Inflammation Markers Identify Sickle Cell Patients at Risk for Worse Outcomes, Study Suggests

High blood levels of two pro-inflammatory molecules, called interleukin-6 (IL-6) and interleukin-8 (IL-8), are linked to more frequent complications in people with sickle cell anemia, a study reports.

The study, “High levels of proinflammatory cytokines IL-6 and IL-8 are associated with a poor clinical outcome in sickle cell anemia,” was published in the journal Annals of Hematology.

Sickle cell anemia (SCA) is characterized by the activation of blood cells and the release of inflammatory molecules, called cytokines. The sickling of blood cells (their distortion into a sickle shape) and cytokine production perpetuate a chronic inflammatory state that impairs blood flow.

Previous research has suggested that the levels of pro-inflammatory cytokines change between steady and crisis states in SCA patients. A team from Brazil hypothesized that such levels could help monitor the clinical progression of the disease. To test this hypothesis, the investigators compared the concentrations of three cytokines — interleukin 1-beta (IL-1B), IL-6, and IL-8 — in blood samples of 79 SCA patients with and without associated complications.

Participants were followed for a median of 18 years (range of five to 34 years). Their median age was 36, and more than half (45 patients, 57%) were men.

Blood samples were collected between March 2016 and July 2018 from patients who were in a stable clinical state for at least three months and not taking hydroxyurea or anti-inflammatory medicines.

Leg ulcers were the most common complication, found in 26 patients (32.9%), followed by osteonecrosis — bone disease caused by reduced blood supply — in 16 patients (20.3%), acute chest syndrome in 11 (13.9%), and stroke in five (6.3%). Sixteen out of 45 men experienced priapism (prolonged erection). Thirty-three patients (41.8%) had one of these complications, while 19 (24%) experienced a higher number of symptoms.

In contrast, 27 participants (34.2%) had none of these main complications and were considered the control group.

The researchers then assessed the rate of vaso-occlusive crisis (VOC), which refers to painful blood vessel obstruction and is one of the most severe complications in SCA. Thirty-four patients (43%) had less than three VOCs that required hospitalization in the past year, while 35 patients (44.3%) experienced three to six annual crises. Ten patients (12.7%) had more than six such episodes.

Results showed that patients with high levels of IL-6 (3.13 picograms per milliliter, pg/mL, or higher) had a more than three-fold higher risk for experiencing leg ulcers and osteonecrosis. A similar link was found between IL-8 high levels (7.48 pg/mL or higher) and leg ulcers.

In addition, patients experiencing more VOCs per year, acute chest syndrome, leg ulcers, osteonecrosis, stroke, and priapism had higher IL-6 levels than patients without these complications. IL-6 levels were higher with increasing number of complications.

Compared to patients with low levels of IL-6 (21%) and IL-8 (22%), the probability of having leg ulcers was significantly higher in patients with elevated IL-6 (58%) and IL-8 levels (54%).

No significant differences were observed for IL-1B levels.

These findings suggest that levels of IL-6 and IL-8 could be useful markers to assess risk for complications.

Overall, this study “indicates that IL-6 levels can be used as a useful predictor for poor outcomes in SCA,” the researchers wrote. “Additionally, an association of IL-8 levels and leg ulcer occurrence was revealed. Together, our data emphasizes the role of inflammation in SCA.”