The indicative role of inflammatory index in the progression of periodontal attachment loss

With a prevalence of 47% in the American population over 30 years old [1, 2], periodontitis impaired the aesthetic and oral function [3, 4], mainly manifested as attachment loss and alveolar bone resorption [5‐7]. Current studies focused on the correlated inflammation or immunity factors of severe periodontitis [8], but the in-depth monitoring of immunological indicators during attachment loss progression remains unknown.

On accounts of the abundant systemic circulation of the maxillofacial region, periodontitis causes or exacerbates comorbidities and resulting changes in circulating immune indicators (including white blood cells, Neutrophils, etc.) [7, 9, 10]. Previous studies showed that severe periodontitis was accompanied by changes in the levels of inflammatory indicators [11, 12], for example, patients with periodontitis are often accompanied by an increase in mean platelet volume and a decrease in eosinophilic counts. Meanwhile, circulatory immune indexes were widely utilized as forewarning or diagnostic criteria of infectious diseases. For instance, white blood cell (WBC) counts were generally expected to be closely associated with a respiratory infection, which diagnoses pneumonia, determines its etiology, and predict disease progression [13, 14]. To forewarn the occurrence and progression of severe periodontitis, it is necessary to explore the potential relationship between circulatory immunological indexes and periodontal attachment loss progression.

In this study, we aimed to explore the association between severe attachment loss progression and circulatory immunological indicators by multivariable linear regression based on the NHANES database. Severe periodontal attachment loss tended to occur in males and was accompanied by higher WBC, Monocytes, and Neutrophils. Furthermore, WBC, Monocytes, and Neutrophils counts were closely associated with periodontal attachment loss. This study sought to shed light on the correlation between the progression of severe periodontitis and immune-related indicators.

The demographic and laboratory data of the 5744 participants (3217 men and 2527 women), with the weighted characteristics of the participants subclassified based on quartiles of attachment loss teeth counts (Q1: 0; Q2: 1; Q3: 2–5; and Q4: 6–27), as presented in Table 1. There were significant differences in baseline characteristics between the attachment loss teeth quartiles, except for the counts of Eosinophils, Basophils, and Lymphocytes. Participants with generalized periodontal attachment loss tend to occur in the elderly or males and are accompanied with higher BMI, WBC, Monocytes, Neutrophils, and Eosinophils, as well as lower PIR and educational qualification.

The results of the multivariate regression analyses are presented in Tables 2 and 3. In the unadjusted model, WBC (β = 0.1632, 95% CI 0.1051–0.2214, P < 0.000001) and Neutrophils (β = 0.2069, 95% CI 0.1344–0.2795, P < 0.000001) were positively correlated to attachment loss progression. After adjustment for confounders, those positive associations were stable in model 2 (P < 0.000001) and model 3 (P < 0.000001). After converting WBC and Neutrophils from continuous variables to categorical variables (quartiles), the trends remained significant among different WBC or Neutrophils quartile groups (P < 0.001). Furthermore, individuals in the highest WBC and Neutrophils quartile had 0.8392 (P < 0.00001) and 0.8663 (P < 0.00001) more attachment loss than those in the lowest quartile, respectively.

Smooth curve fittings and generalized additive models used to characterize the nonlinear relationship between WBC/Neutrophils and attachment loss progression are shown in Figs. 1, 2. The points of inflection were identified using the two-piecewise linear regression models, at 6200 cells/µL (WBC counts) and 3300 cells/µL (Neutrophils counts), respectively (Tables 4 and 5). For WBC < 620 cells/µL or Neutrophils < 3300 cells/µL, every 1000 cells/µL increase of WBC or Neutrophils was correlated with 0.0784 (95% CI −0.2836 to 0.1269) or 0.1494 (95% CI − 0.4550 to 0.1562) less attachment loss; by comparison, for individuals with WBC > 6200 cells/µL or Neutrophils > 3300 cells/µL, every 1000 cells/µL increase of WBC or Neutrophils was significantly associated with 0.2273 (95% CI 0.1492–0.3054) or 0.2737 (95% CI 0.1823–0.3651) more attachment loss.

On subgroup analyses, stratified by sex and race/ethnicity, reported in Tables 2 and 3, the positive correlation among WBC, Neutrophils and attachment loss progression remained in both males (P < 0.0001) and females (P < 0.001), as well as in Mexican American (P < 0.05), Hispanics (P < 0.05), whites (P < 0.000001), and other races (P < 0.05), but not in blacks. Among blacks, WBC (β = -0.0576, 95%CI: -0.1945–0.0793) or Neutrophils (β =  − 0.0527, 95% CI − 0.2285 to 0.1231) were negatively associated with attachment loss progression (Fig. 3).

Accompanied with attachment loss, severe periodontitis caused serious aesthetic problems and reduced chewing efficiency [16, 17]. Previous studies suggested that the progression of attachment loss was accompanied with increasing circulatory immunological indexes in severe periodontitis [13, 14], but immune cell counts serve as forewarning or diagnostic criteria for severe attachment loss or periodontitis progression remains unclear. Our multivariate logistic regression analyses indicated that elevated WBC or Neutrophils was correlated with attachment loss progression. However, on subgroup analysis, we identified the negative relationship between WBC or Neutrophils and attachment loss among blacks.

Phagocytosis by WBC, Neutrophils, and Monocytes constitutes the main defense mechanism against bacterial challenges in periodontitis [18]. As the enriched immune cell killing bacteria and destroying inflamed tissues [19], immunity homeostasis was essential for periodontal attachment maintenance [20]. In consist with our results, a previous study showed that severe periodontitis accompanied with higher WBC or Neutrophils levels than the healthy population [6]. On the other hand, infectious viruses, including Human simplex virus-1, Epstein-Barr virus, and Human cytomegalo virus, were commonly involved in the occurrence and development of periodontitis or attachment loss [21]. Simple viral infections accompanied with the decrease of WBC and Neutrophils [22], while combination of bacterial infections promotes WBC elevation [23]. Recent research identified the inflection point of fluctuating confounder was utilized as forewarning of periodontitis risk, and periodontal status [24]. Our multivariable linear regression analyses suggested that participants with WBC above 6200 cells/µl or Neutrophils above 3300 cells/µl obtained higher risk of periodontal attachment loss, which can serve for severe periodontitis prevention and treatment.

Previous studies identified the racial differences of WBC or Neutrophils counts between blacks and other races [25, 26]. In which, WBC or Neutrophils counts were significantly lower in blacks during dental plaque accumulation, but hyperactivity of circulating neutrophils appeared in blacks [26]. Importantly, the reactivity of oxidative burst was significantly lower in neutrophils from blacks, especially from African American males [27]. Periodontal attachment loss-related racial differences can provide accurate guidance for subsequent community prevention.

This study demonstrated the association between circulatory immunological indicators and periodontal attachment loss. However, several limitations are noticeable. First, all self-reported information might cause recall bias or misclassification bias. Second, further studies with larger sample sizes using more relevant variables (such as gingival sulcus fluid data and bone destruction) may discover more accurate factors in periodontal attachment loss. Third, circulating immune cells counts were affected by the whole-body state, periodontal pocket related immunological indexes may have better reproducibility.

Our study suggested that increasing WBC (above 6200 cells/µL) and Neutrophils (above 3300 cells/µL) counts were potential risk indicators of periodontal attachment loss progression, which provides an early warning for severe periodontitis.