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The clinical significance of CA-125 in pulmonary tuberculosis
Tuberculosis 93 (2013) 222e226
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Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
DIAGNOSTICS
The clinical significance of CA-125 in pulmonary tuberculosis Eun Sun Kim a, Kyoung Un Park b, JungHan Song b, Hyo-Jeong Lim a, Young-Jae Cho a, HoIl Yoon a, JaeHo Lee a, Choon-Taek Lee a, Jong Sun Park a, * a
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumi-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do 463-707, Republic of Korea b Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumi-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do 463-707, Republic of Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 July 2012 Received in revised form 24 September 2012 Accepted 1 October 2012
Cancer antigen 125 (CA-125) is usually elevated in ovarian cancer. However, there are several reports that serum CA-125 is elevated in tuberculosis. This study investigated the clinical significance of serum CA125 measurements in patients with active pulmonary tuberculosis (TB). Between September 2008 and March 2011, Serum CA-125 was measured in patients with active pulmonary TB before treatment (baseline), and 6 and 12 months after initiation of anti-TB treatment. Patients with pulmonary TB confirmed by culture or polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR) were included. The study enrolled 100 patients. The mean serum CA-125 was 38.9 41.4 U/ml (reference value, <35 U/ml). Thirty-eight patients showed elevated CA-125. Significantly more of those with elevated CA125 were female (p < 0.001), and had a positive sputum smear for acid-fast bacilli (AFB) (p ¼ 0.030). They also significantly more showed extensive pulmonary lesions on chest X-ray (p ¼ 0.004). Elevated CA-125 was independently associated with female gender (OR ¼ 12.5, 95% CI: 3.4e45.2), positive acid-fast staining of sputum (OR ¼ 6.0, 95% CI: 1.8e19.7), cavitary lung lesion (OR ¼ 4.0, 95% CI: 1.2e12.9), and involvement of more than one lung on chest X-ray (OR ¼ 9.4, 95% CI: 2.2e40.1). The CA-125 level decreased with anti-TB treatment (p ¼ 0.001). Serum CA-125 was related to the activity and severity of pulmonary TB, and it may be useful in the monitoring of therapeutic responses in certain cases of active pulmonary TB, especially in female patients of active pulmonary TB. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Cancer antigen 125 Diagnosis Pulmonary tuberculosis Serum
1. Introduction Pulmonary tuberculosis (TB) is one of the leading causes of mortality worldwide and has become a global public health emergency.1 Determination of pulmonary TB activity is as important as early diagnosis of pulmonary TB in optimal treatment strategy. Especially in patients with a previous history of cured TB, it is more difficult to discriminate between an old healed TB lesion and reactivation.2,3 Although novel diagnostic tools for serologic tests, including QuantiFERON-TB Gold In-Tube and T-spot.TB have been developed for rapid and accurate diagnosis of Mycobacterium
* Corresponding author. Tel.: þ82 31 787 7054; fax: þ82 31 787 4052. E-mail addresses: [email protected] (E.S. Kim), [email protected] (K.U. Park), [email protected] (J. Song), [email protected] (H.-J. Lim), [email protected] (Y.-J. Cho), [email protected] (H. Yoon), jhlee7@ snubh.org (J. Lee), [email protected] (C.-T. Lee), [email protected] (J.S. Park). 1472-9792/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tube.2012.10.014
tuberculosis infection, the results of these tests have not been correlated with disease activity or therapeutic responses.4,5 Usually chest radiography, sputum acid-fast staining, and mycobacterial cultures are used for evaluating therapeutic responses of pulmonary TB.6e8 However, chest radiography improves slowly with treatment and does not accurately discriminate the activity of pulmonary TB.6,9 Furthermore, sputum examination is impossible in some patients who do not expectorate sputum. Cancer antigen 125 (CA-125) is a high molecular weight glycoprotein that is expressed on the epithelial cells of the fallopian tube, endometrium, and mesothelial cells lining the pleura, pericardium, and peritoneum.10 CA-125 levels are elevated in a number of malignant diseases such as those involving the ovaries, lungs, breasts, colon, pancreas, and in some non-malignant conditions including endometriosis, hepatic cirrhosis or heart failure. Previously, it was reported that serum CA-125 levels were higher in patients with pulmonary and extra-pulmonary TB than healthy subjects.11 However, there have been few reports on the relationship
E.S. Kim et al. / Tuberculosis 93 (2013) 222e226
between the activity of pulmonary TB and CA-125 levels. The clinical usefulness of CA-125 in pulmonary TB is not fully understood. The aim of this study was to investigate the clinical significance of serum CA-125 measurements in patients with active pulmonary TB.
223
Patients with clinically suspicious active pulmonary TB (n=280)
Excluded (n=58) Not meeting inclusion criteria (n=58)
2. Study population and methods 2.1. Patients and study design A prospective study was performed. Patients diagnosed with active pulmonary TB between September 2008 and March 2011 at Seoul National University Bundang Hospital, a university-affiliated tertiary care hospital in Korea, were enrolled. Any patients with progressive malignancy and female patients with non-malignant gynecologic conditions, such as endometriosis, and pregnancy were excluded by medical history taking and interview. The diagnosis of active pulmonary TB was based on positive respiratory specimen culture or polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR). The patients were followedup for at least 1 year after the initiation of the anti-TB treatment. Sputum staining for acid-fast bacilli (AFB), mycobacterial culture and chest radiography were examined every one or two months during the treatment. In patients who did not expectorate sputum, bronchoscopy was done for mycobacterial culture. TB PCR or interferon-gamma release assay was performed according to the physician’s judgment. After written informed consent was obtained, patients underwent blood sampling for CA-125 before receiving the treatment and 6 months and 12 months after initiation of anti-TB treatment. This study was approved by the Institutional Review Board and Ethics Committee of Seoul National University Bundang Hospital, (IRB number: B-0807/059-003) and was conducted in compliance with the Declaration of Helsinki. 2.2. Measurement of serum CA-125 Serum CA-125 levels were measured using a commercial radioimmunoassay kit (Cis Biointernational, Gif sur Yvette, France), and the normal range was defined as <35 U/mL according to the manufacturer’s instructions. 2.3. Statistical analysis Statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). Descriptive data were expressed as mean SD or median and interquartile range. Student’s t-test was used to compare continuous variables, and chi-square or Fisher’s exact tests were used to compare categorical variables. Serial change of CA-125 level was analyzed by repeated measures generalized linear model. A two-tailed p-value of <0.05 was considered to indicate significant difference. 3. Results 3.1. Baseline characteristics of study patients Among 280 patients with suspected pulmonary TB, 58 patients were excluded because they were not confirmed by mycobacterial culture or TB PCR. Finally, 100 patients with active pulmonary TB were enrolled (Figure 1). The demographic and clinical characteristics of the patients included in the study are presented in Table 1. Twenty seven (27.0%) patients had a previous history of TB. No participant suffered from any active or progressive malignancies. Approximately half of the patients (47 patients, 47%) had an initial sputum smear that showed acid-fast bacilli. Cavitation was present in 46% of patients, and 21
Patients with confirmed active pulmonary TB (n=222)
Excluded (n= 122) - Declined to participate (n=118) - Inadequate sample (n=4)
Patients with confirmed active pulmonary TB (n=100) Figure 1. Flow chart of patient enrollment into the study.
patients (21%) showed pulmonary lesions that involved more than one whole lung on chest X-ray (Table 1). The mean serum CA-125 level was 38.9 41.4 U/ml (reference value, <35 U/ml). Female patients had significantly higher serum CA-125 levels (p < 0.001) and had more bronchiectatic lesions on chest X-ray (p < 0.002). 3.2. Comparisons between patients with normal and elevated CA125 levels According to serum CA-125 levels, patients were subdivided into two groups: the normal CA-125 group and the elevated CA-125 Table 1 Baseline clinical characteristics of the study patients.
Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Diabetes mellitus Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Drug susceptibility test Drug susceptible TB Drug resistant TB* Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion CA-125, U/ml
Total (n ¼ 100)
Male (n ¼ 54)
Female (n ¼ 46)
p-value
46.5(15e89) 20.2 2.8
49.0(25e89) 20.4 2.7
43.0(15e87) 20.0 2.9
0.397 0.565 <0.001
53(53) 32(32) 15(15) 11(11)
19(35.2) 29(53.7) 6(11.1) 8(14.8)
34(73.9) 3(6.5) 9(19.6) 3(6.5)
27(27.0) 73(73.0) 47(47.0) 90(90.0) 39/63(61.9) 34/37(91.9)
16(29.6) 38(70.4) 28(51.8) 46(85.1) 23/36(63.9) 18/20(90.0)
11(23.9) 35(76.1) 19(41.3) 44(95.6) 16/27(59.3) 16/17(94.1)
66/83(79.5) 17/83(20.5)
35/42(83.3) 7/42(16.7)
31/41(75.6) 10/41(24.4)
47(47) 21(21)
29(53.7) 11(20.4)
18(39.1) 10(21.7)
0.147 0.867
36(36) 13(13) 38.9 41.4
12(22.2) 4(7.4) 27.6 32.9
24(52.2) 9(19.6) 52.1 46.6
0.002 0.082 0.008
0.187 0.522
0.296 0.145 0.708 0.651 0.383
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125. * Ten patients were multidrug resistant tuberculosis.
224
E.S. Kim et al. / Tuberculosis 93 (2013) 222e226
group. Through univariate analysis, female gender (p < 0.001), a positive sputum smear for AFB (p < 0.030) and extensive pulmonary lesions on chest X-ray (p ¼ 0.004) at diagnosis were significantly associated with an elevated CA-125 levels. The patients with cavity or bronchiectasis on chest radiographs tended to have elevated CA-125 levels, but there was no statistical significance (Table 2). In a subsequent multiple regression model, female gender (OR ¼ 12.5, 95% CI: 3.4e45.2; p < 0.001), a positive sputum smear for AFB (OR ¼ 6.0, 95% CI: 1.8e19.7; p < 0.003), presence of cavity (OR ¼ 4.0, 95% CI: 1.2e12.9; p ¼ 0.020), and involvement of more than one lung on chest X-ray (OR ¼ 9.4, 95% CI: 2.1e40.1; p ¼ 0.003) were significantly associated with an elevated CA-125 levels (Table 3). When we analyzed only in female patients (Table 4), positive AFB smear, presence of cavity and extensive lesion were also associated with elevation of CA-125. 3.3. Changes of CA-125 levels according to the treatment Serial CA-125 measurements were obtained in 32 patients at three times: at the beginning of treatment, and 6 months and 12 months after the initiation of anti-TB medication (Table 5). Serum CA-125 levels decreased significantly after commencement of antiTB treatment in all patients (p ¼ 0.002) (Figure 2). All the patients showed negative conversion of the sputum acid-fast staining and Mycobacterial cultures after treatment. We observed a serial decrease in the CA-125 levels along with a serial improvement in the follow-up chest radiographic findings in all 32 patients. 4. Discussion CA-125 is a high molecular weight glycoprotein that is expressed on the epithelial cells of the fallopian tube, endometrium, and mesothelial cells lining the pleura, pericardium, and peritoneum.10 It is widely used in the diagnosis and monitoring of ovarian cancer. In addition, CA-125 can be elevated in various nonmalignant conditions. Previous studies have reported that serum CA-125 levels were elevated in tuberculosis, mainly in extrapulmonary locations such as peritoneum or pleura.4,12e14 Relatively few studies have evaluated
Table 2 Comparisons of patients with normal CA-125 and elevated CA-125.
Sex, female Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Normal CA-125 (n ¼ 62)
Elevated CA-125 (35 U/ml) (n ¼ 38)
p-value
19(30.6) 45.0(15e89) 20.5 2.4
27(71.1) 48.5(21e89) 19.8 3.4
<0.001 0.417 0.351 0.203
29(56.9) 22(43.1) 11(17.7)
24(70.6) 10(29.4) 4(10.5)
16(25.8) 46(74.2) 24(38.7) 55(88.7) 23/40(57.5) 25/27(92.6)
11(28.9) 27(71.1) 23(60.5) 35(92.1) 16/23(69.6) 9/10(90.0)
0.030 1.000 0.344 1.000
25(40.3) 7(11.3)
22(57.9) 14(36.8)
0.089 0.004
18(29.0) 6(9.7)
18(47.4) 7(18.4)
0.066 0.214
0.768
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125.
Table 3 Factors associated with elevated CA-125 levels in patients with active pulmonary tuberculosis.
Sex, female Sputum smear positivity Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Adjusted odds ratio
95% C.I.
p-value
12.5 6.0 4.0 9.4 1.1 3.0
3.4e45.2 1.8e19.7 1.2e12.9 2.2e40.1 0.4e3.5 0.59e14.6
<0.001 0.003 0.020 0.003 0.817 0.190
the relationship between CA-125 and pulmonary TB. In previous studies, the sensitivity of CA-125 in diagnosing pulmonary TB ranged from 63.0% to 97.5%.11,15 However, detailed data about the demographics of study patients or characteristics of pulmonary TB, the extent of disease, smear positivity or involvement of pleura were limited in those studies. Therefore, it is difficult to interpret the meaning of elevated serum CA-125 in patients with pulmonary TB. In our study, we prospectively measured serum CA-125 in 100 patients with active pulmonary TB that had been confirmed by microbiology or PCR. In addition, detailed clinical characteristics and radiologic features were analyzed. About 40% of the patients with active pulmonary TB showed elevated serum CA-125. The CA125 was higher in patients with a positive sputum AFB, cavitary and extensive pulmonary lesions on chest radiographs. The CA-125 decreased after initiation of anti-TB treatment along with improvement in follow-up chest radiographs, and conversion of sputum AFB stains and Mycobacterium cultures. Therefore, CA-125 might be a useful tool to monitor treatment response especially in cases with a slow radiologic response. However, since more than half of the TB patients showed normal CA-125, its usefulness may be restricted to specific TB patients that have a higher chance of initial elevated CA-125; severe TB or female. In South Korea, which has an intermediate burden of TB, there are many patients who have a history of cured TB or who show old healed TB lesion on chest radiograph.9 Sometimes it is difficult to discriminate old healed TB from a reactivated TB lesion. In cases of ambiguity between active TB versus healed TB, elevated CA-125 level may
Table 4 Comparisons of female patients with normal CA-125 and elevated CA-125.
Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Normal CA-125 (n ¼ 19)
Elevated CA-125 (35 U/ml) (n ¼ 27)
p-value
47.4(15e82) 19.8 2.8
51.5(21e87) 20.2 3.2
0.462 0.692 1.000
13(68.4) 1(5.3) 5(26.3)
21(77.8) 2(7.4) 4(14.8)
4(21.1) 15(78.9) 3(15.8) 19(100.0) 6/12(50.0) 8/9(88.9)
7(25.9) 20(74.1) 16(59.2) 25(92.6) 10/15(66.7) 8/8(100.0)
0.002 0.504 0.381 1.000
4(21.1) 0(0.0)
14(51.9) 10(37.0)
0.035 0.003
9(47.4) 3(15.8)
15(55.6) 6(22.2)
0.584 0.588
1.000
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125.
E.S. Kim et al. / Tuberculosis 93 (2013) 222e226 Table 5 The change of serum CA-125 levels during anti-TB treatment. Patients
Total (n ¼ 32) Male (n ¼ 12) Female (n ¼ 20)
CA-125 level (U/ml)
P-value
Baseline
6 months
12 months
43.8 7.8 31.6 26.8 51.2 50.8
19.6 2.5 17.5 9.4 20.9 16.2
18.5 2.3 16.7 9.9 19.5 14.8
P ¼ 0.002 P < 0.001 P < 0.001
Data are mean SD or number(%) patients. Analyzed by repeated measures generalized linear model (GLM). M.TB, Myobacterium tuberculosis; CA-125, cancer antigen 125.
indicate active TB disease. However, in this study, we did not check the CA-125 level in healed TB patients. Therefore, further studies are needed to verify this hypothesis. The mean value of CA-125 in our study was 38.9 41.4 U/ml, which was much lower than that of Ozsahin et al. They reported that the mean CA-125 in active pulmonary TB was 118.46 248.41 U/ml.15 Recently, one study compared the serum CA-125 level in patients with pulmonary TB alone and in TB serositis (pleuritis, pericarditis, peritonitis).4 Patients with TB serositis revealed higher levels of CA-125 compared with patients with pulmonary TB alone (151.13 109.80 U/ml versus 48.26 53.30 U/ml). Although we could not identify the characteristics of patients in the study of Ozsahin et al., the discrepancy in the mean CA-125 in pulmonary TB may be the result of the different characteristics of enrolled patients. The mean CA-125 serum level was significantly higher in the female group than the male patient group: 52.1 U/ml and 27.6 U/ml respectively (p ¼ 0.008). It is known that healthy premenopausal women present higher serum levels of CA-125 than menopausal women, possibly due to the greater ovarian activity of premenopausal women.16 We can hypothesize that the expected concentration in healthy men is similar to or less than in healthy menopausal women. In our study, the female patients were relatively young (the median age of female patients was 43.0 years), and about 63% of female patients were premenopausal. That might be the reason for the higher elevation of CA-125 in the female patients compared with the male patients. In our study, female was an independent predictive factor for elevated CA-125. However, when we analyzed only in female patients (Table 4), positive AFB smear, presence of cavity and extensive lesion were also associated with elevation of CA-125. Therefore, it would be concluded that CA-125 was associated with activity of pulmonary TB. It has been reported that CA-125 was detected in immunohistochemical analysis of normal and neoplastic human lung tissue.17 The study showed that CA-125 was detected in the normal human tracheal, bronchial, bronchiolar, and terminal bronchiolar
225
epithelium; in the tracheal and bronchial glands in addition to the pleural mesothelium. Because CA-125 was identified in the human airway, it follows that severe pulmonary TB, which is associated with more bronchial epithelial cell destruction, would show higher CA-125. Our study had several limitations. First, not all the study patients underwent the 3 sets of serial blood sampling. Only 32 patients underwent the 3 sets of serial blood sampling. However, 69 patients conducted blood sampling more than two times after commencement of anti-TB treatment. When we analyzed these patients, the serum CA-125 levels decreased with anti-TB treatment (p < 0.001). Second, we did not compare serum CA-125 level of TB patients with that of patients with other pulmonary diseases or normal controls. There was a report that mean serum CA-125 level was 12.26 14.0 U/ml in 320 females who did not have active malignancy and showed normal low dose chest CT.18 It would be a reference value for normal controls. In addition, this study was initially designed to evaluate the meaning of elevated CA 125 level in active pulmonary TB, focused on the relationship between the activity of pulmonary TB and CA-125 levels. Therefore, we measured CA-125 level only in pulmonary TB patients without controls. 5. Conclusions Serum CA-125 was elevated in about 40% of patients with active pulmonary TB. CA-125 elevation was associated with female gender, a positive AFB smear, presence of cavity and extensive pulmonary lesions on chest X-ray. With anti-TB treatment, CA-125 decreased significantly along with a serial improvement in the follow-up chest radiographs. Serum CA-125 was related to the activity and severity of pulmonary TB, and it may assist in the determination of the activity of pulmonary TB and in the monitoring of therapeutic responses in certain cases of active pulmonary TB, especially in female patients of active pulmonary TB. Acknowledgments The authors thank to Dr. Hye-Ryoun Kim for providing CA-125 data. Ethical approval: This study was approved by the Institutional Review Board and Ethics Committee of Seoul National University Bundang Hospital, (IRB number: B-0807/059-003) and was conducted in compliance with the Declaration of Helsinki. Funding: None. Competing interests: None declared. References
Figure 2. The change of serum CA-125 levels during anti-TB treatment.
1. Anonymous. American Thoracic Society. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;142(3):725e35. 2. Krysl J, Korzeniewska-Kosela M, Muller NL, FitzGerald JM. Radiologic features of pulmonary tuberculosis: an assessment of 188 cases. Can Assoc Radiol J 1994;45(2):101e7. 3. Leung AN. Pulmonary tuberculosis: the essentials. Radiology 1999;210(2): 307e22. 4. Huang WC, Tseng CW, Chang KM, Hsu JY, Chen JH, Shen GH. Usefulness of tumor marker CA-125 serum levels for the follow-up of therapeutic responses in tuberculosis patients with and without serositis. Jpn J Infect Dis 2011;64(5): 367e72. 5. Lalvani A. Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy. Chest 2007;131(6):1898e906. 6. Hopewell PC, Pai M, Maher D, Uplekar M, Raviglione MC. International standards for tuberculosis care. Lancet Infect Dis 2006;6(11):710e25. 7. Andreu J, Caceres J, Pallisa E, Martinez-Rodriguez M. Radiological manifestations of pulmonary tuberculosis. Eur J Radiol 2004;51(2):139e49.
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8. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O’Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167(4):603e62. 9. Heo EY, Chun EJ, Lee CH, Kim YW, Han SK, Shim YS, Lee HJ, Yim JJ. Radiographic improvement and its predictors in patients with pulmonary tuberculosis. Int J Infect Dis 2009;13(6):e371e6. 10. Kabawat SE, Bast Jr RC, Bhan AK, Welch WR, Knapp RC, Colvin RB. Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125. Int J Gynecol Pathol 1983;2(3):275e85. 11. Yilmaz A, Ece F, Bayramgurler B, Akkaya E, Baran R. The value of Ca 125 in the evaluation of tuberculosis activity. Respir Med 2001;95(8):666e9. 12. Choi CH, Kim CJ, Lee YY, Kim JS, Song T, Park HS, Kim MK, Kim TJ, Lee JW, Lee JH, Bae DS, Kim BG. Peritoneal tuberculosis: a retrospective review of 20 cases and comparison with primary peritoneal carcinoma. Int J Gynecol Cancer 2010;20(5):798e803.
13. Kuno Y, Iyoda M, Aoshima Y, Hosaka N, Sanada D, Hirai Y, Shibata T, Akizawa T. A case of tuberculous peritonitis in a hemodialysis patient with high serum soluble interleukin-2 receptor and CA-125 levels. Intern Med 2010;49(16):1783e6. 14. Ulusoy AN, Karabicak I, Dicle K, Kefeli M, Tosun M, Cetinkaya M, Alper T, Ustun C. Peritoneal tuberculosis in premenopausal patients with elevated serum CA 125. Arch Gynecol Obstet 2010;282(6):639e42. 15. Ozsahin SL, Turgut B, Nur N, Dogan OT, Erselcan T, Berk S. Validity of the CA125 level in the differential diagnosis of pulmonary tuberculosis. Jpn J Infect Dis 2008;61(1):68e9. 16. Bon GG, Kenemans P, Verstraeten R, van Kamp GJ, Hilgers J. Serum tumor marker immunoassays in gynecologic oncology: establishment of reference values. Am J Obstet Gynecol 1996;174(1 Pt 1):107e14. 17. Nouwen EJ, Pollet DE, Eerdekens MW, Hendrix PG, Briers TW, De Broe ME. Immunohistochemical localization of placental alkaline phosphatase, carcinoembryonic antigen, and cancer antigen 125 in normal and neoplastic human lung. Cancer Res 1986;46(2):866e76. 18. Kim HR, Lee CH, Kim YW, Han SK, Shim YS, Yim JJ. Increased CA 19-9 level in patients without malignant disease. Clin Chem Lab Med 2009;47(6):750e4.
Contents lists available at SciVerse ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
DIAGNOSTICS
The clinical significance of CA-125 in pulmonary tuberculosis Eun Sun Kim a, Kyoung Un Park b, JungHan Song b, Hyo-Jeong Lim a, Young-Jae Cho a, HoIl Yoon a, JaeHo Lee a, Choon-Taek Lee a, Jong Sun Park a, * a
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumi-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do 463-707, Republic of Korea b Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumi-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do 463-707, Republic of Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 July 2012 Received in revised form 24 September 2012 Accepted 1 October 2012
Cancer antigen 125 (CA-125) is usually elevated in ovarian cancer. However, there are several reports that serum CA-125 is elevated in tuberculosis. This study investigated the clinical significance of serum CA125 measurements in patients with active pulmonary tuberculosis (TB). Between September 2008 and March 2011, Serum CA-125 was measured in patients with active pulmonary TB before treatment (baseline), and 6 and 12 months after initiation of anti-TB treatment. Patients with pulmonary TB confirmed by culture or polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR) were included. The study enrolled 100 patients. The mean serum CA-125 was 38.9 41.4 U/ml (reference value, <35 U/ml). Thirty-eight patients showed elevated CA-125. Significantly more of those with elevated CA125 were female (p < 0.001), and had a positive sputum smear for acid-fast bacilli (AFB) (p ¼ 0.030). They also significantly more showed extensive pulmonary lesions on chest X-ray (p ¼ 0.004). Elevated CA-125 was independently associated with female gender (OR ¼ 12.5, 95% CI: 3.4e45.2), positive acid-fast staining of sputum (OR ¼ 6.0, 95% CI: 1.8e19.7), cavitary lung lesion (OR ¼ 4.0, 95% CI: 1.2e12.9), and involvement of more than one lung on chest X-ray (OR ¼ 9.4, 95% CI: 2.2e40.1). The CA-125 level decreased with anti-TB treatment (p ¼ 0.001). Serum CA-125 was related to the activity and severity of pulmonary TB, and it may be useful in the monitoring of therapeutic responses in certain cases of active pulmonary TB, especially in female patients of active pulmonary TB. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Cancer antigen 125 Diagnosis Pulmonary tuberculosis Serum
1. Introduction Pulmonary tuberculosis (TB) is one of the leading causes of mortality worldwide and has become a global public health emergency.1 Determination of pulmonary TB activity is as important as early diagnosis of pulmonary TB in optimal treatment strategy. Especially in patients with a previous history of cured TB, it is more difficult to discriminate between an old healed TB lesion and reactivation.2,3 Although novel diagnostic tools for serologic tests, including QuantiFERON-TB Gold In-Tube and T-spot.TB have been developed for rapid and accurate diagnosis of Mycobacterium
* Corresponding author. Tel.: þ82 31 787 7054; fax: þ82 31 787 4052. E-mail addresses: [email protected] (E.S. Kim), [email protected] (K.U. Park), [email protected] (J. Song), [email protected] (H.-J. Lim), [email protected] (Y.-J. Cho), [email protected] (H. Yoon), jhlee7@ snubh.org (J. Lee), [email protected] (C.-T. Lee), [email protected] (J.S. Park). 1472-9792/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tube.2012.10.014
tuberculosis infection, the results of these tests have not been correlated with disease activity or therapeutic responses.4,5 Usually chest radiography, sputum acid-fast staining, and mycobacterial cultures are used for evaluating therapeutic responses of pulmonary TB.6e8 However, chest radiography improves slowly with treatment and does not accurately discriminate the activity of pulmonary TB.6,9 Furthermore, sputum examination is impossible in some patients who do not expectorate sputum. Cancer antigen 125 (CA-125) is a high molecular weight glycoprotein that is expressed on the epithelial cells of the fallopian tube, endometrium, and mesothelial cells lining the pleura, pericardium, and peritoneum.10 CA-125 levels are elevated in a number of malignant diseases such as those involving the ovaries, lungs, breasts, colon, pancreas, and in some non-malignant conditions including endometriosis, hepatic cirrhosis or heart failure. Previously, it was reported that serum CA-125 levels were higher in patients with pulmonary and extra-pulmonary TB than healthy subjects.11 However, there have been few reports on the relationship
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between the activity of pulmonary TB and CA-125 levels. The clinical usefulness of CA-125 in pulmonary TB is not fully understood. The aim of this study was to investigate the clinical significance of serum CA-125 measurements in patients with active pulmonary TB.
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Patients with clinically suspicious active pulmonary TB (n=280)
Excluded (n=58) Not meeting inclusion criteria (n=58)
2. Study population and methods 2.1. Patients and study design A prospective study was performed. Patients diagnosed with active pulmonary TB between September 2008 and March 2011 at Seoul National University Bundang Hospital, a university-affiliated tertiary care hospital in Korea, were enrolled. Any patients with progressive malignancy and female patients with non-malignant gynecologic conditions, such as endometriosis, and pregnancy were excluded by medical history taking and interview. The diagnosis of active pulmonary TB was based on positive respiratory specimen culture or polymerase chain reaction for Mycobacterium tuberculosis (TB-PCR). The patients were followedup for at least 1 year after the initiation of the anti-TB treatment. Sputum staining for acid-fast bacilli (AFB), mycobacterial culture and chest radiography were examined every one or two months during the treatment. In patients who did not expectorate sputum, bronchoscopy was done for mycobacterial culture. TB PCR or interferon-gamma release assay was performed according to the physician’s judgment. After written informed consent was obtained, patients underwent blood sampling for CA-125 before receiving the treatment and 6 months and 12 months after initiation of anti-TB treatment. This study was approved by the Institutional Review Board and Ethics Committee of Seoul National University Bundang Hospital, (IRB number: B-0807/059-003) and was conducted in compliance with the Declaration of Helsinki. 2.2. Measurement of serum CA-125 Serum CA-125 levels were measured using a commercial radioimmunoassay kit (Cis Biointernational, Gif sur Yvette, France), and the normal range was defined as <35 U/mL according to the manufacturer’s instructions. 2.3. Statistical analysis Statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). Descriptive data were expressed as mean SD or median and interquartile range. Student’s t-test was used to compare continuous variables, and chi-square or Fisher’s exact tests were used to compare categorical variables. Serial change of CA-125 level was analyzed by repeated measures generalized linear model. A two-tailed p-value of <0.05 was considered to indicate significant difference. 3. Results 3.1. Baseline characteristics of study patients Among 280 patients with suspected pulmonary TB, 58 patients were excluded because they were not confirmed by mycobacterial culture or TB PCR. Finally, 100 patients with active pulmonary TB were enrolled (Figure 1). The demographic and clinical characteristics of the patients included in the study are presented in Table 1. Twenty seven (27.0%) patients had a previous history of TB. No participant suffered from any active or progressive malignancies. Approximately half of the patients (47 patients, 47%) had an initial sputum smear that showed acid-fast bacilli. Cavitation was present in 46% of patients, and 21
Patients with confirmed active pulmonary TB (n=222)
Excluded (n= 122) - Declined to participate (n=118) - Inadequate sample (n=4)
Patients with confirmed active pulmonary TB (n=100) Figure 1. Flow chart of patient enrollment into the study.
patients (21%) showed pulmonary lesions that involved more than one whole lung on chest X-ray (Table 1). The mean serum CA-125 level was 38.9 41.4 U/ml (reference value, <35 U/ml). Female patients had significantly higher serum CA-125 levels (p < 0.001) and had more bronchiectatic lesions on chest X-ray (p < 0.002). 3.2. Comparisons between patients with normal and elevated CA125 levels According to serum CA-125 levels, patients were subdivided into two groups: the normal CA-125 group and the elevated CA-125 Table 1 Baseline clinical characteristics of the study patients.
Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Diabetes mellitus Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Drug susceptibility test Drug susceptible TB Drug resistant TB* Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion CA-125, U/ml
Total (n ¼ 100)
Male (n ¼ 54)
Female (n ¼ 46)
p-value
46.5(15e89) 20.2 2.8
49.0(25e89) 20.4 2.7
43.0(15e87) 20.0 2.9
0.397 0.565 <0.001
53(53) 32(32) 15(15) 11(11)
19(35.2) 29(53.7) 6(11.1) 8(14.8)
34(73.9) 3(6.5) 9(19.6) 3(6.5)
27(27.0) 73(73.0) 47(47.0) 90(90.0) 39/63(61.9) 34/37(91.9)
16(29.6) 38(70.4) 28(51.8) 46(85.1) 23/36(63.9) 18/20(90.0)
11(23.9) 35(76.1) 19(41.3) 44(95.6) 16/27(59.3) 16/17(94.1)
66/83(79.5) 17/83(20.5)
35/42(83.3) 7/42(16.7)
31/41(75.6) 10/41(24.4)
47(47) 21(21)
29(53.7) 11(20.4)
18(39.1) 10(21.7)
0.147 0.867
36(36) 13(13) 38.9 41.4
12(22.2) 4(7.4) 27.6 32.9
24(52.2) 9(19.6) 52.1 46.6
0.002 0.082 0.008
0.187 0.522
0.296 0.145 0.708 0.651 0.383
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125. * Ten patients were multidrug resistant tuberculosis.
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group. Through univariate analysis, female gender (p < 0.001), a positive sputum smear for AFB (p < 0.030) and extensive pulmonary lesions on chest X-ray (p ¼ 0.004) at diagnosis were significantly associated with an elevated CA-125 levels. The patients with cavity or bronchiectasis on chest radiographs tended to have elevated CA-125 levels, but there was no statistical significance (Table 2). In a subsequent multiple regression model, female gender (OR ¼ 12.5, 95% CI: 3.4e45.2; p < 0.001), a positive sputum smear for AFB (OR ¼ 6.0, 95% CI: 1.8e19.7; p < 0.003), presence of cavity (OR ¼ 4.0, 95% CI: 1.2e12.9; p ¼ 0.020), and involvement of more than one lung on chest X-ray (OR ¼ 9.4, 95% CI: 2.1e40.1; p ¼ 0.003) were significantly associated with an elevated CA-125 levels (Table 3). When we analyzed only in female patients (Table 4), positive AFB smear, presence of cavity and extensive lesion were also associated with elevation of CA-125. 3.3. Changes of CA-125 levels according to the treatment Serial CA-125 measurements were obtained in 32 patients at three times: at the beginning of treatment, and 6 months and 12 months after the initiation of anti-TB medication (Table 5). Serum CA-125 levels decreased significantly after commencement of antiTB treatment in all patients (p ¼ 0.002) (Figure 2). All the patients showed negative conversion of the sputum acid-fast staining and Mycobacterial cultures after treatment. We observed a serial decrease in the CA-125 levels along with a serial improvement in the follow-up chest radiographic findings in all 32 patients. 4. Discussion CA-125 is a high molecular weight glycoprotein that is expressed on the epithelial cells of the fallopian tube, endometrium, and mesothelial cells lining the pleura, pericardium, and peritoneum.10 It is widely used in the diagnosis and monitoring of ovarian cancer. In addition, CA-125 can be elevated in various nonmalignant conditions. Previous studies have reported that serum CA-125 levels were elevated in tuberculosis, mainly in extrapulmonary locations such as peritoneum or pleura.4,12e14 Relatively few studies have evaluated
Table 2 Comparisons of patients with normal CA-125 and elevated CA-125.
Sex, female Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Normal CA-125 (n ¼ 62)
Elevated CA-125 (35 U/ml) (n ¼ 38)
p-value
19(30.6) 45.0(15e89) 20.5 2.4
27(71.1) 48.5(21e89) 19.8 3.4
<0.001 0.417 0.351 0.203
29(56.9) 22(43.1) 11(17.7)
24(70.6) 10(29.4) 4(10.5)
16(25.8) 46(74.2) 24(38.7) 55(88.7) 23/40(57.5) 25/27(92.6)
11(28.9) 27(71.1) 23(60.5) 35(92.1) 16/23(69.6) 9/10(90.0)
0.030 1.000 0.344 1.000
25(40.3) 7(11.3)
22(57.9) 14(36.8)
0.089 0.004
18(29.0) 6(9.7)
18(47.4) 7(18.4)
0.066 0.214
0.768
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125.
Table 3 Factors associated with elevated CA-125 levels in patients with active pulmonary tuberculosis.
Sex, female Sputum smear positivity Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Adjusted odds ratio
95% C.I.
p-value
12.5 6.0 4.0 9.4 1.1 3.0
3.4e45.2 1.8e19.7 1.2e12.9 2.2e40.1 0.4e3.5 0.59e14.6
<0.001 0.003 0.020 0.003 0.817 0.190
the relationship between CA-125 and pulmonary TB. In previous studies, the sensitivity of CA-125 in diagnosing pulmonary TB ranged from 63.0% to 97.5%.11,15 However, detailed data about the demographics of study patients or characteristics of pulmonary TB, the extent of disease, smear positivity or involvement of pleura were limited in those studies. Therefore, it is difficult to interpret the meaning of elevated serum CA-125 in patients with pulmonary TB. In our study, we prospectively measured serum CA-125 in 100 patients with active pulmonary TB that had been confirmed by microbiology or PCR. In addition, detailed clinical characteristics and radiologic features were analyzed. About 40% of the patients with active pulmonary TB showed elevated serum CA-125. The CA125 was higher in patients with a positive sputum AFB, cavitary and extensive pulmonary lesions on chest radiographs. The CA-125 decreased after initiation of anti-TB treatment along with improvement in follow-up chest radiographs, and conversion of sputum AFB stains and Mycobacterium cultures. Therefore, CA-125 might be a useful tool to monitor treatment response especially in cases with a slow radiologic response. However, since more than half of the TB patients showed normal CA-125, its usefulness may be restricted to specific TB patients that have a higher chance of initial elevated CA-125; severe TB or female. In South Korea, which has an intermediate burden of TB, there are many patients who have a history of cured TB or who show old healed TB lesion on chest radiograph.9 Sometimes it is difficult to discriminate old healed TB from a reactivated TB lesion. In cases of ambiguity between active TB versus healed TB, elevated CA-125 level may
Table 4 Comparisons of female patients with normal CA-125 and elevated CA-125.
Age, yr (median, range) Body mass index, kg/m2 Smoking Never-smoker Ever-smoker Unknown Previous history of TB Yes No AFB smear positivity M.TB culture positivity M.TB PCR positivity IGRA positivity Chest X-ray Cavitary lung lesion Extent, more than one whole lung Bronchiectasis Pleural effusion
Normal CA-125 (n ¼ 19)
Elevated CA-125 (35 U/ml) (n ¼ 27)
p-value
47.4(15e82) 19.8 2.8
51.5(21e87) 20.2 3.2
0.462 0.692 1.000
13(68.4) 1(5.3) 5(26.3)
21(77.8) 2(7.4) 4(14.8)
4(21.1) 15(78.9) 3(15.8) 19(100.0) 6/12(50.0) 8/9(88.9)
7(25.9) 20(74.1) 16(59.2) 25(92.6) 10/15(66.7) 8/8(100.0)
0.002 0.504 0.381 1.000
4(21.1) 0(0.0)
14(51.9) 10(37.0)
0.035 0.003
9(47.4) 3(15.8)
15(55.6) 6(22.2)
0.584 0.588
1.000
Data are mean SD or number(%) patients. TB, tuberculosis; AFB, acid-fast bacilli; IGRA, interferon-gamma release assay; CA125, cancer antigen 125.
E.S. Kim et al. / Tuberculosis 93 (2013) 222e226 Table 5 The change of serum CA-125 levels during anti-TB treatment. Patients
Total (n ¼ 32) Male (n ¼ 12) Female (n ¼ 20)
CA-125 level (U/ml)
P-value
Baseline
6 months
12 months
43.8 7.8 31.6 26.8 51.2 50.8
19.6 2.5 17.5 9.4 20.9 16.2
18.5 2.3 16.7 9.9 19.5 14.8
P ¼ 0.002 P < 0.001 P < 0.001
Data are mean SD or number(%) patients. Analyzed by repeated measures generalized linear model (GLM). M.TB, Myobacterium tuberculosis; CA-125, cancer antigen 125.
indicate active TB disease. However, in this study, we did not check the CA-125 level in healed TB patients. Therefore, further studies are needed to verify this hypothesis. The mean value of CA-125 in our study was 38.9 41.4 U/ml, which was much lower than that of Ozsahin et al. They reported that the mean CA-125 in active pulmonary TB was 118.46 248.41 U/ml.15 Recently, one study compared the serum CA-125 level in patients with pulmonary TB alone and in TB serositis (pleuritis, pericarditis, peritonitis).4 Patients with TB serositis revealed higher levels of CA-125 compared with patients with pulmonary TB alone (151.13 109.80 U/ml versus 48.26 53.30 U/ml). Although we could not identify the characteristics of patients in the study of Ozsahin et al., the discrepancy in the mean CA-125 in pulmonary TB may be the result of the different characteristics of enrolled patients. The mean CA-125 serum level was significantly higher in the female group than the male patient group: 52.1 U/ml and 27.6 U/ml respectively (p ¼ 0.008). It is known that healthy premenopausal women present higher serum levels of CA-125 than menopausal women, possibly due to the greater ovarian activity of premenopausal women.16 We can hypothesize that the expected concentration in healthy men is similar to or less than in healthy menopausal women. In our study, the female patients were relatively young (the median age of female patients was 43.0 years), and about 63% of female patients were premenopausal. That might be the reason for the higher elevation of CA-125 in the female patients compared with the male patients. In our study, female was an independent predictive factor for elevated CA-125. However, when we analyzed only in female patients (Table 4), positive AFB smear, presence of cavity and extensive lesion were also associated with elevation of CA-125. Therefore, it would be concluded that CA-125 was associated with activity of pulmonary TB. It has been reported that CA-125 was detected in immunohistochemical analysis of normal and neoplastic human lung tissue.17 The study showed that CA-125 was detected in the normal human tracheal, bronchial, bronchiolar, and terminal bronchiolar
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epithelium; in the tracheal and bronchial glands in addition to the pleural mesothelium. Because CA-125 was identified in the human airway, it follows that severe pulmonary TB, which is associated with more bronchial epithelial cell destruction, would show higher CA-125. Our study had several limitations. First, not all the study patients underwent the 3 sets of serial blood sampling. Only 32 patients underwent the 3 sets of serial blood sampling. However, 69 patients conducted blood sampling more than two times after commencement of anti-TB treatment. When we analyzed these patients, the serum CA-125 levels decreased with anti-TB treatment (p < 0.001). Second, we did not compare serum CA-125 level of TB patients with that of patients with other pulmonary diseases or normal controls. There was a report that mean serum CA-125 level was 12.26 14.0 U/ml in 320 females who did not have active malignancy and showed normal low dose chest CT.18 It would be a reference value for normal controls. In addition, this study was initially designed to evaluate the meaning of elevated CA 125 level in active pulmonary TB, focused on the relationship between the activity of pulmonary TB and CA-125 levels. Therefore, we measured CA-125 level only in pulmonary TB patients without controls. 5. Conclusions Serum CA-125 was elevated in about 40% of patients with active pulmonary TB. CA-125 elevation was associated with female gender, a positive AFB smear, presence of cavity and extensive pulmonary lesions on chest X-ray. With anti-TB treatment, CA-125 decreased significantly along with a serial improvement in the follow-up chest radiographs. Serum CA-125 was related to the activity and severity of pulmonary TB, and it may assist in the determination of the activity of pulmonary TB and in the monitoring of therapeutic responses in certain cases of active pulmonary TB, especially in female patients of active pulmonary TB. Acknowledgments The authors thank to Dr. Hye-Ryoun Kim for providing CA-125 data. Ethical approval: This study was approved by the Institutional Review Board and Ethics Committee of Seoul National University Bundang Hospital, (IRB number: B-0807/059-003) and was conducted in compliance with the Declaration of Helsinki. Funding: None. Competing interests: None declared. References
Figure 2. The change of serum CA-125 levels during anti-TB treatment.
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