Mean platelet volume (MPV): new diagnostic indices for co-morbidity of tuberculosis and diabetes mellitus

Tuberculosis (TB) is a global health disease caused by infection with Mycobacterium tuberculosis (MTB), despite its advanced developments in diagnosis and therapy [1]. In 2018, 10.0 million people were diagnosed with tuberculosis worldwide. China has the second largest tuberculosis epidemic worldwide, behind India, with more than 1.3 million new cases of tuberculosis every year. Ending the TB epidemic by 2030 is among the health targets of the Sustainable Development Goals.

Studies have demonstrated that some diseases accelerate TB occurrence and development [2]. Type 2 diabetes mellitus (DM) has been verified as one of the threatening risk factors for TB, and patients have three times the risk of developing TB compared to nondiabetic patients due to pathogenic mechanisms and metabolic factors [3‐5]. The DM prevalence among patients with TB in diversified low-income and middle-income countries ranged from 1.8 to 45%, and TB prevalence among individuals with DM varied from 0.1 to 6.0% [6]. A national survey performed in 2010 found that the prevalence of DM was 11.2% (95% confidence interval 10.5 to 11.9%) in China [7]. Nearly 40% of TB cases in China and India are diabetes-related [8]. Clinically, DM facilitates TB development and hampers TB therapy, while conversely, TB impairs blood glucose control [9]. In addition, some studies have shown that proper blood glucose control will have a positive effect on reducing TB morbidity and mortality [10‐12]. Published studies on the full prevalence of tuberculosis in Chinese patients with diabetes are far from sufficient. On the other hand, global evidence on the relationship between tuberculosis risk and blood glucose is still inconsistent [13‐15]. To a great extent, TB and DM diagnoses are based on definitive detections, including clinical symptoms and characteristic X-ray and laboratory examinations, with separate limitations [16]. Given the increasing global burden of DM, clinical and public health interventions against this co-epidemic may lead to better tuberculosis prevention and treatment. However, due to the lack of established screening standards and methods, the effectiveness and reliability of screening for tuberculosis in patients with DM are not convincing [17]. In addition, few studies have focused on diagnostic markers to predict whether TB or DM will develop into a TB-DM coinfection (TB + DM). Thus, finding a feasible and cost-effective marker from laboratory reports for the early prevention and control of TB + DM is essential.

Platelets are enucleate cells and have critical roles in thrombosis, homeostasis and the inflammatory response [18]. When the internal environment is changed, platelet morphology may be altered and play a role in certain platelet-associated parameters, mainly including platelet count (PC), plateletcrit (PCT), platelet distribution width (PDW) and mean platelet volume (MPV). MPV detection and assays are generally valid in the clinic as they are routinely performed. MPV is increased in intestinal diseases, respiratory diseases, cardiovascular diseases, cerebral stroke, several cancers and diabetes. Conversely, MPV is decreased in ulcerative colitis, neoplasm, Systemic Lupus Erythematosus (SLE) and tuberculosis [19]. The mechanisms for an increased MPV are not well clarified. Several factors may influence MPV levels, including genetic variations, applied treatment drugs, lifestyle (diet, smoking, alcohol consumption, and physical activity), pre- and analytical procedures, hormonal profile, age, gender and race/ethnicity [19, 20]. Studies have demonstrated that changes in PC, especially during the process of TB infection, might be correlated with the mortality and severity of the infection [21, 22]. MPV is a marker reflecting the average size of platelets present in various diseases, such as DM, metabolic syndrome and TB [23]. However, the role of MPV in TB is disputed. A study conducted by Gunluoglu et al. suggested that MPV, as an inflammation marker, decreased in active pulmonary tuberculosis related to the formation of microthrombi in TB cavities [24]. Conversely, Tozkoparan et al. suggested that MPV was significantly increased in patients suffering from active TB and downregulated with anti-TB treatment [21]. In addition, MPV also served as a clue for the reflection of platelet activation in DM regardless of the diabetic retinopathy stage [25]. In addition to MPV, additional platelet indices PDW and PCT calculated by PC and MPV have been reported to play roles in atherosclerosis and thrombosis, as well in TB [26]. Higher PDW and PCT values developed frequently in patients with PTB with a strong correlation between phase reactants and acute thrombocytosis [27]. However, few studies have explored the relationship between platelet-associated parameters and TB-DM coinfection patients.

The prediction of the risk of TB-DM coinfection is absolutely vital for TB and DM patients. The purpose of the study is to assess the possible relationships of TB-DM coinfection with platelet indices PC, MPV, PCT and PDW. To this end, we also determined the relationship of these parameters with inflammatory markers (CRP and ESR index). We propose new novel biomarkers for diabetes with tuberculosis for earlier diagnosis and treatment.

The diagnosis of TB has always used a compound method, combining clinical symptoms, etiological examination of MTB, radiology examination and TB-associated molecular testing [28]. The diagnosis of DM is based on globally accepted criteria, relying on fasting plasma glucose measurement, 2-h postchallenge results in an oral glucose tolerance test (OGTT), or a hemoglobin A1c report [29]. Unfortunately, there are no diagnostic standards for DM-TB coinfection. The International Diabetes Foundation predicted a prevalence of DM among patients with TB at 8.8% in 2017. The global prevalence is almost twice that reported by the International Diabetes Foundation. However, Noubiap concluded that the population may recommend screening for TB patients for diabetes in high-income countries, and in low-income countries, diabetes has a lower prevalence and lower health status and fewer medical resources and screening methods and requires more research to determine the most systematic diagnostic strategies [9].

Platelet indices have been associated with multiple diseases of the immune system and hemopoietic system [30]. In our study, we found that MPV and PCT were significantly decreased in TB-DM coinfections compared with DM individuals. The indices of MPV were higher in DM combined with TB than in TB patients. The increase in MPV was correlated with ESR and CRP in DM + TB patients. For the PLT and PDW indices, there was no significant change among TB, DM, and TB combined with DM and in healthy controls. Moreover, the factors of age and gender did not significantly affect the MPV and PLT indices.

The MPV reflects platelet size and the extent of inflammation and is used to reveal the function of platelets. The platelet size is associated with the inflammatory intensity [31]. In patients infected by M. tuberculosis, acute phase reactants and proinflammatory cytokines affect megakaryocytes, which decrease the platelet size, and smaller platelets are delivered from the bone marrow [32], which can be used to explain the decrease in MPV. Tozkoparan E et al. found that PDW and PCT were higher in active TB patients and decreased significantly after anti-tuberculosis therapy [21]. Sahin et al. indicated that MPV in active TB patients was identical to that in healthy individuals and nonspecific pneumonia patients [23]. These results were in accordance with our findings, in that there were no significant differences between TB patients and healthy controls. Gunluoglu et al. suggested that the value of MPV was slightly decreased in TB patients, and the MPV never reflected the severity of tuberculosis [24].

ESR has also been regarded as a predictor of inflammatory and autoimmune diseases. In principle, the increase in ESR is due to changes in serum proteins, or it is due to changes in erythrocytes. The former usually includes hypergammaglobulinemia, monoclonal blood diseases, and elevated fibrinogen levels. The latter is mainly to reduce the number of erythrocytes and the size of erythrocytes [33]. Our results showed that MPV, but not PLT, was correlated with ESR in TB patients with DM. Thus, it can be deduced that, as an index of blood in patients with TB and DM, MPV may be an important hematological indicator to evaluate the risk of TB and DM along with ESR.

It is well known that DM is a metabolic dysfunction characterized by hyperglycemia, which leads to vascular complications. TB is an immemorial and common infectious disease. DM and TB coinfection is a widespread public health issue. There is still a lack of knowledge and assessment regarding whether TB makes individuals susceptible to DM. Several cross-sectional studies have displayed the relationship between TB outcome and the occurrence of hyperglycemia [34]. As DM and TB increase in low- and middle-income countries, WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) encourage the establishment of a cooperative framework that recommends bidirectional screening including TB testing among individuals with DM [35]. The WHO recommends screening for DM at the start of TB treatment. In China, the bidirectional screening program was implemented in September 2011 [36]. At the time of registration, TB patients were asked if they have diabetes and for those who deny any known disease, a random blood glucose test is performed to determine who is at risk. Patients with high blood glucose levels were randomly followed up with glucose concentration testing. These patients were willing to be screened. A total of 12–13% of TB patients have diabetes, of which 3% of Chinese patients are diagnosed with previously unrecognized diabetes based on fasting blood glucose values [8].

A major aim of this study is the comparison of platelet indices (MPV and PCT) and ESR in DM, TB and DM with TB patients to assess whether patients with TB or DM are at risk for developing TB + DM. Screening for TB or DM using platelet indices may improve early TB-DM coinfection detection and diagnosis. This analytical approach meets a clinical goal and establishes a potential diagnosis standard for the clinical laboratory. There is great potential for meaningful research on DM-TB in low- and middle-income regions. Prospective studies are urgently needed to resolve the differences between DM and non-DM tuberculosis patients and TB-DM diagnosis strategies. Identifying the population at risk and then conducting bidirectional screening across the entire region should be the ultimate goal of the health authorities.

MPV is a valuable candidate marker to screen for TB-DM coinfection risk, as the occurrence of TB developing into TB-DM coinfection will increase MPV levels, and DM developing into a DM-TB coinfection will decrease MPV levels. Moreover, MPV has a positive correlation with ESR and CRP. MPV has significant specificity and sensitivity for predicting and diagnosing DM-TB coinfection. Therefore, fasting blood testing (including glucose and MPV) should be carried out in active/suspected patients with high-risk TB or DM. It is our responsibility to take care of all TB patients, not only in the diagnosis of TB but also because they are at increased risk of diabetes. Since DM can increase the risk of TB infection and the goal of the WHO strategy to end tuberculosis is to reduce TB deaths by 90% and TB incidence by 80% by 2030, we suggest free treatment policies for DM patients in low- and middle-income countries so that DM and DM-TB coinfection can be better controlled. In conclusion, MPV has potential value as a candidate marker for dual screening algorithms. Screening for diabetic tuberculosis patients should be considered in low-income countries and should be integrated at a culturally educational level and social policy-driven behavior.