Study Highlights Value of PROs in Children With Sickle Cell Disease During Acute Pain Episodes

A research letter published in Blood Advances reports that collecting pain-related patient-reported outcomes (PROs) in clinical trials of acute pain intervention for children with sickle cell disease (SCD) is feasible and provides valuable context to clinical outcomes.

Individuals with SCD, an inherited disorder characterized by misshapen “sickled” red blood cells, are prone to acute pain episodes.But data on the impact of acute episodes on PROs of pain interference and fatigue for children who present in acute care settings are limited.

The Patient-Reported Outcomes Measurement Information System (PROMIS) has been used to assess children with SCD during outpatient visits, instances of acute care utilization, and clinical trials. The current study aimed to assess the feasibility of collecting PROs and the impact of acute pain on PROs upon clinical trial enrollment. Clinical characteristics served as covariates in the analysis.

PROs were collected at or shortly after enrollment in a phase 2, randomized, double-blind, placebo-controlled trial of intravenous arginine therapy for acute pain episodes in SCD (NCT02536170). Participants were aged 3 years to 21 years old, with a mean age of 12.8 years.

Of 108 participants enrolled in the study, 98 (90.7%) completed at least 1 of 2 self-reported pediatric or parent-proxy PROs. Each survey produced domain-specific standard T-scores. There were 3 established T-score thresholds for symptom severity in the analysis: scores of 48 or lower were considered mild, scores between 48 and 64 were moderate, and scores above 64 were considered severe.

Data collected as part of the trial included information on demographics, laboratory measures, and clinical outcomes. Information on prior healthcare utilization (HCU) for pain, defined as 3 or more instances of HCU for pain in the 12 months prior to the trial, was also included in the analysis.

A total of 94 patients completed the PROMIS Pediatric Pain Interferencesurvey, and 98 completed thePROMIS Pediatric Fatigue survey. A group of 94 patients completed both surveys. For 64 participants, at least 1 self-report pediatric PROMIS survey was available, while 35 had at least 1 parent-proxy PROMIS survey was available.

“Our experience confirms that collection of pain-related PROs is feasible in a clinical trial of an acute pain intervention in SCD, consistent with previous experience in observational and intervention studies of acute pain in SCD,” the authors wrote.

Most pain interference scores (88.3%) were moderate or severe in the study, as were the majority of the fatigue scores (64%). Female patients were more likely to report moderate to severe fatigue compared with males (78.1% vs 50%), which reflects previous reports of higher fatigue in females versus males with SCD in general.

Individuals prescribed hydroxyurea, the standard of care for SCD, were more likely to have moderate to severe fatigue compared with other patients. However, a separate association between severe SCD genotype and higher HCU for pain suggests that disease severity may be related to the increased fatigue in this population. Patients with moderate to severe pain interference were also more likely to be prescribed non-steroidal anti-inflammatory drugs compared with patients who reported mild pain interference in the study.

There were no significant differences in fatigue or pain interference between age groups, contrary to past reports of children ages 12 and older experiencing greater pain interference and fatigue compared with younger children. SCD genotype did not correlate with PROs in the study, nor did high HCU for pain. Hydroxyurea prescription and pain interference were also not associated in this study, which is in line with previous reports that hydroxyurea does not significantly change pain interference PROs after an acute pain episode.

There were also no significant associations between the highest pain score reported at baseline and pain interference or fatigue. Finally, neither pain nor fatigue correlated with hemoglobin measures or mean corpuscular volume values—a finding that differs from prior reports in the clinic and hospital settings.

The authors emphasize a need for more studies focusing on potential clinical and biological correlations with PRO measures. The study did not collect data on chronic pain, which also impacts PROSs. Therefore, gaining insight into the impact of acute pain in patients with chronic pain should be prioritized. Another randomized study of arginine in SCD (NCT04839354) is investigating this relationship, the authors noted.

Overall, the study reinforces the value of PROs to complement clinical findings and supports the inclusion of PROs as end points in clinical trials, as the American Society of Hematology recommends. Further, the authors emphasize a need for sufficiently powered studies to investigate potential associations between clinical measures and PROs in children with SCD experiencing acute pain episodes.

Reference

Bakshi N, Liu Z, Gillespie S, et al. Patient reported outcomes in children with sickle cell disease at presentation for an acute pain episode. Blood Adv. Published online November 2, 2022. doi:10.1182/bloodadvances.2021006794