Our data shows that as the RCI value increases, the respiratory function decreases, which is manifested as a decrease in FEV1%, deterioration of lung function, and an increase in the severity of COPD, and finally an increase in the level of GOLD. Because RCI is obtained by calculating (RBC × Hb) / (Lym × PLT) and is closely related to the four indicators of RBC, Hb, Lym, and PLT, the above results also indicate that it may be related to low lymphocyte count and PLT level.
In this study, we found that the lymphocyte count of COPD patients was significantly lower than that of healthy controls. Previously, studies have also shown that patients in the acute exacerbation of COPD have a decreased lymphocyte count compared with healthy controls or patients in the stable phase[20], and lymphopenia may have a higher risk of respiratory infections, one of the reasons for exacerbation of COPD is an increase in respiratory infections[3].
A low relative lymphocyte count is associated with a high mortality rate in elderly patients with severe COPD[21]. A characteristic cellular immune response with important diagnostic significance in the airway and lung parenchyma. This immunopathology is driven by lymphocytes and responds to the targeted immune regulation of human lymphocytes. This is often seen in Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED). In APECED, the pathogenesis of lung autoimmune diseases with impaired central immune tolerance was found[22]. Hence, when the lymphocyte count is less than 1500, it often indicates malnutrition. Collins PF et al.[23] explained the relationship between the severity of COPD and malnutrition in a study. Malnutrition and nutritional deprivation are common among COPD patients.
COPD is related to systemic inflammation, and activated platelets can recruit inflammatory cells to make them aggregate. In patients with stable and acute COPD, platelet activation continues to increase, and platelet function may change due to COPD. The interaction between platelets and inflammatory cells can stimulate the release of chemokines and the further recruitment of immune substances[24]. In patients with stable COPD, the platelet count is associated with a U-shaped increase in the risk of all-cause death at 3 years. Despite this, it is still not clear that platelet levels above or below this level will increase mortality[25]. In addition, platelet reactivity will increase accordingly[26].
Karina et al.[11] believe that the abnormal inflammatory response associated with COPD may cause other diseases, such as anemia. Anemia is defined as Hb < 13.0 g/dL for males, and Hb < 12.0 g/dL for females which should be added to the overall management of respiratory diseases. The incidence of anemia in the general population increases with age. Inflammatory anemia or anemia of chronic disease occurs in many diseases.
In adults with COPD, anemia is associated with worse exercise capacity, greater breathing difficulties, and more serious diseases. The biomarkers found in the body weight of anemia suggest that inflammation, lung tissue, and oxidative stress may be the pathways for the poor prognosis of anemia and COPD. For example, increasing systemic inflammation and airway epithelial damage may cause anemia to adversely affect the outcome of COPD. Anemia may be one of several independent factors for poor outcomes in the subgroup of COPD patients with high levels of systemic inflammation and burden of comorbidities[11]. In addition, studies have shown that anemia is associated with an increase in the long-term mortality of COPD, and even mild anemia is also associated with a significant increase in risk[27]. In patients with acute exacerbations of COPD, anemia may be risk factors of hospital death for patients with severe COPD who need mechanical ventilation support[28]. As for red blood cell, red blood cell oxidative modification is a valuable biological indicator in the clinical treatment of COPD[29].
Increased levels of RBC and Hb can compensate for poor respiratory function[30, 31]. Therefore, these values can be used as appropriate criteria for evaluating respiratory function, under the premise of excluding the influence of other factors on the changes in red blood cell proliferation on RBC and Hb levels. Lym and PLT are rarely affected by other factors, so they are a benchmark used to measure the general level of blood cell roliation. The red blood cell index obtained from this can accurately reflect the degree of compensation.
It is known that the increase in RBC and Hb levels reflects the sensitivity to hypoxia[32, 33]. When the body has respiratory failure, it is often in a poor state, so that the general blood cell proliferation level may be abnormal. Hence, it is necessary to determine that a variable accurately reflects the changes in blood cell proliferation levels. The COPD group is higher than the control group, which can further confirm that RCI is an effective and reliable indicator for the assessment of chronic pulmonary insufficiency. RCI is considered to reflect the compensatory increase in RBC count and Hb level secondary to poor lung function which can also reflect the true state of respiratory function[15]. Our research results indicate that RCI increases with the decrease of FEV1%, and there is a significant correlation between RCI and FEV1 (p = 0.016), FEV1% (p = 0.001) and FVC (p = 0.027), but there is no correlation between RCI and FEV1/FVC (p = 0.150). Compared with NLR and PLR, NLR, PLR and pulmonary function have no correlation, but there is a significant correlation between RCI and FVC (p = 0.004), indicating comparing with NLR and PLR, RCI can better predict the changes of COPD' s respiratory function.
Other research results show that the NLR of COPD patients in the stable phase is significantly higher than that of the healthy control group, and compared with the stable phase, it further increases in the acute exacerbation of the disease. Therefore, NLR is a fast, cheap, and easy-to-measure indicator that can be used for routine whole blood technical analysis[34]. The same conclusion was also drawn in the meta-analysis conducted by Paliogiannis et al.[35]
As for PLR, PLR is the same as NLR. The PLR of patients with stable COPD is significantly higher than that of healthy controls, while the PLR level of non-survivors with acute exacerbation of COPD is significantly higher, but compared with NLR, PLR is still more effective and simple prognostic indicators[36]. The cross-sectional multi-center study of Alexa et al.[8] showed that NLR and PLR are predictors of COPD, but there is no correlation between the two and FEV1, and there is no correlation between the two groups and the GOLD A-D group.
In addition, we also conducted a sub-group analysis of COPD patients, and conducted correlation studies according to gender, duration of disease, smoking, hypertension, diabetes, and hyperlipidemia. The results are presented in Fig. 2A. It can be observed that among the above-mentioned sub-groups, only the gender and hypertension sub-groups, there are differences between the RCI of COPD patients. The results in the figure cannot accurately illustrate that gender and hypertension must have an impact on RCI. Further research is needed.
Our article is the first to use RCI as a prognostic biomarker for the diagnosis of COPD. Previously, RCI was only used as an effective index for evaluating respiratory function, a replacement index for evaluating respiratory function with complete blood count parameters. Compared with the healthy control group, the COPD combined elderly group has high RCI, and the positive rate of abnormally elevated RCI in the COPD group and the elderly group is significantly higher than that of the control group[15].
However, our study also has certain limitations. Firstly, the sample size is relatively small. Secondly, we are a single-center cross-sectional survey that only focuses on the Chinese population. In addition, we only explored the clinical significance of the impact of RCI on COPD, lack of influence on cellular and molecular mechanisms. In this regard, we need to conduct prospective cohort studies, conduct research on different ethnic groups, recruit more volunteers from multiple centers, and further study the mechanism of RCI in the progress of COPD to solve the above problems.