The etiology of pleural effusion is complex, especially in the middle-aged and older people, and it is difficult to distinguish it from TPE, which is often a difficult problem in the process of clinical diagnosis. Combining different causative factors, TPE is still the most common cause of exudative pleural effusion in developing countries[11, 14]. TPE is caused by Mycobacterium tuberculosis (MTB) infection. MTB detection is the gold standard for the diagnosis of TPE, but the detection rate of MTB in pleural effusion is very low and has a high false-positive rate, which is easy to be missed and the culture time is long[15, 16]. In particular, TPE patients aged ≥ 40 years face diagnostic challenges in worldwide, but there is no consensus in the literature on diagnosis in this age group, so further studies are needed[17, 18]. As the population ages, the number of people over the age of 60 is increasing. Previous studies have shown that advanced age, disease severity, and organ failure will affect the accuracy of ADA in diagnosing TPE. Based on this, we included patients with exudative pleural effusion age ≥ 40 years and divided them into 40-59-year-old group and age ≥ 60-year-old group for separate research, hoping to provide some help for the diagnosis of TPE patients of different ages.
A large number of previous studies have shown that ADA 40U/L is a widely accepted cut-off value for the diagnosis of TPE, but in recent years, there has been a lot of controversy over the optimal cut-off value of ADA in a series of studies, especially regarding the greater influence of age and local tuberculosis prevalence on it[10, 14, 19, 20]. We analyzed the included patients with exudative pleural effusion aged ≥ 40 years and obtained the optimal cut-off value of TPE is 31.5 U/L and AUC is 0.94 (95% CI, 0.90–0.97), which has a good clinical diagnostic value. Burcu Arpinar Yigitbas[3] found that ADA 26U/L was 84.3% sensitive, 80.4% specific, and 82.35% accurate for TPE diagnosis in people aged ≥ 40 years. We also used ADA 26U/L as the cut-off value analysis and found that the sensitivity of this group of patients was 92%, the specificity was 78%, and the accuracy was 85.23%, which was close to the results reported above but the specificity and accuracy were lower than ADA31. 5 U/L.It can be seen that there are certain differences in the optimal ADA thresholds for different groups of people in different regions of the same age. Tay et al[7] found that ADA 26 IU/L was the best for the diagnosis of TPE in people older than 55 years, with a sensitivity of 94.7% and a specificity of 80%. However, Abrao et al[8] and other studies believe that ADA 43 IU/L is the best for the diagnosis of TPE when the age is older than 45 years, with a sensitivity of 82.7 and a specificity of 72.4%.
The optimal ADA 29 IU/L for the age of less than 45 years had a sensitivity of 88.6 and a specificity of 91.5%. A recent study found that only 4.65% of elderly TPE patients had an ADA greater than 40 IU/L[14, 21].In order to explain the above differences, we included ADA40IU/L in the age group ≥ 40 years old and found that the sensitivity was 70%, the specificity was 97%, and the accuracy was 82.95%. It can be seen that using ADA40IU/L as the best cut-off value for the diagnosis of TPE has great differences in different research samples, populations, and regions, and ADA can also be elevated by other diseases in the body, but this serious influencing factor has not been considered in many studies. Therefore, there are some differences in the results of different samples. How to accurately correct the optimal threshold of ADA or seek more accurate diagnostic indicators needs further research.
The stimulatory antigens ESAT-6 and CFP10 used in the IGRA test are unique to MTB and are not affected by BCG and body immunity, which improves the diagnostic specificity and avoids the influence of non-tuberculous bacilli and BCG on the results, and has good diagnostic value for TPE[22, 23]. A recent study reported significant differences in IGRA between TPE and non-IGRA groups due to antigen-specific responses to MTB, including malignant pleural effusion, pneumonia, and cirrhosis[21]. It has been reported that IGRA has a high diagnostic accuracy of more than 90.2% for patients with ADA uncertain TPE[24].
The data analysis of this group found that IGRA has a greater diagnostic advantage in the age ≥ 60 years old group than the group of 40–59 years old, with sensitivity(93%vs.88%), specificity(86%vs.81%) and diagnostic accuracy rates (89% vs. 85%) are both high.The diagnostic accuracy rate of the whole population is 87%, which is close to the results of Mollo B[25] study (sensitivity is 80%, specificity is 72%), but lower than some other related reports, which may be related to the high comorbidity and age of this group[26].Unfortunately, we did not perform immune function tests such as lymphocytes and their subsets in peripheral blood and pleural effusion to judge the function of peripheral and local lymphocytes in the pleural cavity, so as to conduct a more in-depth analysis of the influencing factors of IGRA and ADA. Previous studies have found that ADA detection has low diagnostic sensitivity for patients aged ≥ 60 years. We also performed ROC curve analysis on ADA alone for patients aged ≥ 60 years and found that the optimal cut-off value was 19.5 U/L, and the AUC was 0.57 (95% CI, 0.45–0.70), which shows that its diagnostic value is limited, but this may be related to the age(average age was 69.62 ± 6.31 years), which is basically consistent with previous reports[7, 24, 27]. Therefore, we analyzed ADA combined with IGRA and found that the sensitivity of ADA combined with IGRA in pleural effusion was 100% in the 40-59-year-old group. The detection rate of TPE has good application value and is worthy of clinical promotion. However, its specificity is 73%, so exudative pleural effusion in this population should be combined with other more specific biomarkers or biopsy to diagnose TPE. The combined detection and analysis of IGRA and ADA found that the specificity was 100% in the age ≥ 60 years old group, which has great clinical application for excluding TPE in patients with exudative pleural effusion who are elderly, unwilling to biopsy, and difficult to diagnose,which is consistent with the results of some Chinese related studies[28]. Although the above analysis has obtained promising results, the biomarkers of TPE have their own limitations, and more in-depth research is needed for more economical, non-invasive and accurate diagnostic methods[14, 22].In conclusion, ADA combined with IGRA has good diagnostic and differential diagnostic value in patients with exudative pleural effusion over the age of 40, especially for elderly patients with suspected TBE who are unwilling to undergo medical thoracoscopy or pleural biopsy, and those medical units that do not have thoracoscopy equipment.Moreover, the application of ADA combined with IGRA detection can eliminate the pain and risk caused by invasive operations, reduce the medical burden, and promote more accurate diagnosis of TBE.