Idiopathic acquired aplastic anemia (AA), an uncommon and potentially fatal bone marrow failure, is identified by hypocellular bone marrow and peripheral blood cytopenias [1]. Its effects may range in severity from mild to severe cytopenia [2]. AA is classified into three clinical and hematological categories, which are determined by evaluating the cellularity of the bone marrow (BM), platelet count, absolute neutrophil count (ANC), and reticulocyte count [3]. AA is a disease based on an immune meditated pathway in which the dysfunctional effector cells recognize and destroy the marrow progenitor cells, resulting in pancytopenia [4,5]. The immunopathology theory of AA is supported by the positive response to immunosuppressive therapy with the administration of anti-thymocyte globulin and cyclosporine [5]. A variety of growth factors and cytokines, specifically chemokines, synthesized by stem cells, regulatory cells, and marrow stromal cells, play vital roles in the BM microenvironment. These components exert regulatory control over hematopoiesis through autocrine and paracrine mechanisms [6,7]. Interleukin-8 (IL-8), a pleiotropic prototype CXC chemokine, is produced by different cell types, primarily by macrophages and fibroblasts in the BM, and neutrophils and T-cells in the peripheral blood [8,9]. Via a receptor-ligand mediated mechanism, IL-8 may contribute to the suppression of hematopoiesis, a process by which the blood cells are originated [8]. It serves as a powerful inhibitor of myelopoiesis and assumes an essential role in both the initiation and progression of acute inflammation and tissue damage [10,11]. Research conducted on the pathophysiology of the disease has predominantly centered on stem cell abnormalities and immunological pathways, while, limited data exists regarding the involvement of the BM microenvironment in this condition [1]. Consequently, it is postulated that the sustained elevation in IL-8 production could potentially play a role in the onset of immune-mediated BM failure in individuals with AA [11]. Furthermore, evidence shows that IL-8 correlates with disease severity and progression [12]. This study evaluates the serum IL-8 concentrations in individuals with AA as well as investigates potential connections with disease severity.

Twenty-eight AA patients were included in this study with a median age of 36.5 ranging from 8–68 years. Of these patients, 15 (53.6 %) were male and 13 (46.4 %) were female with a M:F ratio of 1:1. Thirty samples of apparently healthy volunteers were included as a control group in the analysis with median age of 36.5 ranging between 17 and 67 years and a M:F ratio of 1:1 (Table 1).

Moreover, a significant difference in mean serum level of IL-8 was observed between different age groups of patients with AA; higher mean serum levels were found in older patients (p-value = 0.0406). While there was no statistically difference observed in the mean serum level of IL-8 between sexes in AA patients (Tables 4 & 5).

IL-8 has the ability to suppress the production of myeloid progenitor cells by impeding their proliferation through a mechanism involving a receptor-ligand interaction (transmitting an inhibitory signal), specifically, IL-8 (CXCR-2), which is expressed on progenitor cells [15]. Since IL-8 has strong stimulatory effects on neutrophils [16], elevated concentrations of this cytokine in the blood stream have the potential to promote activation-induced apoptosis of fully developed neutrophils in the peripheral system [17].

This study shows that AA patients have elevated, albeit non-significant, mean serum IL-8 concentrations in comparison to the control group (p-value >0.05). Previous studies conducted in pediatric and adult patients by Gupta et al., Bhargawa et al., and Singh et al. revealed significant increments (p-value <0.001) in the IL-8 level of AA patients in comparison to controls (15.58 ± 18.0 versus 1.85 ± 0.95, 122.56 ± 97.79 versus 3.42 ± 1.73, and 120.28 ± 94.98 versus 1.79 ± 0.78, respectively). A recent study confirms these results showing that the median IL-8 level is significantly higher in AA patients than in a control group (320 versus 97; p-value <0.0001) [2,12,18,19]. These findings may give us an idea about the pathology of the AA and the role of cytokines like IL-8 in disease activity and marrow suppression.

Additionally, in the current study, patients diagnosed with AA showed significantly increased mean serum levels of IL-8 in severe AA patients, signifying that IL-8 levels may be playing a role in exacerbating disease progression and severity. This finding agrees with many other studies such as those by Gupta et al., Bhargawa et al., Singh et al., and Khalifa et al., that revealed a significant correlation between an elevated level of IL-8 and the severity of the disease [2,12,18,19]. A study conducted by Tripathy et al. examining bone marrow and peripheral blood samples obtained from AA patients, demonstrated an increase of IL-8 in both samples that correlated with disease severity [8]. Tang et al. also demonstrated the same result using peripheral blood samples [20].

There are several studies that revealed a substantial association between elevated levels of IL-8 in peripheral blood and the severity of the disease. Therefore, IL-8 could have a significant role in the pathogenesis of a severe type of idiopathic AA [18,21]. The present study confirmed other studies suggesting that patients with AA may have an inflammatory background mediated by IL-8 acting as a negative regulator of hematopoiesis [19]. Further studies are encouraged to explore a targeted therapy that inhibits IL-8 in the context of hematological and immunological settings.

Higher levels of IL-8 were detected in the older age group in comparison to patients aged between 20–40 years. This finding is inconsistent with the data on serum IL-8 levels detected in children diagnosed with AA, as elevated concentrations were associated with younger severe AA patients [18].

There was no statistically significant relationship between the mean IL-8 serum level and the mean levels of hemoglobin, platelets, and ANC in the AA patient group. The relationship between IL-8 and peripheral blood indices might not be consistent across patients due to heterogeneity in disease pathophysiology or the severity of AA.

When combining other investigations with our findings, it is evident that patients diagnosed with severe and very severe AA exhibit considerably higher peripheral blood IL-8 levels compared to those with non-severe AA. Moreover, these elevated IL-8 levels demonstrate a positive correlation with disease severity, suggesting a crucial role in the pathogenesis of AA [9,12,19]. Thus, IL-8 might be useful as a discrimination marker with the current study suggesting that the cutoff value of 7.71 pg/mL may separate severe from non-severe AA.

One of the primary limitations of this study is the limited sample size only from a single institution. Consequently, further research involving a large sample size from many institutions is imperative to enhance the generalizability of these findings. Additionally, the lack of patient follow-up after therapy in this study represents a constraint that should be acknowledged.

IL-8 may have a role in the clinical presentation and severity of the AA; the immune-mediated action of IL-8 in patients diagnosed with AA may be associated with an increment in BM hypocellularity and subsequently more profound peripheral blood cytopenias.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Self-funded.

Informed consent was obtained from each participant prior to enrollment in this study

All the authors.

Ethics approval is sought from the scientific ethical committee in the National Center of Hematology/ Mustansiriyah University (Reference: nch-erc-20-27), and it conformed to the ethics guidelines of the Declaration of Helsinki.

Shahla’a Fadhil Sabir: Methodology, Data curation, Project administration, Writing – review & editing. Huda Ibraheem Abd AL-Lateef: Project administration, Writing – review & editing. Naam Ali Hamza: Project administration, Writing – original draft.