acute chest syndrome (ACS) and an increased susceptibility to infection. SCD severity varies among individuals and fetal hemoglobin (HbF) is known as a major modulator of the disease. To date, hydroxyurea (HU) is a known intervention that acts by increasing HbF in individuals with SCD. The increase in HbF reduces the risk of ‘sickling’ events and improves clinical outcomes. This is the first study on the use of HU in individuals with SCA in Tanzania.Methods: A case-control study to determine the proportion, indications, clinical and laboratory outcomes of SCD patients with HU use was conducted at Muhimbili National Hospital in Dar Es Salaam, Tanzania.Results: Forty-two patients with Sickle cell anemia (SCA) on HU treatment and 32 patients with SCA not on HU treatment were enrolled. The proportion of HU use by individuals with SCA at Muhimbili National Hospital was 10 per 1000. The mean HbF % was 9.8 ± 2.4 vs 6.2 ±1.4 for controls (P <0.001). Thirty (71.4%) were enrolled for HU treatment due to central nervous system (CNS) events, frequent painful crises 11(26.2%) and recurrent anemia 1(2.4%). Thirty-two SCA patients (76.2%) reported improvements after being on HU for at least six months. Of these, 91% reported no history of severe pain that required hospitalizations since they started HU. Twenty patients (66.7%) out of those with CNS events reported not to have experienced convulsions after HU initiation.Conclusions: HbF was higher in patients who were on HU and had positive correlation with clinical outcomes. Further clinical trials are required to evaluate more effects of HU use among SCA individuals in Tanzania. Keywords: Sickle cell anemia, HU, Fetal hemoglobin, Tanzania.

2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2379-2384
Author(s):  
Mabel Koshy ◽  
Louise Dorn ◽  
Linda Bressler ◽  
Robert Molokie ◽  
Donald Lavelle ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Complete Blood Count ◽  
Fetal Hemoglobin ◽  
Therapeutic Benefit ◽  
Additional Treatment ◽  
Acute Chest Syndrome ◽  
F Cells ◽  
Pain Crisis ◽  
Globin Synthesis

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

scholarly journals Clinical and Hematological Evaluation of Patients with Sickle Cell Anemia Before and After Four Years of Using Hydroxyurea

10.3823/2469 ◽  
2017 ◽  
Vol 10 ◽  
Author(s):  
Ieda Maria Gonçalves Pacce Bispo ◽  
Maria Lúcia Ivo ◽  
Valter Aragão do Nascimento ◽  
Alexandra Maria Almeida Carvalho de Pinto ◽  
Olinda Maria Rodrigues de Araújo ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hematological Parameters ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Teaching Hospitals ◽  
Acute Chest Syndrome ◽  
Mean Values ◽  
Significant Difference ◽  
Before And After

Objective: Evaluating clinical and hematological-clinical parameters of patients with sickle cell anemia (SCA) before and after four years of using hydroxyurea (HU).  Method: A retrospective cohort study implementing a quantitative, descriptive and analytical approach developed in two public teaching hospitals located in the Central-West region of Brazil, from November 2010 to October 2011. Data collection was performed through medical records of 32 patients with SCA to assess clinical and hematological parameters before and after HU treatment. The study was approved by the UFMS Ethics Committee under protocol number 1890/2010. Results: All of the 32 patients were homozygous with a mean age in the prescription of hydroxyurea of 19.72±7.58 years, an initial dose of 15.59±4.27 mg/kg/day, and 22.48±5.35 mg/kg/day in the fourth year of treatment. Regarding the use of HU, average values of some hematological parameters presented a significant difference in the fourth year compared to the mean values prior to HU use, such as fetal hemoglobin (14.49±7.52%), red blood cells (2.54±0.38x1012/L), hematocrit (25.30±4.03%) and hemoglobin (9.22±3.34g/dL).  Conclusion: Treatment with hydroxyurea showed a significant increase in fetal hemoglobin levels, increased hemoglobin, hematocrit and average corpuscular hemoglobin concentration, with reduced episodes of pain, infection and acute chest syndrome in such a way as to reaffirm its efficiency in treating these patients. Keywords: Hemoglobin; Sickle Cell Anemia; Hydroxyurea.

Genetic and Epigenetic Regulation of the Gamma Globin Locus Is Associated with Fetal Hemoglobin Levels and Frequency of Pain in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3230-3230
Author(s):  
Blair Anderson ◽  
Ebenezer Enchia ◽  
Karen Soldano ◽  
Melanie Garrett ◽  
Jude Jonassaint ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variation ◽  
Sickle Cell Disease ◽  
Clinical Outcomes ◽  
Sickle Cell ◽  
Severe Pain ◽  
Methylation Status ◽  
Fetal Hemoglobin ◽  
European Ancestry ◽  
Cell Disease

Abstract Abstract 3230 Sickle cell disease (SCD) is caused by a single amino acid substitution of the β-globin chain of hemoglobin, resulting in abnormal red blood cells that occlude vessels, causing tissue damage, pain, and anemia. While all individuals with SCD have the same β-globin mutation, disease severity varies and is correlated with the concentration of retained fetal hemoglobin (HbF) (Akinsheye et al, 2011). After birth, a switch from γ- to β-globin gene expression occurs and HbF (α2γ2) is replaced by HbA (α2β2). In patients with SCD, increased levels of γ-globin can help compensate for the effects of the β-globin mutation. SCD patients with higher than normal retention of HbF frequently have more benign disease symptoms and longer life expectancy (Platt et al, 1994). Increased HbF expression through the use of hydroxyurea (HU) is a frequently used therapy and the only FDA-approved medication for SCD. However, due to the toxicity and inconsistent efficacy of HU, further understanding regarding the regulation of this “hemoglobin switch” is essential for developing alternative treatments. DNA methylation is central to the silencing of γ-genes during the switch to β-globin expression (Goren et al, 2006). Methylation marks are established by the DNA methyltransferase DNMT3A, which is recruited to the γ-promoter by the protein arginine methyltransferase, PRMT5 (Rank et al, 2010). We first hypothesized that genetic variation in DNMT3A and PRMT5 contributes to HbF levels. To test this, we performed a genetic association study on 603 unrelated, adult SCD patients. 21 haplotype-tagging SNPs in DNMT3A (n=17) and PRMT5 (n=4) were genotyped in the patients. SNPs were evaluated for association with HbF levels, as well as the occurrence of severe pain and narcotic use, which were used as surrogates for non-hemoglobin effects of HU. HbF levels were measured when the patients were at steady state and not taking HU. Severe pain was defined as a history of hospitalization for pain within a 12 month period. Narcotic use was defined as taking long- or short-acting narcotics to alleviate pain at home. To evaluate associations between the SNPs and clinical outcomes, we used linear and logistic regression (SAS Systems, Cary, NC), while controlling for age, sex, degree of European ancestry and HU treatment. European ancestry was estimated from 4331 genome-wide ancestry informative markers (Ashley-Koch et al, 2011). HbF levels were log-transformed prior to analysis in order to achieve a normal distribution. We corrected for multiple comparisons using the Li and Ji method (Li & Ji, 2005). Two SNPs in DNMT3A were significantly associated with the occurrence of severe pain and HbF levels after correcting for multiple testing. Additionally, two SNPs in DNMT3A and one in PRMT5 were nominally associated with severe pain, two SNPs in DNMT3A were nominally associated with narcotic use, and one SNP in PRMT5 was nominally associated with HbF levels. These findings demonstrate that genetic variation in key genes responsible for the regulation of DNA methylation at the γ-globin locus is associated with SCD clinical outcomes. We next hypothesized that the variability in clinical outcomes might be due to epigenetic variation at the γ-globin locus. In order to determine specific DNA methylation patterning of γ-globin genes (HBG1 and HBG2), we performed pyroseqencing subsequent to bisulfite treatment of DNA from a subset of 72 SCD patients, all of whom were HbSS, and 50% of whom were not on HU treatment. Percent methylation at the γ-globin locus was nominally associated with HbF levels among patients not taking HU (p=0.03), but not among patients taking HU. Additionally, we investigated whether SNPs predicted methylation status and identified two SNPs in DNMT3A (rs734693 and rs7583409) to be predictive of methylation status at the γ-globin locus. These data provide further insight into the complex regulation of the γ-globin locus and suggest that genetic variation in DNMT3A and PRMT5 is associated with clinical outcomes and methylation status in SCD patients. Future studies are needed to further investigate the impact of epigenetic processes as a potential mechanism for HbF expression and induction. Disclosures: Telen: GlycoMimetics: Research Funding.

scholarly journals Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2269-2275 ◽  
Author(s):  
Jane S. Hankins ◽  
Russell E. Ware ◽  
Zora R. Rogers ◽  
Lynn W. Wynn ◽  
Peter A. Lane ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
White Blood Cells ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Extension Study ◽  
Acute Chest Syndrome ◽  
Event Rates ◽  
Hydroxyurea Therapy

AbstractThe long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/β0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P &lt; .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function.

scholarly journals Low Nocturnal Hemoglobin Oxygen Saturation Does Not Predict Pain or Acute Chest Syndrome Episodes in Children with Sickle Cell Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1320-1320
Author(s):  
Shaina Willen Johnson ◽  
Susan Redline ◽  
Carol Rosen ◽  
Mark J. Rodeghier ◽  
Michael DeBaun
Keyword(s):  
Oxygen Saturation ◽  
Incidence Rate ◽  
Sickle Cell ◽  
Opposite Direction ◽  
Sickle Cell Anemia ◽  
Rate Ratio ◽  
Severe Pain ◽  
Incidence Rate Ratio ◽  
Acute Chest Syndrome ◽  
School Of Medicine

Abstract Background: Previous evidence has shown that low mean nocturnal oxyhemoglobin saturation is significantly associated with a higher number of pain days per year Hargrave et al. (Blood. 2003; 101(3)846-8). We tested the primary hypothesis that sleep disordered breathing, described by low mean nocturnal oxygen saturation (SpO2), is associated with increased rates of severe vaso-occlusive pain and acute chest syndrome (ACS). Our secondary hypothesis investigated the association between high obstructive apnea hypopnea index (OAHI; the number of obstructive apneas and hypopneas with >3% SpO2desaturations or arousals per hour of sleep) with increased incidence of severe pain requiring hospitalization and ACS episodes. Study design: A prospective cohort study of children and adolescents from the Sleep and Asthma Cohort (SAC) was assembled. Children with sickle cell anemia (SCA), defined as HgbSS or Hb Sβ°, were enrolled from 4 to 18 years of age at three clinical centers, Washington University School of Medicine in St. Louis, Missouri; Case Western Reserve University in Cleveland, Ohio; and University College London in London, UK (which recruited from three London hospitals). At each site, SAC study-certified technicians performed full 12 channel in-laboratory research polysomnography (PSG) including continuous measurements of nocturnal oxygen saturation using standardized protocols according to American Academy of Sleep Medicine guidelines for data acquisition and scoring. All PSGs were read centrally at Vanderbilt University School of Medicine. Negative binomial regression was used to test the association between nocturnal SpO2 and the incidence rate of severe pain requiring hospitalization and ACS episodes. Covariates in the primary models for pain and ACS included: age at polysomnography, sex, hemoglobin, white blood cell count (WBC), OAHI, and mean nocturnal SpO2. All covariates meeting a significance criteria of p<0.20 were subsequently included in the final model for pain or ACS. Pain rate was defined as number of vaso-occlusive pain events that required hospitalization per year. ACS event was defined as an episode of acute respiratory distress associated with a new radiodensity on chest roentgenogram and at least one of the following: temperature greater than 38° Celsius, increased respiratory effort, decreased oxygen saturation, or increased respiratory rate documented in the medical record. A diagnosis of pneumonia was considered an ACS episode. If a pain event occurred with an ACS episode, the participant was counted as having an ACS event. Results: A total of 252 participants with SCA underwent polysomnography and after quality control, 243 were included; of these 223 had values for pain and ACS after polysomnography; missing data were due to lack of follow-up. Of the 223 participants, 18 on hydroxyurea therapy at the time of PSG and one with missing hydroxyurea status were excluded in primary analyses as hydroxyurea treatment is known to significantly influence pain incidence. The final sample included 204 participants, median age 10.4 years (interquartile range 7.3). Participants were followed for median 5.0 years (interquartile range 1.8 after PSG). After adjusting for age, sex, WBC, and hemoglobin, higher nocturnal SpO2 was associated with increased incidence of pain, which is in the opposite direction of our hypothesis (incidence rate ratio 1.11, 95% CI 1.06-1.17, p<0.001). Mean nocturnal SpO2 was not associated with ACS (incidence rate ratio 1.02, CI 0.96-1.09, p=0.500). In separate models, adjusting for age, sex, WBC, and hemoglobin, OAHI was not associated with future pain using either the log OAHI (IRR 0.99, CI 0.88-1.10, p=0.805) or with OAHI ≥2 (IRR 0.87, CI 0.55-1.41, p=0.569). After adjustment for covariates, OAHI was not associated with ACS using either the log OAHI (IRR 1.06, CI 0.92-1.21, p=0.450) or with OAHI ≥2 (IRR 0.86, CI 0.53-1.39, p=0.541). In an attempt to replicate the Hargrave analysis (Blood. 2003; 101(3)846-8), we investigated whether pain days per year was associated with nocturnal SpO2. Nocturnal SpO2was associated with pain days per year, but in the opposite direction of our hypothesis (IRR 1.12, 95% CI 1.05-1.20, p= 0.001). Conclusion: In an unselected group of children with SCA, low mean nocturnal SpO2 and elevated OAHI are not associated with clinically relevant increased incidence rates of vaso-occlusive pain or ACS. Disclosures No relevant conflicts of interest to declare.

Modeling Phenotype Interactions in Sickle Cell Anemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1659-1659 ◽  
Author(s):  
Paola Sebastiani ◽  
Vikki Nolan ◽  
Clinton T. Baldwin ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Predictive Power ◽  
Complex Structure ◽  
Laboratory Data ◽  
Fetal Hemoglobin ◽  
Early Death ◽  
Acute Chest Syndrome ◽  
Increased Risk ◽  
Laboratory Variables

Abstract Predicting a broad risk of selected serious vasoocclusive complications of sickle cell anemia is possible. For example, patients with higher hemoglobin concentrations are less likely to have a stroke. Yet, it has not been feasible to integrate the many clinical and laboratory abnormalities of sickle cell anemia into a predictive model that permits an understanding of the interactions among common clinical and laboratory abnormalities. From the database of the Cooperative Study of Sickle Cell Disease, we examined clinical and laboratory data from nearly 1500 individuals with sickle cell anemia, with or without coincident α thalassemia. We used these data to develop a Bayesian network that describes the interactions between clinical and laboratory data and their associations with the risk for complications of sickle cell anemia. Bayesian networks are multivariate models that represent the complex structure of interactions between many variables by a network of interrelated modules. The modules can be learned from data using statistical techniques and can be used to describe how changes in some variables affect other variables and ultimately the risk for phenotypes of interest. Our model shows that a complex network of interactions between clinical and laboratory variables underlies common complications of sickle cell anemia and ultimately death. Particularly important is the protective role that α thalassemia appears to play in common complications of sickle cell anemia. For example, α thalassemia, by decreasing erythrocyte density, reduces hemolysis and is associated with lower levels of bilirubin and an associated decreased risk for priapism. Bilirubin levels may reflect nitric oxide (NO) availability and NO may be invoved in the etiology of priapism. α thalassemia is also associated with smaller numbers of reticulocytes that are strongly associated with a decreased risk for acute chest syndrome and osteonecrosis; and it is associated with higher level of fetal hemoglobin and a reduction in leukocyte counts with a significant decreased risk for stroke and death. This model can be used to predict the occurrence of certain complications of sickle cell anemia and early death, given the presence of other disease complications and variations among common laboratory variables. For example, our model predicts a 10% risk for stroke at early age and an 11% risk for early death in patients with sickle cell anemia without α thalassemia compared with a 4% risk for stroke and 1.5% risk for early death for individuals with coincident α thalassemia. However, the predictive power of this model is limited, and we conjecture that this is a reflection of the omission of the genotypic changes that underlie the phenotypes. In related work using this same patient population, we analyzed genetic polymorphisms in candidate genes and showed than 25 SNPs and 4 clinical variables, including α thalassemia and fetal hemoglobin, were associated with increased risk of stroke and that this model predicted the occurrence of stroke in 114 individuals in a different population with 98% accuracy. The lack of the same predictive power of our current model suggests that genetic variants play a fundamental role in susceptibility to stroke and other complications of sickle cell anemia.

2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2379-2384 ◽  
Author(s):  
Mabel Koshy ◽  
Louise Dorn ◽  
Linda Bressler ◽  
Robert Molokie ◽  
Donald Lavelle ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Complete Blood Count ◽  
Fetal Hemoglobin ◽  
Therapeutic Benefit ◽  
Additional Treatment ◽  
Acute Chest Syndrome ◽  
F Cells ◽  
Pain Crisis ◽  
Globin Synthesis

Abstract Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

Functional polymorphisms of BCL11A and HBS1L-MYB genes affect both fetal hemoglobin level and clinical outcomes in a cohort of children with sickle cell anemia

2020 ◽  
Vol 99 (7) ◽  
pp. 1453-1463
Author(s):  
Rahyssa Rodrigues Sales ◽  
André Rolim Belisário ◽  
Gabriela Faria ◽  
Fabiola Mendes ◽  
Marcelo Rizzatti Luizon ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Hemoglobin Level ◽  
Functional Polymorphisms ◽  
Myb Genes ◽  
Fetal Hemoglobin Level

Predicting Acute Chest Syndrome in Sickle Cell Disease Patients Hospitalized for Acute Vasoocclusive Events.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3390-3390
Author(s):  
Daniel A. Dworkis ◽  
Vikki G. Nolan ◽  
Lillian C. McMahon ◽  
Elizabeth S. Klings ◽  
Martin H. Steinberg
Keyword(s):  
High Risk ◽  
Sickle Cell Disease ◽  
Hospital Admission ◽  
Clinical Outcomes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Alpha Thalassemia ◽  
Significant Difference

Abstract Acute painful vasoocclusive events (VOE) and acute chest syndrome (ACS) are the leading causes of hospitalization among patients with sickle cell disease (SCD). Although most patients with ACS are hospitalized explicitly for that reason, up to 36% of patients who were admitted for VOEs subsequently developed ACS, usually within several days of admission. Since ACS can be associated with hypoxemia and respiratory failure, leading to a need for blood transfusion and ventilatory support, the ability to predict which patients are at high risk for this serious complication might lead to better clinical outcomes. Using the results of standard-of-care blood testing obtained upon hospital admission, we present a novel model to predict the risk of developing ACS following hospitalization for a VOE. To generate this model, we retrospectively evaluated the records of 1,263 participants in the Cooperative Study of Sickle Cell Disease (CSSCD), with either sickle cell anemia (with or without co-incident alpha thalassemia) or HbSC disease, who were hospitalized for an acute VOE. During their hospitalization, 148 of these patients developed ACS, defined in the CSSCD as a new pulmonary infiltrate on a chest x-ray or evidence of pleuritic chest pain, with or without dyspnea; the remaining patients, who did not develop ACS, served as controls. Case patients were aged 7 to 55 years, with a mean age of 23 years; control patients were aged 5 to 72 years with a mean age of 24.5 years. Males were slightly more likely to develop ACS; 56% of case patients were male, compared with 46% of control patients (OR 1.5, 1.05–2.10). There was a significant difference in the distribution of SCD genotype, with fewer patients with HbSC disease and sickle cell anemia-alpha thalassemia in the control group (p=0.002). For each patient, we included in the model the hematocrit, hemoglobin concentration, mean corpuscular volume, reticulocyte count, white blood cell count with differential, and platelet count at hospital admission, along with their age, gender, and SCD genotype. Random Forest (RF) software, implemented in the R language, was used to create a set of 500 classification and regression trees using 80% of the subjects, and was then tested on the remaining 20%. For each test patient, each randomly generated decision tree classified the patient as high or low risk, and the consensus of the 500 tree forest was used to predict if the patient would develop ACS. This data driven approach produced a robust predictive model, while reducing analyst input and eliminating the need to identify important confounders a priori, as would be the case if attempting these analyses using stepwise logistic regression. The RF model correctly classified 95% of the patients for the development of ACS, with 67% sensitivity and 99% specificity. Neutrophil bands and platelet counts were identified by RF as the two most important predictors for the development of ACS, concordant with the potential roles of infection and infarction in its pathogenesis. With future validation, perhaps including prospective studies, this simple model, along with other predictors such as serum phospholipase A2 and studies of genetic modulators of this phenotype, could aid in identifying individuals who are at high risk for developing ACS. Ultimately, for patients hospitalized with VOEs, better identification of the risk of developing ACS might lead to more appropriate treatment with better clinical outcomes.

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