Obstructive sleep apnea (OSA) is defined as a collapse of the upper airway, resulting in hypoxemia, sleep disturbance, and systemic inflammation. Systemic inflammation may contribute to a higher risk of cardiovascular disease in patients with OSA [1]. A meta-analysis found higher levels of systemic inflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, IL-8, vascular endothelial growth factor, and tumor necrosis factor (TNF)-α, in patients with OSA [2]. Treatments for OSA, including positive airway pressure, tonsillectomy, and adenoidectomy in pediatric patients, have been reported to reduce inflammatory serum markers, including CRP [3,4].

Recently, the systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR), which can be derived from neutrophil, platelet, and lymphocyte counts, have been used as inflammatory markers for several diseases. For example, SII elevation is associated with a worse prognosis in solid tumors, pulmonary embolism, cardiovascular diseases, and even coronavirus disease 2019 (COVID-19) infection [5-7]. A positive correlation was found between the SII and the severity of OSA in a small retrospective study [8]. Similarly, the NLR was reported to be elevated in OSA patients [9], and it decreased after continuous positive airway pressure therapy [10]. The PLR has been reported to be associated with OSA severity and concurrent hypertension [11]. In this study, we assessed the relationship between OSA severity and systemic inflammatory markers that can be derived from simple blood tests.

In total, 1,102 patients (968 men and 134 women) were included in the study. According to the AASM guidelines, 95 patients were simple snorers, 204 had mild OSA, 286 had moderate OSA, and 517 were diagnosed with severe OSA (Table 1). The proportion of men was 73.7%, 85.3%, 85.0%, and 93.0% in the simple snoring, mild, moderate, and severe groups, respectively (P< 0.001). The mean age was 38.4, 46.9, 48.0, and 47.1 years in the simple snoring, mild, moderate, and severe groups, respectively (P<0.001). The mean BMI was 23.8, 25.1, 26.0, and 28.4 kg/m² in the simple snoring, mild, moderate, and severe groups, respectively (P<0.001).

Our study investigated the associations between OSA severity and systemic inflammatory markers that could be simply derived from blood cell counts, and we found that the SII was associated with AHI in severe OSA. Clinically, the impact of chronic systemic inflammation is important for assessing OSA complications, and exploring the value of inflammation markers derived from a simple complete blood count profile would be useful. Complete blood count analysis can be performed more quickly, easily, and cost-effectively than measuring inflammatory markers such as IL-6 or TNF-α in the serum. The SII, which was used in this study to assess systemic inflammation levels in patients with OSA, has been reported to be related to the prognosis of pulmonary embolism, coronary artery disease, solid tumors, and even COVID-19 infection [5-7,17].

A meta-analysis including 15 articles showed that higher SII values were associated with worse outcomes in many solid tumors, including hepatocellular carcinoma, urinary cancers, gastrointestinal tract cancers, and small-cell lung cancers [5]. In a retrospective study of 442 patients, the SII was associated with the severity and prognosis of acute pulmonary embolism [6]. Furthermore, a cohort study of 5,602 coronary artery disease patients after intervention showed that the SII had predictive value for major cardiovascular events, including myocardial infarction, stroke, and death [17]. As the inflammatory status is known to be related to the disease progression and comorbidities of OSA, we attempted to explore the relationship between the SII and the clinical condition of OSA patients. To our knowledge, there has only been one retrospective study regarding SII and OSA in a small group of 194 patients with OSA, and a positive correlation was noted between OSA severity and the SII, a positive correlation with the NLR, and an insignificant correlation with the PLR [8]. However, in the above-mentioned study, a subgroup analysis between the different OSA severity groups was not performed.

Our study, with a larger population including more than 1,000 OSA patients and blood tests that were drawn within a 2-week interval of PSG testing, showed that the PSQI was associated with the SII. The PSQI provides a general assessment of the subjective quality of sleep over a 1-month interval [18], and the association between the subjective sleep quality parameter PSQI and increasing levels of systemic inflammation has been reported before. In a study of 114 patients who underwent hemodialysis, patients with a PSQI >5 tended to have significantly higher serum CRP levels [19]. Higher PSQI scores were also positively correlated with serum CRP levels in a study of 281 postmenopausal women [20]. In our study, the SII was correlated with PSQI in the severe OSA subgroup, as well as the AHI, suggesting a relationship between impaired sleep quality and systemic inflammation in OSA. Among the various sleep variables used in this study, the PSQI was the only parameter that showed a significant correlation with SII. Therefore, assessing sleep quality in clinical settings might be important not only for patients’ quality of life, but also for evaluating patients’ systemic inflammation levels and the development of comorbidities of OSA.

The severity of OSA, represented by the AHI, is known to be associated with systemic inflammation [1,21]. The prevalence of comorbidities in severe OSA may increase because of the higher level of systemic inflammation. In a retrospective study of 1,119 patients, the NLR and PLR were reported to be significantly higher in OSA patients with chronic obstructive pulmonary disease, asthma, and congestive heart failure [22]. Similarly, a metaanalysis showed that the NLR was higher in patients with OSA than in normal controls [9] and decreased after continuous positive airway pressure [10]. The PLR has been reported to be lower in patients with OSA than in normal controls [23]. Our study showed a similar tendency, but no significant difference was found in the post hoc analysis. The limitations of this study include the fact that an individual’s systemic inflammation status is affected by numerous variables that cannot be controlled. For example, the comorbidities and medication status of each individual were not included in the statistical analysis in this study. Furthermore, due to the retrospective nature of this study, other systematic conditions of individuals that may affect the immuneinflammation system could not be fully considered when blood tests were conducted within a 2-week interval after PSG. In addition, systemic inflammatory markers of healthy subjects without any symptoms of OSA could not be explored since the study only included subjects who had visited a sleep clinic. Furthermore, the study was performed at a single center. Therefore, future studies in a more diverse population might be helpful to validate the results.

In conclusion, our study analyzed systemic inflammatory markers based on a simple, relatively cost-effective test (the complete blood count) and showed that the AHI increased as systemic inflammation reflected by the SII became more severe in the severe OSA subgroup. In the mild and moderate subgroups, increased AHI was not related to increased systemic inflammatory markers. This result might suggest that the role of systemic inflammation could be more important in OSA patients with a higher AHI than those with a lower AHI, and the severity of OSA might need to be over a certain level to provoke meaningful changes in systemic inflammation levels in patients with OSA. Further studies are needed to explore the relationship between increased systemic inflammation and OSA comorbidities, particularly in patients with severe OSA.