A united-states nationwide analysis of sickle cell genotype-specific differences in inpatient outcomes

Abstract Introduction The clinical diagnosis of sickle cell disease (SCD) encompasses several genotypes. Hb-SS, Hb-SC, Hb S β+, and HbSβ0 thalassemia are the most common genotypes in the United States. Phenotypically, there is a wide spectrum of presentations, with Hb-SS generally considered the most severe form. However, there exists limited data comparing clinical outcomes of vaso-occlusive crisis (VOC) across genotypes. This study assesses genotype-specific outcomes and healthcare utilization in hospitalized patients with VOC. Methods The National Inpatient Sample (NIS) database was used to identify admissions for SCD with VOC (2016 - 2019). Subjects identified were further stratified by sickle cell genotypes using ICD-10 codes. Discharge weights were applied in the database to generate national estimates. Pearson's Chi-Squared test for categorical variables and Student's t-tests/one-way ANOVA for continuous variables were applied to compare the baseline demographics and hospital characteristics between the groups. The primary outcome was mortality. Secondary outcomes were length of stay (LOS), acute hypoxemic respiratory failure requiring mechanical ventilation, renal replacement therapy (RRT) and red blood cell transfusion. Multivariate linear and logistic regression models were used to adjust for confounders such as age, tobacco use, hypertension, ischemic heart disease and prior chronic obstructive pulmonary disease (COPD). Results We identified a total of 71,536 admissions, involving 62,845 patients with Hb-SS, 4,407 with Hb-SC, 3,655 with Hb-S β+ or S β0- thalassemia, and 629 with other sickle cell variants. Hb-SS was the most common genotype. Compared to patients with Hb-SS disease, those with Hb-SC disease had significantly higher in-hospital mortality (aOR 1.54, 95% CI 1.02–2.31, p=0.038). Rates of mechanical ventilation were also significantly elevated in the Hb-SC group (0.9% vs 0.5%, aOR 1.82, 95% CI 1.36–2.44, p<0.001). Compared to Hb-SS, RRT was significantly less likely in patients with Hb-SC (aOR 0.46, 95% CI 0.33–0.65, p<0.001) and Hb S β thalassemia (aOR 0.73, 95% CI 0.53–1.00, p=0.047). Relative to Hb-SS, red blood cell transfusion was also less frequent in both Hb-SC (6.8% vs 23.3%, aOR 0.24, 95% CI 0.21–0.26, p<0.001) and Hb S β- thalassemia (14.8%, aOR 0.56, 95% CI 0.51–0.61, p<0.001). Regarding healthcare utilization, patients with Hb-SC, Hb S β- thalassemia, and other genotypes incurred higher hospitalization costs relative to those with Hb-SS (Hb-SC: aRR 1.05, p=0.033; Hb S β thalassemia: aRR 1.14, p<0.001; other genotypes: aRR 1.11, p=0.006). No statistically significant differences were observed in length of stay. Discussion During acute hospitalization for VOC, outcomes in patients with SCD vary based on genotype. Our study, albeit limited by accuracy of ICD-10 coding, demonstrates that despite being considered to have “milder” disease, patients with Hb-SC and Hb S β- thalassemia experience considerable morbidity and mortality while admitted. Despite fewer transfusion needs, Hb-SC was furthermore associated with higher odds of mechanical ventilation and mortality. Finally, higher hospitalization costs across all non-Hb-SS genotypes—despite similar lengths of stay—may reflect differences in care complexity, resource use, or billing patterns that warrant further exploration. Overall, these data challenge assumptions that non-Hb-SS genotypes are less severe. Our data also highlight the need for genotype-level incorporation into clinical trials to help inform management strategies. Further is also needed to address underlying drivers of genotypic/phenotype differences amongst individuals with SCD.