Sickle Cell Disease
Conditions
Keywords
Anemia, Sickle Cell, Acute Chest Syndrome, Secretory phospholipase A2(sPLA2)
Brief summary
Acute chest syndrome (ACS) is similar to severe pneumonia and is a common cause of hospitalizations for people with sickle cell disease (SCD). Blood transfusions are one treatment option for ACS. High levels of an enzyme called secretory phospholipase A2 (sPLA2) may be present in people before they develop ACS. This study will determine how well sPLA2 levels can predict the onset of ACS and whether identifying high sPLA2 levels allows enough time to prevent ACS with blood transfusions. Results from this study will help to determine the feasibility of conducting a larger study that would further examine the use of sPLA2 levels and blood transfusions to prevent ACS in people with SCD.
Detailed description
SCD is an inherited blood disorder, and symptoms include anemia, infections, organ damage, and intense episodes of pain, which are called sickle cell crises. ACS, characterized by fever, respiratory distress, and lung tissue damage, is the second most common cause of hospitalization and the leading cause of death among people with SCD. Most people with SCD will experience at least one episode of ACS, and repeated episodes can result in progressive lung disease. ACS can appear suddenly and often requires immediate hospitalization and treatment, which can include blood transfusions. People with elevated blood levels of sPLA2 may be at risk for developing ACS, and this enzyme is often detectable before the onset of ACS symptoms. The purpose of this study is to examine the use of sPLA2 as a predictor of ACS and to determine whether subsequent blood transfusions can be administered early enough to prevent the onset of ACS in people with SCD who are at risk for ACS. Study researchers will also assess the feasibility of conducting a larger study that would further examine the effectiveness of using sPLA2 levels and blood transfusions to prevent ACS. This study will involve two parts. In the first part of the study, participants with SCD who are admitted to the hospital with an acute sickle cell pain event will be randomly assigned to receive either a single blood transfusion or standard care for ACS and no blood transfusion. All participants will be closely monitored while in the hospital for the development of ACS, and study researchers will review participants' medical records. All participants will undergo daily blood collections, which will include testing for sPLA2 levels, and at least two chest x-rays. Twenty-eight days after hospital discharge, all participants will attend a follow-up study visit for blood collection, again to determine sPLA2 levels. In the second part of the study, participants who are not eligible or who do not choose to participate in the first part of the study will be enrolled into an observational group. These participants will receive standard care for ACS, but will not receive a blood transfusion. They will undergo daily blood collection during their hospital stay and at least one chest x-ray. While participants are in the hospital and 28 days after discharge, study researchers will review participants' medical records.
Interventions
BIOLOGICALSingle blood transfusion
Participants will receive a single transfusion of 7-13cc/kg packed red blood cells (RBCs) while in the hospital.
BEHAVIORALStandard care
Participants will receive standard care for ACS while in the hospital.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Carelon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for the Observational and Trial Cohorts: * Hemoglobin diagnosis of SS (two copies of the hemoglobin S gene), SC (one copy of the hemoglobin S gene and one copy of the hemoglobin C gene), or S-β thalassemia (β+ or β0) * No clinically apparent ACS * No prior participation in either part of the study Inclusion Criteria for the Trial Cohort, in addition to the above criteria: * sPLA2 level greater than 100 ng/mL within the same 24-hour window that coincides with fever and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window * Fever greater than 38.0º C within the same 24-hour window that coincides with elevated sPLA2 level (greater than 100 ng/mL) and chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window * Chest radiograph negative for new pulmonary infiltrate within the last 12 hours of the 24-hour window of an abnormal sPLA2 level and fever * Hemoglobin levels equal or less than 10 g/dL at time of study entry * Informed consent of parent(s) or legal guardian; informed consent or assent of participant as applicable
Exclusion criteria
for Observational and Trial Cohorts: * Existing diagnosis of a new pulmonary infiltrate diagnosed by chest radiography (pleural effusion not obscuring lung parenchyma will not exclude the person from the study) * Any coexisting medical condition for which the physician feels that a transfusion may be needed within 24 hours (e.g., severe anemia, stroke) * Red Blood Cell (RBC) transfusion in the 60 days before study entry * Unwillingness to sign consent form, or if a minor, unwillingness of parent/guardian to sign consent form * Treatment with any investigational drug or device in the 30 days before study entry (hydroxyurea is allowable) * History of alloimmunization that would prevent the participant from receiving blood within 8 hours of eligibility for study entry or history of a life-threatening transfusion reaction * Objection to transfusion for religious or other reasons from either the participant or guardian * History of treatment with systemic steroids within 1 week of study entry (inhaled steroids are acceptable) * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Chest Syndrome | Chest x-rays (CXR) were ordered for trial eligibility, as a result of clinical indications, or at discharge or 72 hours if no prior CXR. | First occurence of positive infiltrate on chest x-ray |
Countries
United States
Participant flow
Recruitment details
In the period June 2009 - June 2010, 237 subjects from 25 sites were enrolled in the feasibility study. Of 237 enrolled, only 10 were randomized (six subjects in the Standard Care Arm and four subjects in the Transfusion Arm). The randomization trial has been terminated due to the lack of enrollment.
Participants by arm
| Arm | Count |
|---|---|
| All Participants 237 subjects enrolled in the feasibility study. | 237 |
| Total | 237 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 122 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 114 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 230 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Maximum secretory phospholipase A2 (sPLA2) value >0 - 25 ng/ml | 106 participants |
| Maximum secretory phospholipase A2 (sPLA2) value >100 - 200 ng/ml | 13 participants |
| Maximum secretory phospholipase A2 (sPLA2) value >200 - 800 ng/ml | 28 participants |
| Maximum secretory phospholipase A2 (sPLA2) value >25 - 50 ng/ml | 34 participants |
| Maximum secretory phospholipase A2 (sPLA2) value >50 - 100 ng/ml | 22 participants |
| Maximum secretory phospholipase A2 (sPLA2) value Not applicable | 34 participants |
| Race/Ethnicity, Customized Black or African American | 230 participants |
| Race/Ethnicity, Customized More than one race | 1 participants |
| Race/Ethnicity, Customized Other | 3 participants |
| Race/Ethnicity, Customized White | 3 participants |
| Sex: Female, Male Female | 119 Participants |
| Sex: Female, Male Male | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Acute Chest Syndrome
First occurence of positive infiltrate on chest x-ray
Time frame: Chest x-rays (CXR) were ordered for trial eligibility, as a result of clinical indications, or at discharge or 72 hours if no prior CXR.
Population: Of 237 enrolled subjects, 27 subjects who received a transfusion and 7 subjects who had insufficient sPLA2 measurements were excluded. Therefore, two hundred and three (203) subjects were included in the analysis. Results were not reported by Arm due to the lack of enrollment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Adults | Acute Chest Syndrome | Yes | 11 participants |
| Adults | Acute Chest Syndrome | No | 85 participants |
| Children | Acute Chest Syndrome | Yes | 11 participants |
| Children | Acute Chest Syndrome | No | 96 participants |
| Overall | Acute Chest Syndrome | Yes | 22 participants |
| Overall | Acute Chest Syndrome | No | 181 participants |
Comparison: The optimal threshold level (TL), determined via receiver operating characteristic (ROC) curve analysis, maximizes the difference between the true positive rate (TPR) and the false positive rate (FPR). Since there is no corresponding analytic standard deviation (SD) for this value, we computed a robust SD based upon the interquartile range (IQR)/1.35 from a bootstrap sample of optimal TLs.95% CI: [38, 58]