Systemic Steroids and the Risk of Vasoocclusive Events in Patients with Sickle Cell Disease

Sickle cell disease (SCD) is a genetic hemoglobinopathy characterized by ongoing intravascular hemolysis and recurrent episodes of vasoocclusion impacting the systemic and pulmonary vasculature. SCD affects 100,000 people living in the United States and 250–300,000 births each year worldwide. Vasoocclusive events (VOEs), typified by acute, severe pain (often superimposed on chronic pain), are the most common cause of hospitalization in SCD and significantly impact patients’ disease severity and quality of life (1). Adult and pediatric pulmonologists participate in the care of patients with SCD because of the spectrum of acute and chronic complications impacting nearly every cell and structure of the lungs. Acute chest syndrome (ACS) is the second most common cause of hospitalization and is often the consequence of a VOE. Asthma and lower airway dysfunction are common in SCD, particularly in children, and asthma has been associated with an increased risk of ACS (2). A recently published article by Walter and colleagues in the journal Blood, linking exposure to systemic corticosteroids with an increased risk of VOEs in SCD, brings into question the safety of corticosteroid use to treat pulmonary disease in these patients (3). The goal of this paper is to highlight this association for the pulmonary community to improve clinical outcomes for our patients.

Vasoocclusion in SCD is the consequence of abnormal interaction of sickle erythrocytes, leukocytes, and platelets with the endothelium. Numerous inflammatory pathways have been implicated in its pathogenesis. Despite the heightened inflammatory state in SCD, the link between corticosteroid use and VOEs has been controversial. Systemic steroids have been utilized to decrease the inflammation of VOEs and ACS. Two randomized studies demonstrated a reduction in hospital length of stay and need for transfusion in patients with SCD who had a VOE treated with steroids, whereas two retrospective studies demonstrated rebound pain in patients with ACS treated with steroids (4, 5). Several case series suggest that steroid use in SCD for other reasons increases the risk of de novo VOEs, suggesting that this is not just a reemergence of an ongoing VOE (6, 7).

To address the conflicting and incomplete information about the potential benefits and risks of corticosteroid use in individuals with SCD, Walter and colleagues conducted the largest analysis of observational data to date utilizing a French national health insurance system database, the Système National des Données de Santé (National Health Data System). They utilized a case-case-time control design to analyze data from 5,151 patients with SCD who were hospitalized with a VOE (defined by ICD-10 [International Classification of Diseases, 10th Revision] code) between 2010 and 2018. The primary exposure of interest was dispensing of an outpatient prescription for oral, intravenous, or intraarticular corticosteroids in the 28 days preceding the hospitalization. The overwhelming majority of these prescriptions (95.4%) were for oral steroids. The use of inhaled corticosteroids (ICSs) was not included in this analysis, as prior studies have not demonstrated an increased VOE risk with ICS use (8). Additionally, the inpatient use of systemic steroids was not included. Forty-five percent of the cohort was exposed to systemic corticosteroids during the study period. Exposure to systemic steroids was associated with an overall increased odds of a VOE: adjusted odds ratio (aOR), 3.8; 95% confidence interval (95%CI), 2.4–5.6. Concurrent exposure to hydroxyurea (HU) decreased the effect of this association (in HU-exposed patients, aOR, 2.6; 95% CI, 1.1–6.4; in HU-unexposed patients, aOR, 4.0; 95% CI, 2.5–6.3). Those under the age of 15 years had a lower risk than those 15 and older (for those <15 years of age, aOR, 2.8; 95% CI, 1.5–5.3; for those :15 years of age, aOR, 4.5; 95% CI, 2.4–8.4), and males had a reduced odds of subsequent VOEs after steroid use (aOR, 2.1; 95% CI, 1.1–4.0) compared with females (aOR, 6.5; 95% CI, 3.5–12.3). Thirteen percent of the VOE cases after outpatient corticosteroid use required an ICU admission. Unfortunately, the percentage of VOE hospitalizations that included ACS could not be ascertained from this dataset. Limitations of the study include its observational study design (which leads to the question of confounding by indication) and a lack of information about the indications for systemic corticosteroids. Perhaps the risk of VOEs associated with corticosteroid use for status asthmaticus is different from the risk of VOEs associated with corticosteroid use for a different indication. Despite these limitations, these findings should be recognized by pediatric and adult pulmonologists as a rationale to increase our understanding of the association between all-cause corticosteroid use and VOEs.

In terms of treating respiratory disease, systemic corticosteroids are utilized in patients with SCD for treatment of asthma and, more recently, as a supportive treatment for patients hospitalized with coronavirus disease (COVID-19) pneumonia and hypoxia. Given that asthma is the most common chronic disease in childhood (particularly among low-income African American children in the United States) and that physician diagnosis of asthma is associated with increased incidence of ACS (9), earlier onset of the first episode of ACS (2), and increased risk of mortality (10), optimizing asthma management to prevent unnecessary use of systemic corticosteroids for acute asthma exacerbations should be a priority. It is, of course, important to weigh the risks of VOEs from administering corticosteroids versus the risks of withholding corticosteroids for status asthmaticus. Steroid tapers are used anecdotally to potentially reduce the risk of rebound sickle cell pain, but the benefit of a steroid taper in preventing subsequent VOEs is unclear; a randomized controlled trial that attempted to answer this question was unfortunately stopped early for low enrollment (11). Fortunately, there has been increasing attention paid to systematically improving guideline-based asthma care for patients with SCD (12), which, in turn, has been associated with improved asthma- and SCD-related outcomes (13, 14).

In addition to acute status asthmaticus, SARS-CoV-2 (COVID-19) infection represents another potential acute pulmonary indication for systemic corticosteroid use. Infection with COVID-19 increases morbidity and mortality for patients living with SCD (15). Twenty to 30% of those infected with COVID-19 develop ACS (15), an umbrella term defined by an infiltrate on chest radiography involving at least one segment of the lung with associated respiratory symptoms. COVID-19 pneumonia is included under the umbrella of ACS. Typically, individuals without SCD who develop COVID-19 pneumonia are treated with 6 mg dexamethasone for 10 days. At our institution, to date, a similar strategy has been used in SCD patients. Dexamethasone use has been associated with reduced mortality from COVID-19 among those requiring either invasive mechanical ventilation or supplemental oxygen (16). The risk of VOEs in patients treated for COVID-19 is unknown, as the data from the study by Walter and colleagues were collected before the COVID pandemic, but one could assume that it might be similar. The benefits and risks of dexamethasone use in SCD-associated COVID-19 need to be assessed on a case-by-case basis. The potential risk associated with corticosteroid use heightens the rationale for the optimization of the patient’s underlying SCD with either early simple transfusion to increase the hemoglobin concentration to at least 9 g/dl or the utilization of exchange transfusion for those with higher Hb concentrations (17). It is essential to utilize early simple or exchange transfusion in the management of patients with SCD who have pneumonia and hypoxia related to COVID-19, regardless of corticosteroid use. One potential benefit of this strategy is reduction of the Hemoglobin S concentration, which may mitigate the toxicity of steroids in this population (4).

In summary, publication of the largest study to date linking the use of systemic steroids to an increased frequency of VOEs is noteworthy, as this is a major cause of morbidity for patients living with SCD worldwide. As pulmonary and critical care physicians, it is important to understand this association to provide the best care for our patients. Further research is clearly needed to understand whether the risk of corticosteroid use is higher in certain disease states than others, and the extent to which confounding by indication plays a role in this association. Until these questions have been more thoroughly investigated, however, the potential for an unfavorable risk–benefit ratio should be carefully considered before reflexively prescribing systemic corticosteroids for individuals with SCD.