Clinical Research Directory

Tocilizumab for Acute Chest Syndrome

The investigators are evaluating the role of a low dose of tocilizumab in treating acute chest syndrome in patients with sickle cell disease. Tocilizumab inhibits interleukin-6 (IL-6) receptors and is used to treat rheumatoid arthritis and severe cytokine release syndrome, which can be seen with chimeric antigen receptor T-cell (CAR-T) therapy, and it is also authorized for treatment of COVID-19. Since IL-6 levels are elevated in the sputum of patients with acute chest syndrome, the investigators are hopeful that this will be an effective strategy. The investigators will be looking at how a low dose of tocilizumab affects oxygen status, clinical outcomes, and laboratory markers in patients admitted to the hospital with acute chest syndrome.

Ultrasound Acute Chest Syndrome Sickle Cell Disease

Feasibility and reliability of ultrasound in the inpatient hematology setting.

Pleuropulmonary Ultrasound Imaging in Patients With Sickle Cell Disease in a Vaso-occlusive Crisis. "ECHODREP"

Introduction Sickle cell disease is the most common inherited genetic disorder in France and worldwide. Its main acute manifestation is vaso-occlusive crisis, a frequent reason for emergency department visits. Acute chest syndrome is the leading complication and cause of death during vaso-occlusive crisis, occurring in approximately 15-20% of hospitalized episodes, often within the first few days after symptom onset. Early identification of patients at risk of developing acute chest syndrome remains a major clinical challenge. Although predictive clinical and biological scores exist, their ability to identify high-risk patients remains limited in daily practice. Chest X-ray has traditionally been used to support the diagnosis of acute chest syndrome, but its diagnostic performance and repeated radiation exposure are increasingly questioned. Lung ultrasound is a non-invasive bedside imaging tool that has shown good performance for detecting pleural effusion, alveolar consolidation and interstitial syndrome, and is increasingly used by emergency physicians. However, its diagnostic performance when systematically performed by emergency physicians in adult sickle cell patients presenting with vaso-occlusive crisis has not yet been specifically assessed. Hypothesis / Objective We hypothesize that systematic pleuropulmonary ultrasound performed early after emergency department admission may help identify patients with vaso-occlusive crisis who are at risk of developing acute chest syndrome, and may allow earlier diagnostic assessment. The primary objective of the ECHODREP study is to evaluate the diagnostic performance of systematic pleuropulmonary ultrasound, performed by an emergency physician within six hours of admission, for the diagnosis of acute chest syndrome during hospitalization in adult sickle cell patients presenting with vaso-occlusive crisis. Secondary objectives are to assess the association between ultrasound findings and the final diagnosis of acute chest syndrome, to describe patient outcomes according to ultrasound results, including hospitalization, admission to intermediate care, emergency department revisits and mortality at day 3, day 7 and day 28, and to compare ultrasound performance according to the operator's level of experience. Method ECHODREP is a prospective, observational, single-arm, monocentric diagnostic performance study conducted in the Emergency Department of Henri-Mondor University Hospital. The study will include 200 adult patients with sickle cell disease - SS, SC or S-beta-thalassemia - presenting to the emergency department for vaso-occlusive crisis. Patients with a diagnosis of acute chest syndrome already established on arrival, patients previously included in the study, protected adults, and patients refusing participation will not be included. After informed consent, a pleuropulmonary ultrasound will be performed within six hours of emergency department admission by an emergency physician investigator who is not involved in the patient's clinical care. The examination will assess twelve predefined lung zones. In order to avoid influencing standard care and to preserve the objectivity of the study, ultrasound findings obtained for research purposes will not be communicated to the treating medical team and will not be used for diagnostic or therapeutic decisions. Patients will receive standard care for vaso-occlusive crisis according to local practice. A telephone follow-up will be performed at day 28 to collect vital status, emergency department revisits, hospitalizations and any secondary diagnosis of acute chest syndrome. At the end of follow-up, an independent adjudication committee, blinded to the research ultrasound findings, will determine the final diagnosis: uncomplicated vaso-occlusive crisis or acute chest syndrome. The primary endpoint will be the diagnosis of acute chest syndrome within seven days after emergency department admission or before hospital discharge, based on the medical record. Diagnostic performance will be assessed by calculating sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the ROC curve, with 95% confidence intervals. Additional analyses will compare outcomes according to ultrasound findings and operator experience. Conclusion This exploratory study will provide original data on the diagnostic performance of early pleuropulmonary ultrasound performed by emergency physicians in adult sickle cell patients presenting with vaso-occlusive crisis. If ultrasound demonstrates adequate diagnostic accuracy, it could contribute to earlier identification of acute chest syndrome, improve risk stratification in the emergency department and help optimize the management pathway of these patients. By evaluating both diagnostic performance and patient outcomes, ECHODREP may support the integration of lung ultrasound into future diagnostic strategies for acute chest syndrome in sickle cell disease.

Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Patients With Sickle Cell Disease

The purpose of this study is to determine whether a single infusion of tocilizumab is effective in reducing the time to successful weaning from both supplemental oxygen and any respiratory support, in pediatric and adult patients with sickle cell disease (SCD) during acute chest syndrome (ACS).

Morphine Clearance and Glomerular Filtration in Sickle Cell Patients in Crisis in Intensive Care

Background: Sickle cell disease is a genetic disorder of haemoglobin (which carries oxygen in red blood cells). The shape of sickle cell-patients' red blood cells is abnormal. Thus, red blood cells can be blocked in small vessels, responsible for painful crises due to a lack of downstream circulation. These crisis (acute vaso-occlusive crisis) require strong treatment based on morphine, and often require intensive care.However, treatment is often insufficiently effective. Patient can also experiment acute chest syndrome, a complication of vaso-occlusive crisis, which can be responsible for respiratory failure. In addition, patients with sickle cell disease frequently have kidney damage called sickle cell nephropathy, which in the early stages of the disease is responsible for renal hyperfiltration, meaning that the kidneys filter the blood more than necessary, with faster elimination of drugs. For example, it is known that higher doses of antibiotics must be used in these patients than in the general population for the same effectiveness. The hypothesis of the study is that morphine, a drug eliminated by kidneys, is underdosed in patients with sickle cell disease, which is responsible for the difficulties in achieving sufficient analgesia. Objective: To determine the glomerular filtration rate threshold for which it is necessary to prescribe higher doses of morphine in sickle cell patients with vaso-occlusive crisis. Methods: inclusion of 100 patients admitted to intensive care for an acute vaso-occlusive crisis or acute chest syndrome and receiving morphine. Within 24 hours of study inclusion, four morphine dosages will be performed, in parallel with a precise determination of the glomerular filtration rate by measuring the elimination rate of a tracer, 100% eliminated by the kidneys and injected at the start of the study. This tracer is iohexol, a contrast agent commonly used in radiology. Morphine underdosage will be interpretated regarding glomerular filtration rate. The effectiveness of analgesia and the amount of analgesics required will be also be analyzed. Outlook: At the end of this study, the investigators will be able to offer adapted doses of morphine for sickle cell patients in crisis, adapted to glomerular filtration rate, in the aim of personalizing analgesia.

Awake Prone Positioning for Severe Acute Chest Syndrome

Acute chest syndrome (ACS) is the leading cause of admission to intensive care and the leading cause of death in patients with sickle cell disease. Irrespective of the cause of ACS, there is an heterogeneity in pulmonary ventilation/perfusion ratios, leading to worsening of the disease. Efficiency of awake prone positioning (APP) in acute respiratory failure (ARF) was particularly highlighted during the COVID-19 pandemic. Several physiological factors contribute to this benefit including an improvement in ventilatory drive and gas exchange. The investigator hypothesize that APP could lead to clinical improvement in ACS in terms of oxygenation and ventilatory drive, by improving the heterogeneity of ventilation

Early-goal Directed Automated Red Blood Cell Exchange for Acute Chest Syndrome in Sickle Cell Disease

Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive pain crisis (VOC), which may evolve to acute chest syndrome (ACS), the most common cause of death among adult patients with SCD. Currently, there is no etiologic treatment to abort ACS. Therefore, management of ACS mostly involve a symptomatic approach including in routine, and as per recommendations, hydration, analgesics, supplemental oxygen, and transfusion. The polymerisation of sickle haemoglobin (HbS) is one major feature in the pathogenesis of vaso-occlusion. Current guidelines recommend red blood cell exchange transfusion (REX) in patients with severe ACS in order to improve oxygenation and reduce HbS concentration to blunt sickling. REX is often preferred over simple transfusion in this setting because it rapidly reduces HbS without raising final haematocrit. There are currently two methods for REX: manual (with sequential phlebotomies and transfusions) or automated (erythrocytapheresis). The former allows a sober use of red blood cell packs, while the latter achieves haematological targets (HbS and haematocrit) quickly and more consistently, but requires a special equipment and trained staff. As a result of inflammation and intravascular hemolysis, the plasma of patients with ACS may also contain several components that promote vaso-occlusion, lung injury and organ failure, including cytokines (e.g., IL-6), free haemoglobin and free haem. Conversely, it is depleted in haptoglobin and hemopexin, which normally bind to and clear cell-free haemoglobin. The addition of therapeutic plasma exchange to erythrocytapheresis during automated REX may therefore have a dual beneficial effect in patients with overt intravascular hemolysis: i) deplete the inflammatory mediators and products of hemolysis; ii) replete haptoglobin and hemopexin. REX modalities (automated vs manual) have not been tested during ACS. The hypothesis is that early-goal directed automated REX may accelerate the resolution of severe ACS as compared to manual REX.