Evaluation of Pan-immune Inflammation Value and Systemic Immune Inflammation Index in Different Mood Episodes of Bipolar Disorder

Abstract

Objective

Pan-immune inflammation value (PIV) and systemic immune-inflammation index (SII) have recently been investigated as new inflammatory markers. The aim of this study was to investigate and compare the PIV and SII in different mood episodes in bipolar disorder (BD) and healthy controls (HC).

Methods

In this study, white blood cells, neutrophil, monocyte, lymphocyte, and platelet counts of 339 BD patients (138 manic, 100 depressive, and 101 euthymic patients) along with 117 HC were evaluated. The PIV and the SII were calculated using these parameters and compared between the groups.

Results

PIV (p < 0.001) and SII (p = 0.002) were significantly higher in the manic group than in the HC. A comparison of the HC with the depressed and euthymic groups indicated no significant difference in PIV (p = 0.086, p = 0.139, respectively) and SII (p = 0.555, p = 0.244, respectively), while neutrophil (p = 0.043, p = 0.042, respectively) and monocyte (p = 0.010, p = 0.023, respectively) counts were significantly higher. Compared to the depressed and euthymic patients, the manic patients had significantly higher PIV (p <0.001, p <0.001, respectively) and SII (p = 0.019, p = 0.034, respectively). PIV could to be predictive in distinguishing manic episode patients from the other groups.

Conclusion

Our findings highlight the role of the low-grade systemic inflammation in the pathophysiology of BD, particularly during the manic episode, and suggest that PIV could serve as an inflammation marker to distinguish the manic episode of BD from other phases.

INTRODUCTION

Bipolar disorder (BD) is a severe and recurrent psychiatric disorder with a prevalence of approximately 1 to 2% in the general population. BD is characterized by mood shifts that can be classified into three phases: mania, depression and euthymia, and is associated with disability, morbidity and a high economic burden to the society [1,2]. The etiology of the disease, albeit largely unclear, is manifold and has been associated with different biological mechanisms such as genetic, neuroendocrine and metabolic processes [3-5].

A growing number of studies indicate that low-grade inflammatory processes play an important role in the pathophysiology of BD [3,4,6]. Fluctuations in the serum levels of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, TNF receptor-1 and IL-2 receptor [7-11] and high-sensitivity C-reactive protein (CRP) have been reported in BD [12]. The quantification of many of these serum biomarkers is very costly. Therefore, inflammatory biomarkers such as neutrophil, monocyte and lymphocyte counts, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR), which can be derived from complete blood count in routine examinations and are therefore relatively cheap, have been investigated in the psychiatric disorders including BD, supporting the existence of low-grade inflammation [13-16].

Systemic immune-inflammation index (SII) is relatively a new integrated biomarker reflecting systemic inflammation. SII is calculated from platelet, neutrophil and lymphocyte counts [16] and is considered to be an indicator of subclinical inflammation. SII has also been reported as a marker of severity of disease and prognosis in cancers, cardiovascular disease and acute pancreatitis [17-19]. Various studies have reported higher SII index in psychiatric disorders such as depression [20], schizophrenia [13,21] and BD [13,16,21,22] compared to controls, suggesting that SII can be used as a marker of low-grade inflammation.

Pan-immune-inflammation value (PIV) is a new, cost-effective and simple complete blood count-based biomarker that is calculated from platelet, neutrophil, monocyte and lymphocyte counts [23,24]. PIV has been reported to be a prognostic marker in some cancer types [24-26]. PIV was suggested to be superior to other inflammation markers, such as NLR, PLR, MLR and SII, in determining prognosis in myocardial infarction and breast cancer and was a better indicator of mortality [26,27]. Two recent studies have reported significantly elevated levels of PIV and SII in patients with obsessive compulsive disorder and attention deficit hyperactivity disorder [28,29]. However, to the best of our knowledge, PIV has not been evaluated in patients with BD. Therefore, in the current study, we aimed to investigate blood cell counts, PIV and SII values in different mood states of BD (euthymic, manic and depressive episodes) and compared the values with healthy controls.

METHODS

In this retrospective study, a total of 1,422 inpatients/outpatients diagnosed with BD Type I according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [30] who were admitted to our psychiatry clinic between January 2018 and December 2023 were evaluated. Sociodemographic features such as sex, age and clinical features such as diagnosis at the time of admission using DSM-5 criteria, medical services provided or drugs prescribed, comorbid diseases, body mass index (BMI) and laboratory test results were retrieved from the databases. Patients whose records in the hospital database lacked sufficient sociodemographic and clinical data were not included in the study.

The inclusion criteria for the BD group were as follows: (1) age 18 years and older and (2) meet the diagnostic criteria for BD Type I according to the DSM-5 (3). The exclusion criteria were as follows: (1) presence of other psychiatric comorbidities, including alcohol or substance use disorder; (2) medical conditions that could lead to abnormal levels of inflammatory parameters (i.e., infection, fever, chronic inflammatory conditions; autoimmune, endocrinological, neurological or cerebrovascular diseases; pulmonary, renal, cardiac, or hepatic failure; cancer; diabetes mellitus; hypertension; bone marrow disease/myelodysplastic syndrome (3) BMI > 30 kg/m², heavy smoking (more than 20 cigarettes/day), or pregnancy; (4) treatment with non-steroidal anti-inflammatory drugs, aspirin, corticosteroid, antibiotics or any other immunosuppressive medication in the last two weeks prior to admission and (5) mental retardation or neurodevelopmental disorders, severe cognitive impairment, or presence of traumatic brain injuries.

A healthy control group comparable in age, sex and BMI to the patient group was recruited from the routine examination results of hospital staff. The control subjects who had a family history of BD, as well as current or past personal history of any psychiatric disorders or suicidal attempts were not included in the study. The same exclusion criteria for the patient group were also applied to the control group. The final study population consisted of 138 manic, 100 depressive, 101 euthymic patients with BD, as well as 117 control subjects.

The sociodemographic data, neutrophil, lymphocyte, monocyte and platelet counts of the participants were recorded. PIV and SII were calculated using the following formulae:

PIV = (platelets count × neutrophils count × monocyte count) / lymphocytes count

SII index = (platelets count × neutrophils count) / lymphocytes count.

The study was approved by the local Ethics Committee (2023/6; decision no.6/20) and carried out in accordance with the Declaration of Helsinki.

Statistical Analyses

The data were analyzed using SPSS (version 22.0; IBM Co.). The chi-square test was used for categorical variables. Kolmogorov–Smirnov test was used to determine whether the parameters were normally distributed. Kruskal–Wallis test and Mann–Whitney Utest were used for statistical analysis. A binary logistic regression analysis was carried out to determine the independent predictors of manic episodes. The manic state was used as the dependent variable, while age, sex, PIV and SII were used as independent indicators. All variables for the binary logistic regression models were introduced in the analysis using the Enter method. Significance was accepted as p < 0.05.

RESULTS

The study included 456 participants aged 18 to 65 years; 53.9% (n = 246) were female and 46.1% (n = 210) were male. The mean age of the sample was 35.73 ± 10.58 years. One hundred and thirty eight patients were in the manic group, 100 were in the depressed group, and 101 were in the euthymic group. The control group consisted of 117 individuals. There was no significant difference between the groups with regard to age and sex (p = 0.077, p = 0.520, respectively). The demographic characteristics of the groups are shown in Table 1.

Table 1.

The comparison of sociodemographic characteristics and inflammatory markers between groups

	Depressive (n = 100)	Manic (n = 138)	Euthymic (n = 101)	Control (n = 117)	p
Age (yr)	37.83 ± 11.29	34.55 ± 11.41	35.09 ± 10.85	35.87 ± 8.34	0.077a
Sex
Female	53 (53.0)	68 (49.3)	58 (57.4)	67 (57.3)	0.520b
Male	47 (47.0)	70 (50.7)	43 (42.6)	50 (42.7)
PIV	275.17 ± 164.49	405.11 ± 266.83	271.99 ± 132.15	243.55 ± 150.96	< 0.001a
SII	451.61 ± 215.76	551.84 ± 295.12	444.85 ± 167.01	423.26 ± 171.95	0.009a
Neutrophil (103/ml)	4.35 ± 1.53	4.82 ± 1.72	4.11 ± 1.10	3.85 ± 1.18	< 0.001a
Monocyte (103/ml)	0.64 ± 0.26	0.74 ± 0.30	0.61 ± 0.18	0.56 ± 0.20	< 0.001a
Lymphocyte (103/ml)	2.59 ± 0.77	2.50 ± 0.73	2.42 ± 0.57	2.39 ± 0.58	0.505a
Platelet (103/ml)	251.81 ± 64.49	262.64 ± 67.17	256.11 ± 71.01	253.33 ± 64.48	0.545a

Values are presented as number (%) or mean ± standard deviation.

PIV, pan-immune-inflammation value; SII, systemic immune-inflammation index.

^aKruskal-Wallis; ^bχ² test.

The PIV and SII values were 405.11 ± 266.83 and 551.84 ± 295.12 in the manic group, 275.17 ± 164.49 and 451.61 ± 215.76 in the depressed group, 271.99 ± 132.15 and 444.85 ± 167.01 in the euthymic group, and 243.55 ± 150.96 and 423.26 ± 171.95 in the control group, respectively. The PIV, SII, and the other counts (lymphocyte, neutrophil, monocyte and platelet counts) are summarized in Table 1. Significant differences in PIV (p < 0.001), SII (p = 0.009), neutrophil (p < 0.001) and monocyte counts (p < 0.001) were identified between all the groups (Fig. 1).

Fig. 1.

Box plots for PIV and SII of the four (manic, depressive, euthymic BD patient, and control) groups.

PIV, pan-immune-inflammation value; SII, systemic immune-inflammation index; BD, bipolar disorder.

The PIV and SII values were found to be significantly higher in the manic group compared to the depressive, euthymic and control groups (manic vs. depressive, p < 0.001, p = 0.019; manic vs. euthymic, p < 0.001, p = 0.034; manic vs. control, p < 0.001, p = 0.002 for PIV and SII, respectively). Neutrophil and monocyte counts were significantly higher in BD patient groups compared to the control group (manic vs. control, p < 0.001, p < 0.001; depressive vs. control, p = 0.043, p = 0.010; euthymic vs. control, p = 0.042, p = 0.023 for neutrophil and monocyte counts, respectively). These counts were also higher in the manic group compared to the depressive and euthymic groups (manic vs. depressive, p = 0.028, p < 0.001; manic vs. euthymic, p = 0.005, p < 0.001 for neutrophil and monocyte counts, respectively) (Table 2). A binary logistic regression analysis was carried out where the manic status was used as the dependent variable, and age, sex, PIV and SII values were used as covariates. We observed that PIV (but not SII) could significantly predict the presence of manic episode, suggesting that it can serve as an independent positive predictor of the manic state (Table 3).

Table 2.

A comparison of laboratory variables and immune cells ratios between the four groups^a

	Depressive vs. Manic	Depressive vs. Euthymic	Depressive vs. Control	Manic vs. Euthymic	Manic vs. Control	Euthymic vs. Control
PIV	< 0.001	0.662	0.086	< 0.001	< 0.001	0.139
SII	0.019	0.692	0.555	0.034	0.002	0.244
Neutrophil (103/ml)	0.028	0.668	0.043	0.005	< 0.001	0.042
Monocyte (103/ml)	< 0.001	0.624	0.010	< 0.001	< 0.001	0.023
Lymphocyte (103/ml)	0.385	0.380	0.146	0.836	0.402	0.530
Platelet (103/ml)	0.173	0.764	0.788	0.375	0.273	0.940

PIV, pan-immune-inflammation value; SII, systemic immune-inflammation index.

^aMann-Whitney U test.

Table 3.

Results of binary logistic regression analyses

	Age	Sex	PIV	SII
Manic vs. Control
B	−0.016	−0.422	0.006	−0.001
95% CI	0.958−1.011	0.874−2.662	1.003−1.009	0.997−1.001
p	0.245	0.138	0.000	0.292
Manic vs. Depressive
B	−0.028	0.078	0.004	−0.001
95% CI	0.948−0.996	0.620−1.884	1.002−1.007	0.997−1.001
p	0.023	0.783	0.001	0.290
Manic vs. Euthymic
B	0.008	−0.263	−0.005	0.001
95% CI	0.983−1.033	0.438−1.350	0.992−0.998	0.999−1.003
p	0.536	0.360	0.001	0.291

PIV, pan-immune-inflammation value; SII, systemic immune-inflammation index; CI, confidence interval.

DISCUSSION

To the best of our knowledge, the current study is the first to investigate PIV as an inflammatory marker in the different episodes of BD and compare the values to healthy controls. An increase in PIV and SII in bipolar patients during the manic episode was demonstrated when compared to the euthymic and depressive episodes as well as controls in the current study. This suggests that systemic inflammation occurs in BD with different inflammation patterns observed in the different mood episodes. Our data also suggest that PIV could significantly predict the presence of manic episodes.

SII reflects systemic inflammation and has been used as a predictor of prognosis in several diseases [17-19,31]. However, to our knowledge, this parameter has not been adequately investigated in BD [13,16,21,22,32-34]. Previous studies suggest that SII values of patients with manic episode were generally higher compared to depressive and euthymic episodes and healthy controls [13,21,22,33,34], corroborating the findings of the current study. On the other hand, Dadouli et al. [16] reported that although SII was higher in patients with BD, no significant difference was found between patients undergoing manic or depressive episodes [16]. Wei et al. [21] reported higher SII values in the manic group compared to a control group, but did not report any differences between the depressive and control groups. These authors suggested that SII was an independent indicator of manic episodes. However, in the present study, regression analyses did not suggest the presence of any significant relationship between SII and manic episodes, which is also corroborated by the findings of Xu et al. [34]. Longitudinal studies are needed to further investigate the relationship between SII values and the states and severity of BD.

PIV is a new biomarker of inflammation that is based on neutrophil, monocyte, lymphocyte and platelet counts [23,24]. Similar to SII, PIV has been studied in several different diseases and is an indicator of systemic inflammation [24,25,35,36]. However, there are limited studies examining PIV in psychiatric disorders [28,29]. Various studies suggest that peripheral inflammation biomarkers such as CRP, TNF-alpha, NLR, MLR and ILs are increased in BD independently of the mood episode; therefore, these inflammatory parameters can be considered as trait markers of the disorder [37-40]. In addition, studies have reported increased activation of inflammation, particularly in manic episodes [11,37,39,41-45], while a decrease in inflammatory markers has been reported upon recovery from the manic episode [37,39,46]. Supporting these studies, we report here that PIV and SII were significantly higher in manic episodes compared to depressed, euthymic and control groups suggesting the presence of significantly higher inflammation in manic episodes. Additionally, we report for the first time that PIV could significantly predict manic episodes.

Previous studies have reported that monocyte and neutrophil counts are higher in BD patients compared to controls, as well as higher in the manic episode than in the depressive and euthymic phases [13,16,21,22,33,37,39,42,47], in line with our findings. Considering that monocytes and neutrophils are the most important cells of the innate immune system that secrete inflammatory cytokines [21,22,48,49], the activation of monocytes and neutrophils indicates the presence of low-grade systemic inflammation [48]. Therefore, the present findings strongly suggest the presence of inflammatory dysregulation in BD, independent of its episodes. However, Inaltekin et al. [13] reported no differences in the number of monocytes between patients undergoing a manic episode and the control group, while the neutrophil count was significantly higher in the manic episode. On the other hand, previous studies have also shown that lymphocytes, that are active in adaptive immunity, were reduced or did not differ significantly between BD patients and healthy subjects [16,50,51], supporting the findings of the current study. Overall, our findings as well as previous studies suggest that BD patients show changes in the innate immune system, rather than in acquired immunity [16,32]. Therefore, the innate immunity response may be a critical factor that precipitates BD, as a trait marker on a genetically adequate basis [16,37,52-55]. Xu et al. [34] have reported that the monocyte count was an independent risk factor for manic patients in a logistic regression analysis. We observed that monocyte and neutrophil counts were not only significantly higher in the BD patient groups compared to the control group, but also significantly higher in the manic group compared to the depressive and euthymic groups, suggesting that the innate immune response was exacerbated during manic episodes. However, since the current findings are based solely on complete blood count analysis, possible mechanisms orchestrating the inflammatory response still need to be evaluated.

Previous studies suggest that the levels of inflammatory markers can vary across different the mood episodes in BD [38,39,42,56-58]. The current study, as well as previous reports [11,37,39,41-45,59] suggest a particularly increased inflammatory response in the manic episode of BD, as quantified by monocyte and neutrophil counts, PIV and SII. Therefore, while an overall increase in inflammation can be purported to occur in BD, a more robust activation of the immune-inflammatory response system takes place in the manic episode [16,21,32,39,42,60]. However, whether this increase is a cause or a consequence of the manic episode and its mechanism of exacerbation are not clear. Data from several studies link the activation of monocytes to the pathophysiology of various psychiatric disorders, including BD [61]. Proinflammatory cytokines, whose levels increase with monocyte activation, can affect neurotransmitter metabolism, neuroendocrine functions, and synaptic plasticity in the central nervous system and cause neuropsychiatric disorders [62]. Low-grade inflammation was also thought to trigger manic episodes by disrupting the internal clock [3] or via other mechanisms. Overall, our data suggest that PIV can be used as a biomarker of manic episodes in BD. The inclusion of monocyte count in the PIV formula may increase the power of PIV as a biomarker of inflammation during manic episodes. However, whether there is a correlation between PIV and CRP and other inflammatory cytokines should be investigated simultaneously in longitudinal studies.

The current study had some limitations. Firstly, the study had a retrospective design; therefore, cause effect relationships could not be evaluated. Although heavy smokers were not included in the study, this can be considered as a limitation because of the effects of smoking on hematological parameters. The other limitation includes the inability to control the effects on the variables of the use of psychotropic drugs. Any possible correlations between the severity of mood symptoms and PIV and SII measured in the study as inflammatory markers were not analyzed may be a limitation. Only the results of the blood samples taken at the time of the first application to the clinic were evaluated; the blood samples taken at the end of the treatment was not evaluated. The lack of patients with unipolar depression in the study sample in order to compare with BD can also be counted as a limitation.

In conclusion, the current study is the first to evaluate PIV in patients diagnosed with BD. PIV was significantly higher in patients with manic episode compared to euthymic or depressive patients as well as healthy controls, independently of sex and age. PIV was sensitive to the stage of the disease and could significantly distinguish the manic episode of BD from other episodes, suggesting that the inflammatory response could be modulated by the type of mood episode. Our findings will shed light on future prospective studies about the presence of low-grade systemic inflammation in different mood states, especially in the manic phase of BD. However, new prospective follow-up studies with a larger number of patients and simultaneous evaluation of other inflammatory markers are needed to achieve more precise and accurate data in this field. Elucidating the mechanistic underpinnings in the relationship between BD and inflammation will be crucial for the prevention of mood attacks and the development of potential treatments.