Clinical presentation of severe anemia in pediatric patients with sickle cell anemia seen in Enugu, Nigeria

Introduction:Significant morbidity and mortality in patients with sickle cell disease (SCD) is attributed to the pulmonary sequalae of the disease. Patients with SCD often suffer airway hyper-reactivity, acute chest syndrome (ACS), chronic lung disease, pulmonary hypertension (PHTN), and obstructive sleep apnea (OSA). Recent literature has provided evidence supporting the strong association between asthma and airway hyper-reactivity in SCD. One of the factors linked to chronic inflammation and asthma is iron status. The present study examined whether iron levels are associated with pulmonary complications in pediatric patients with SCD. Method:Through retrospective review of electronic medical records (EMR) we evaluated patients with diagnosis of asthma and SCD. All patients with available PFT (3/21/2013-3/11/2020) and iron studies were included in the analysis. Chi square and ANOVA tests were used to explore relationships of respiratory conditions with lab data and relevant medical history. Results:The analysis reviewed information of 100 patients with SCD -- 56 males and 44 females The sample population had the following genotypes: 63% Hemoglobin (Hb) SS, 23% Hb SC, 2% Hb S Beta Zero Thalassemia, and 12% Hb S Beta Thalassemia. 38% of these patients were receiving treatment via hydroxyurea. The results generated found that patients with a large airway obstruction (LAO) had a marginally statistically significantly higher serum iron level than those with no LAO (p=0.067.) Patients with homozygous Hb S disease were four times as likely to have a history of ACS (p=0.004) than those without and were marginally significantly more likely to be SS and SB0Thal (p=0.052). Patients with history of ACS had a significantly higher mean iron saturation and lower total iron binding capacity (TIBC.) Patients with PHTN had significantly higher serum iron levels (p=0.029). Conclusion:Our findings reveal that while iron might play a more significant role in the development of PHTN and ACS in patients with SCD, the role in asthma is borderline in our sample. These findings, although of borderline statistical significance p=0.067, are clinically noteworthy. These results may open a new window for therapy targeted at maintaining iron in normal physiologic ranges to decrease pulmonary complications in patients with sickle cell anemia. Further studies with larger samples are necessary to clarify the meaning of our marginally significant findings. Disclosures No relevant conflicts of interest to declare.

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Hydroxyurea Shows Clinical Benefit without Alteration of Fetal Hemoglobin, MCV, or Hemoglobin in Unselected Adult and Pediatric Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood.v126.23.2187.2187 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2187-2187

Author(s):

Crawford John Strunk ◽

Biree Andemariam ◽

Fredericka Sey ◽

Fatimah Farooq ◽

Rebekah Urbonya ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Multicenter Study ◽

Pediatric Patients ◽

Laboratory Data ◽

Fetal Hemoglobin ◽

Adult Patients ◽

Clinical Severity ◽

Laboratory Studies ◽

Laboratory Values

Abstract Introduction Sickle cell anemia is the most common single gene defect in the United States, affecting approximately 100,000 individuals (Hassel Am J Prev Med 2010). It is characterized by chronic hemolysis, unpredictable vaso-occlusive episodes (VOEs), and chronic organ damage leading to early death in patients affected by the disorder. Hydroxyurea, a small molecule chemotherapeutic agent, has been used to treat patients with severe sickle cell disease since 1984 (Brawley Ann Intern Med 2008). Two randomized controlled trials, the Multicenter Study of Hydroxyurea (Charache N Engl J Med 1995) in adults and the Baby HUG trial (Wang Lancet 2011) in children, showed that hydroxyurea reduced the number of VOEs and hospital admissions, while simultaneously increasing hemoglobin and fetal hemoglobin in patients with sickle cell anemia. The goal of this study was to determine the clinical effectiveness of hydroxyurea in reducing the number VOEs and hospitalizations in unselected patients with sickle cell anemia. Methods The CASIRE group is an international multi-institutional collaborative group evaluating the clinical severity of patients with sickle cell anemia through a validated questionnaire, chart review and laboratory studies. Patients were enrolled on the CASIRE study after informed consent and assent was obtained from either the parent or patient when appropriate. The study was approved at each participating institution's IRB. A questionnaire was answered by the parents and/or patient, and baseline and current laboratory studies were collected. Patients were stratified into those who were not on hydroxyurea, and those who were currently on hydroxyurea. Number of VOEs, admissions, baseline and current fetal hemoglobin, and change in hemoglobin and MCV were compared. Results There were 349 patients in this study (134 on hydroxyurea). Baseline laboratory data are reported in table 1. Hemoglobin level and MCV were not statistically different in patients prior to and after taking hydroxyurea (table 2). Fetal hemoglobin in adults increased 2.7 times baseline, whereas in children it was unchanged. All patients on hydroxyurea had a reduction of VOEs, ED visits and admissions compared to prior to hydroxyurea (see table 3). Table 1. Baseline laboratory data Baseline data Patients on Hydroxyurea Patients not on Hydroxyurea Pediatric Adult Pediatric Adult N 78 56 140 75 Age 10 26.9 8.6 28.3 Hemoglobin (g/dL) 8.7 9.7 9.39 9.4 MCV (fL) 91 91.5 79 86 Fetal Hemoglobin (%) 15.1 12.4 9.6 5 Table 2. Clinical data for patients on HU Patients on Hydroxyurea Pediatric (78) Adult (56) Dose of HU (mg/kg) 23.8 20.5 # doses missed/wk 1 1.55 Fetal Hemoglobin on HU (%) 14.5 13.8 D MCV from baseline (fL) +5.4 +0.1 D Hgb from baseline (g/dL) +0.23 +0.4 Table 3. Number of pain episodes in patients on HU. Prior to HU In last year on HU 2 tailed paired t test Pediatric patients (N = 78) # pain episodes/year 25 12.9 0.62 # requiring ED/year 2.66 1 0.93 # requiring admission/year 4.28 1.79 0.017 Adult patients (N = 56) # pain episodes/year 36.7 28.6 0.021 # requiring ED/year 5.7 2.4 0 # requiring admission/year 6.6 3.15 0.117 Conclusion The Multicenter Study of Hydroxyurea and the BABY HUG study showed that hydroxyurea is efficacious for patients with sickle cell anemia. No previous study has evaluated the effectiveness of hydroxyurea in clinical practice. Our study suggests that, although baseline and current laboratory values are similar in patients prior to versus after taking hydroxyurea, there was a clear reduction in the number of VOEs and admissions, similar to the Baby HUG and MSH studies. These results suggest that the reduction of VOEs could be the product of a generalized decrease in overall inflammation and hemolysis or increased nitric oxide production rather than an increase in fetal hemoglobin by itself. Reasons for the similarity in laboratory values could include the length of time patients have been on hydroxyurea or that hydroxyurea was not escalated to maximum tolerated dose. Another reason may be the degree of compliance of patients in a clinical setting. We noted that 1/3 of our pediatric and ½ of our adult patients missed at least 1 dose of hydroxyurea per week suggesting that even partial compliance with hydroxyurea may prove beneficial clinically. This study demonstrates that hydroxyurea is effective in reducing the number of VOEs and admissions for unselected patients with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.

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Malaria in patients with sickle cell anemia: burden, risk factors, and outcome at the outpatient clinic and during hospitalization

Blood ◽

10.1182/blood-2009-07-233528 ◽

2010 ◽

Vol 115 (2) ◽

pp. 215-220 ◽

Cited By ~ 75

Author(s):

Julie Makani ◽

Albert N. Komba ◽

Sharon E. Cox ◽

Julie Oruo ◽

Khadija Mwamtemi ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Outpatient Clinic ◽

Hospital Admissions ◽

Clinical Malaria ◽

Dar Es Salaam ◽

Severe Illness ◽

Severe Anemia ◽

Prospective Surveillance

Abstract Approximately 280 000 children are born with sickle cell anemia (SCA) in Africa annually, yet few survive beyond childhood. Falciparum malaria is considered a significant cause of this mortality. We conducted a 5-year prospective surveillance study for malaria parasitemia, clinical malaria, and severe malarial anemia (SMA) in Dar-es-Salaam, Tanzania, between 2004 and 2009. We recorded 10 491 visits to the outpatient clinic among 1808 patients with SCA and 773 visits among 679 patients without SCA. Similarly, we recorded 691 hospital admissions among 497 patients with SCA and 2017 in patients without SCA. Overall, the prevalence of parasitemia was lower in patients with SCA than in patients without SCA both at clinic (0.7% vs 1.6%; OR, 0.53; 95% CI, 0.32-0.86; P = .008) and during hospitalization (3.0% vs 5.6%; OR, 0.46; 95% CI, 0.25-0.94; P = .01). Furthermore, patients with SCA had higher rates of malaria during hospitalization than at clinic, the ORs being 4.29 (95% CI, 2.63-7.01; P < .001) for parasitemia, 17.66 (95% CI, 5.92-52.71; P < .001) for clinical malaria, and 21.11 (95% CI, 8.46-52.67; P < .001) for SMA. Although malaria was rare among patients with SCA, parasitemia during hospitalization was associated with both severe anemia and death. Effective treatment for malaria during severe illness episodes and further studies to determine the role chemoprophylaxis are required.

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Risk Factors and Complications Among Pediatric Patients With Sickle Cell Anemia: A Single Tertiary Center Retrospective Study

Cureus ◽

10.7759/cureus.12440 ◽

2021 ◽

Author(s):

Fatma Alzahrani ◽

Anas M Fallatah ◽

Fatimah M Al-Haddad ◽

Shahad T Khayyat ◽

Wasayf M AlMehmadi ◽

...

Keyword(s):

Risk Factors ◽

Retrospective Study ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Pediatric Patients ◽

Tertiary Center

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STUDIES ON CONGENITAL HEMOLYTIC SYNDROMES

PEDIATRICS ◽

10.1542/peds.23.3.462 ◽

1959 ◽

Vol 23 (3) ◽

pp. 462-475

Author(s):

Marion E. Erlandson ◽

Irving Schulman ◽

Carl H. Smith

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Pediatric Patients ◽

Clinical Manifestations ◽

Adult Patients ◽

Present Series ◽

Risk Of Infection ◽

Laboratory Examination ◽

Careful Observation ◽

Compensation Index

Four adult patients were studied in whom classic congenital spherocytic anemia was evident clinically and by laboratory examination. Anemia, as determined by total volume of erythrocytes, was marked although concentrations of hemoglobin were only slightly low. Rates of destruction and production of erythrocytes were markedly accelerated. Six pediatric patients with minimal clinical manifestations but definite laboratory evidence of congenital spherocytosis were evaluated. Anemia, in terms of total volume of erythrocytes, was present in all patients despite normal concentrations of hemoglobin in some patients. A potential for future severe clinical manifestations was shown to be present in five of six children by the demonstration of marked hemolytic defects equivalent to the hemolytic defects present in adult patients with classic congenital spherocytic anemia. In the present series of patients with congenital spherocytosis in whom concentrations of hemoglobin were normal or slightly low, values for the total volume of erythrocytes and the compensation index were similar to values in patients with intermediate (homozygous) thalassemia and in many patients with sickle cell anemia. Abnormally low values for total volume of erythrocytes and compensation index were present in four patients in whom the rate of destruction of erythrocytes was less than six times normal. Rates of production of erythrocytes were less than six times normal in the majority of patients studied. This is contrary to a previous concept of the capacity for erythropoietic compensation in such patients. These values imply that some factor(s) which has not as yet been identified regulates the rate of erythropoiesis in these patients. Studies of four family groups of patients with congenital spherocytosis demonstrated the absence of any specific familial pattern of manifestations of the disease. It has been suggested that management of children with minimal symptoms resulting from the presence of this disease consists of careful observation, splenectomy being deferred until late in childhood to avoid a maximal risk of infection after splenectomy. It has also been suggested that splenectomy be performed before the age of 10 years in order to avoid the complication of gallstones, and that splenectomy be performed at an even earlier age if persistent severe symptoms are present. The existence of a truly mild hemolytic defect was demonstrated in only 1 of the 10 patients studied. It would seem that splenectomy is not indicated in this unusual patient.

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Influence of Hemoglobin Level on Clinical Findings In Infants with Sickle Cell Anemia: Data From BABY HUG

Blood ◽

10.1182/blood.v116.21.1631.1631 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1631-1631 ◽

Cited By ~ 1

Author(s):

Jeffrey D. Lebensburger ◽

Scott T Miller ◽

Thomas H. Howard ◽

James F. Casella ◽

R. Clark Brown ◽

...

Keyword(s):

Platelet Count ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Organ Damage ◽

Hemoglobin Level ◽

Phase Iii ◽

Acute Chest Syndrome ◽

Severe Anemia ◽

Laboratory Findings ◽

Baseline Hemoglobin

Abstract Abstract 1631 Introduction: Infants with sickle cell anemia (SCA) are at risk for organ damage and clinical events. Risk may vary depending on steady state hemoglobin level. BABY HUG (ClinicalTrials.org, NCT00006400), a NHLBI-NICHD supported phase III randomized placebo-controlled trial, examined the ability of hydroxyurea (HU) to reduce end organ damage to the kidneys and spleen and attenuate other complications of SCA in infants. In this secondary study, we investigated whether placebo-treated subgroups defined by extremes of baseline hemoglobin level differed from one another in frequency of sickle cell-related complications and other laboratory findings, and then compared these data to the entire group of infants treated with HU. Methods: BABY HUG subjects randomized at ages 9 – 18 mo were treated with hydroxyurea (20 mg/kg/d) (N=96) or with placebo (N=97) for 2 years. Those randomized to placebo were classified according to their age-adjusted baseline hemoglobin level and subgroups in the lowest (n=24) and highest (n=24) quartiles compared. (Demarcating Hb values were: age 9 to <12 mo, <8.0 vs. >10.2gm/dL; age12 – 18 mo, <8.1 vs. >9.9gm/dL.) Results: BABY HUG primary endpoints of spleen (splenic uptake of 99mTc sulfur colloid on liver-spleen scan) and kidney (GFR by DTPA clearance) function did not differ in placebo group subjects who were in the lowest and highest quartile hemoglobin levels. However, those in the lowest hemoglobin quartile had a higher incidence of acute chest syndrome (ACS) than those in the highest quartile (0.31 vs. 0.02 events/person-year, RR 14.4, p=0.01) and this difference was significantly attenuated by HU (0.05 events/person-year). The relative risk for developing a pain crisis did not differ between the two placebo subgroups (2.2 vs. 2.1 events/person-year), but HU significantly reduced pain frequency compared to either subgroup (0.94 events/person-year, p<0.001). Subjects in the lowest hemoglobin quartile had higher baseline mean TCD velocities than those in the highest quartile (126.2 vs. 112.4 cm/sec, p=0.008). These differences persisted over the two-year period of study, with exit values of 164.9 and 139.6 cm/sec, respectively (p=0.003). By comparison mean TCD velocity in the HU-treated group was 124.5 cm/sec at baseline and 145.6 at exit. Results of neurocognitive testing were not statistically different between groups; however, a trend toward a lower performance developmental index (PDI, p=0.07), but not a lower mental development index (MDI, p=0.15), was observed in subjects with the lowest hemoglobin levels. Subjects in the lowest quartile also had a higher mean WBC (18.0 vs. 11.4 × 109/L, p<0.001), absolute neutrophil count (5.3 vs. 3.6 × 109/L, p=0.001), and platelet count (416 vs. 315 × 109/L, p=0.0001) compared to those with the highest hemoglobin. The laboratory findings of patients receiving HU also were significantly lower than those of subjects in the lowest hemoglobin group and similar to those in the highest hemoglobin group. Conclusions: Severe anemia in very young patients with SCA was associated with elevated WBC and platelet counts and higher TCD velocities. Interestingly, severe anemia also was associated with increased frequency of ACS, in contrast to the association of ACS with higher hemoglobin levels in older patients. Future studies will need to confirm this relationship and clarify to what extent associated findings (e.g., hyposplenia, elevated WBC or platelet count) contribute to this susceptibility. Severe anemia in young SCA patients is a negative prognostic factor that is significantly impacted by early hydroxyurea therapy. Disclosures: Off Label Use: Hydroxyurea is not approved by FDA for infants with sickle cell disease. Miller:NIH/NHLBI; Emmaus Med Inc, Novartis Pharmaceutical; St Jude Childrens Hospital: Research Funding.

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Long Term Safety and Efficacy Of Low Fixed Dose Hydroxyurea In Pediatric Patients With Sickle Cell Anemia: A Single Center Study From Central India

Blood ◽

10.1182/blood.v122.21.1000.1000 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1000-1000 ◽

Cited By ~ 1

Author(s):

Dipty L. Jain ◽

Lakshmanan Krishnamurti ◽

Vijaya Sarathi ◽

Saumil Desai ◽

Amruta Gokhale

Keyword(s):

Sickle Cell Anemia ◽

Low Dose ◽

Pediatric Patients ◽

Central India ◽

Fixed Dose ◽

Acute Chest Syndrome ◽

Severe Anemia ◽

Safety And Efficacy

Abstract Introduction Hydroxyurea (HU) therapy ameliorates the morbidity associated with Sickle cell anemia (SCA). HU is typically escalated to maximum tolerated doses (MTD) for treatment of SCA patients. Monitoring HU for toxicity poses potential challenges in low resource settings. We have previously reported the safety and efficacy of fixed low dose HU at 10mg/kg body weight ( Jain et al 2013). We studied the long term safety and efficacy of low dose HU in pediatric patients with SCA. Methods Long term observational follow up of 40 young Indian SCA patients was carried out for a period of 10 years in a single tertiary care center in central India. The number of clinical events including vasocclusive crises, acute chest syndrome, stroke, sequestration crises, avascular bone necrosis in the entire cohort was assessed prior to starting HU and subsequently every 3 months. Laboratory parameters including hemoglobin levels, Hb F levels, mean corpuscular volume, mean corpuscular hemoglobin concentration were also followed up over the same time period. Results The total number of patients in this study was 40 (17 females & 23 males). Mean age was 12.95 years ± 9.62. All patients had HbSS. There was an increase in mean hemoglobin, HbF, MCV and MCH over time in the patient population ( Table 1). There was a decrease in the mean number of hospitalizations, vasocclusive crises, acute chest syndromes, stroke and severe anemia ( Table 2). HU was well tolerated with minimal hematological or other toxicity (Table3). Patients who experienced transient hematological, liver or renal toxicity were able to resume HU at the same dose. HU was permanently discontinued in 2 patients who had manifestations of HIV/AIDS. HU was temporarily interrupted in one patient who was receiving treatment for tuberculosis and in one patient for the duration of a normal pregnancy. There was one death attributable to severe septicemia without evidence of neutropenia after 2 years follow up. There were 3 subjects who were lost to follow up, one after 2 years follow up and remaining 2 after 5 years of follow up. Of note, patients had a high HbF level at baseline. High HbF levels at baseline, the variable relationship of HbF to disease severity and amelioration of disease in Indian patients with high HbF has been previously reported ( Jain et al 2012, Patel et al 2012, Italia et al 2009). Conclusions Low fixed dose HU is well tolerated and is efficacious in reducing incidence of VOC, hospitalizations, severe anemia, stroke and acute chest syndrome. Low fixed dose HU may be advantageous in low resource settings because of lower toxicity and consequently less need for monitoring. There is a need for multi-center randomized comparisons of low fixed dose HU with conventional escalation of HU dose to MTD. Disclosures: Krishnamurti: GlycoMimetics, Inc.: Research Funding.

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