Reduction in Opioid Use and Clinical Complications in Vitamin D Deficient Pediatric SCD Patients Following Vitamin D Replacement

Background: Hydroxyurea, the most common drug used to treat SCD patients, has several limitations: inadequate clinical benefit in 50% of adults, poor compliance, teratogenicity, marrow toxicity, and reduced fetal hemoglobin (HbF) induction over time. Thus, there is a need for additional treatment options. Vitamin D (vitD) could be a potential treatment option because it: 1) increases HbF and mean corpuscular volume, 2) reduces white cell (WBC) and platelet counts, and 3) is associated with increased morbidity in SCD patients. However, insufficient data demonstrating clinical benefits following vitD replacement prevents its routine use. To address this knowledge gap, we analyzed the change in emergency room visits/hospital admissions (admission rate), opioid use, clinical complications, HbF levels, and WBC count in pediatric SCD patients after vitD replacement.

Methods: SCD patients 21 years and younger who received vitD at Texas Children's Hospital from 2007 to 2021 were included in this retrospective longitudinal study. Patients on chronic transfusions were excluded. Three-month data after an on-demand blood transfusion was also excluded from the analysis set as transfusion affects HbF levels temporarily. The study period included two years before vitD replacement (pre-vitD period, referent category ), vitD replacement period, and one year after cessation of vitD (post-vitD period). The patients with vitD levels < 30 ng/ml and ≥ 30 ng/ml were considered vitD deficient and not deficient, respectively. VitD levels or the vitD replacement status (pre-vitD, vitD, and post-vitD) were the exposure variables. Age and folic acid were considered potential confounders, and genotype and maximum tolerated dose of hydroxyurea (MTD) were effect modifiers. Hydroxyurea dose of ≥ 35 mg/kg/day or the dose that achieved absolute neutrophil count between 2000-4000/cmm was considered MTD.

Statistical analyses: Two-level linear mixed model and Wilcoxon rank-sum tests were used. WBC, admission rate, and opioid use-related variables required log transformation to meet the model assumptions. A covariate was retained if its exclusion changed the beta coefficient of the exposure variable by over 10%. A backward selection method was used to derive a final model. P-values were adjusted for the multiple testing.

Results: We analyzed 136 patients (male=68, average age=12.3 years, SCA=129) with a total of 534 clinic visits. The median follow-up was 3.5 years. 47.4% did not exhibit an elevation of vitD levels and 10.9% had a recurrence of deficiency despite an adequate replacement dose (median 2000 IU/day). Patients were on a stable dose of hydroxyurea (median: 19.9 mg/kg/day) during the study period. The reduction in hospital admissions, emergency room visits, infections, transfusions, and acute chest syndrome was higher during the vitD period than post-vitD period (Table1, Figure 1). The loss/reduction in benefits during the post-vitD period could be due to falling vitamin D levels and recurrence in 10.9% of patients. A comparable reduction in opioid use during the vitD and post-vitD replacement periods (81 vs.82%) suggests sustained benefit in pain reduction beyond the replacement period. (Table 1). Higher vitamin D levels were associated with higher HbF levels and lower WBC counts (Table1). There was a higher increase in HbF levels in patients at MTD (1.89% points) compared to the patients not at MTD (0.38% points) for each 10 ng/ml increase in vitD levels (p<0.01). Similarly, there was a higher reduction in WBC count in patients at MTD (15%) compared to the patients not at MTD (1%) (p<0.01).

Conclusion: Our data show a statistically significant reduction in emergency visits/hospital admissions, opioid use, infections, transfusions, and acute chest syndrome following vitD replacement. The clinical improvement may be due to increased HbF levels and decreased WBC count observed with the increase in vitD levels. All subjects were on hydroxyurea; of note, subjects at MTD had a greater HbF response with vitD replacement than those not at MTD, suggesting an additive interaction between vitD and hydroxyurea. We, therefore, conclude that regular vitD screening followed by vitamin D replacement to achieve adequate vitamin D levels will likely reduce the public health burden of the SCD population significantly.

Sheehan:Global Blood Therapeutics: Research Funding.