Low Arginine Bioavailability Predicts Poor Clinical Outcomes in Sickle Cell Disease


Two experts describe the correlation between the severity of arginine deficiency and worse clinical outcomes among hospitalized children with sickle cell disease experiencing vaso-occlusive pain episodes.

Arginine bioavailability may represent a novel biomarker of pain severity among children with sickle cell disease hospitalized with vaso-occlusive pain episodes (SCD-VOE), according to new research.

The analysis, presented at the 2023 American Society of Hematology (ASH) Annual Meeting, showed low arginine bioavailability predicted longer time-to-crisis resolution and higher use of intravenous opioids in children with SCD-VOE, in the absence of arginine replacement therapy.

In an interview with HCPLive, study authors Dunia Hatabah, MD, and Claudia R. Morris, MD from the department of pediatrics at Emory University School of Medicine, described how worse clinical outcomes stemming from low arginine bioavailability ceased after arginine treatment in children with SCD.

“These observations are actually even more interesting because we saw this association of low arginine bioavailability and a worse clinical outcome in the placebo group only,” Hatabah said. “This association was lost when we treated our patient with arginine, so this adds to prior observations that the severity of arginine deficiency is associated with worse clinical outcomes.”

Hatabah and colleagues suggested the association between arginine bioavailability and clinical outcomes has not been sufficiently assessed in children with SCD-VOE. In a secondary analysis of a prospective, single-center, double-blinded randomized controlled trial, the investigative team assessed the association between arginine bioavailability and clinical outcomes in children with SCD-VOE who received intravenous arginine replacement therapy.

Patients were randomized into 1 of 3 arms: 100 mg/kg/dose arginine (standard dose), 200 mg/kg (loading dose) followed by standard dose, or placebo. A total of 1,548 patients were screened and 266 were eligible for analysis – of this population, 108 were randomized and consisted of 54.4% female patients with a mean age of 12.44 years. All patients identified as African American, 75% had genotype Hb-SS, and 69.1% were on hydroxyurea.

At the VOE presentation, plasma arginine levels were considered low (mean, 50 ± 28 µm), with low arginine levels (<60 µm) observed in 74% of the population. Upon analysis, investigators found arginine replacement therapy increased arginine concentration by 182% (P <.001) compared to 26% (P = .24) in placebo-treated patients.

Moreover, the arginine-to-ornithine ratio correlated to arginase concentration (r = -.38; P <.0001). Investigators found that the time-to-crisis resolution was strongly associated with total parenteral opioid use (r = .72; P <.0001).

Arginine bioavailability at hospital presentation was inversely correlated to time-to-crisis resolution for both the arginine-to-ornithine ratio and global arginine bioavailability ratio (GABR) (r = -0.37; P = .02) in the placebo arm only, but not those who received arginine therapy (GABR: r = -.05, P = .6; arginine-to-ornithine ratio: r = -.07, P = .55).

Investigators observed similar trends for total parenteral opioid use. The data showed pain scores at presentation were positively correlated with total parenteral opioid use (r = .33; P = .04) in the placebo arm, but not in the arm that received arginine therapy (r = .03; P = .76). Meanwhile, the time-to-crisis resolution was associated with age (r = .2; P = .03).

For more insight into the findings, watch the full interview with Drs. Hatabah and Morris in the above video.


Hatabah D, Bakhsi N, Brown LA, Harris F, Leake D, Korman R, Rees C, Griffiths M, Dampier C, Morris CR. Low Arginine Bioavailability and Clinical Outcomes in Children with Sickle Cell Disease Hospitalized with Vaso-Occlusive Pain Episode. Paper presented at 2023 American Society of Hematology (ASH) Annual Meeting in San Diego, California. December 9 - 12, 2023.

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