Cytokine/Chemokine Profiles In Sickle Cell Disease Patients With and Without Prior History of Acute Chest Syndrome
Kwabena A Osman, Hari Bandla, Ashima Singh, Mehri Bagheri Mohamadi Pour, Lin Chien-Wei, Amanda BrandowAbstract
Background
Sickle cell disease (SCD) is a multisystem inherited hemoglobinopathy characterized by chronic hemolysis, recurrent vaso-occlusion with ischemia-reperfusion injury, and systemic inflammation that results in cumulative end-organ damage. Pulmonary complications are prevalent in SCD, with acute chest syndrome (ACS) being a frequent and severe manifestation, however there is interindividual heterogeneity of the development of ACS among individuals with SCD. Despite being a chronic inflammatory disease, data on whether a relationship exists between chronic elevation of inflammatory mediators during baseline state of health and the occurrence of SCD-related pulmonary complications are limited. Understanding steady state immune phenotypes associated with ACS susceptibility may inform future biomarker based risk prediction and guide targeted interventions to prevent pulmonary complications in SCD. Therefore, we sought to evaluate the relationship between baseline plasma cytokine/chemokine profiles and a history of ACS in individuals with SCD. We hypothesized individuals with SCD who have a history of ACS exhibit higher pro-inflammatory mediators during baseline state of health as compared to those without a history of ACS.
Methods
We conducted a retrospective case-control study of individuals with SCD aged 5-22 years. Cases included individuals who had ACS (yes/no); controls had no ACS at any point during the study duration. Plasma samples were obtained during baseline health, defined as absence of acute illness within the preceding 2 weeks, and analyzed in duplicate using a 96-multiplex cytokine/chemokine assay. ACS episode(s) could have occurred either before or after plasma collection. Demographic and clinical data including age, gender, genotype, and history of asthma were obtained from medical records. Descriptive statistics summarized demographic and clinical characteristics. Cytokine/chemokine levels were compared between cases and controls using Wilcoxon testing, with false discovery rate (FDR) adjustment applied for multiple comparisons.
Results
A total of 74 individuals with SCD were included, with a mean age of 13.6 years (SD 4.9) and 55.4% (n = 41) were male. The majority had hemoglobin SS disease (71.6%, n = 53). There were 69% (n = 51) who had ACS and 31% (n = 23) who did not. ACS was more common in males than females (80.5% vs 54.5%, p = 0.023); other characteristics were similar between genders (Table 1). Of the 96 cytokine/chemokine levels assessed, there were 8 that showed nominal differences between cases and controls on initial analyses with lower baseline levels of IL-1β, IL-2, IL-15, IL-17A, GM-CSF, TNF-β, and MCP-1 observed in the ACS group compared to the non-ACS group and higher levels of MPIF-1 (CCL23) in the ACS group (all p < 0.05). However, after adjusting for FDR, no cytokine/chemokine differences reached statistical significance, highlighting the exploratory nature of this analysis. Figure 1 displays a heat map of cytokine/chemokine expression patterns between the two groups. The cytokine/chemokine levels did not appear to show a pattern based on gender.
Conclusions
Contrary to expectations, we observed a trend towards lower steady state inflammatory cytokines/chemokines among those with history ACS challenging the assumption of persistent hyperinflammation as an etiology of ACS. These data suggest potential immune modulation, reprogramming, and/or exhaustion. While these findings did not withstand multiple-comparison correction, they highlight potential biologically plausible immune phenotypes associated with ACS in SCD. Larger, longitudinal studies are needed to determine whether steady state cytokine/chemokine profiles can inform risk stratification or mechanistic pathways underlying ACS. Such approaches may ultimately inform biologically grounded treatment and preventive strategies for ACS in SCD.