- Email: [email protected]
Value of the Tuberculin Skin Test in Screening for Tuberculosis in Dialysis Patients
Value of the Tuberculin Skin Test in Screening for Tuberculosis in Dialysis Patients M.A. Habesoglu, D. Torun, Y.Z. Demiroglu, M. Karataslı, N. Sen, H. Ermis, Nurhan Ozdemir, and F.O. Eyuboglu ABSTRACT Background. Hemodialysis patients are at high risk for tuberculosis, and a tuberculin skin test (TST) is not usually helpful in detecting tuberculosis infection because of anergic reactions. Prophylactic therapy against tuberculosis in dialysis patients is important to enhance transplantation success. Herein we evaluated the value of TST in screening for tuberculosis and analyzed any compounding factors that might affect the results of the test in hemodialysis patients in an endemic area of Turkey. Methods. A total of 187 (96 female, 91 male) patients were screened using a 2-step TST. Test results were compared with clinical, radiologic, and laboratory data. Results. None of the patients had active tuberculosis during the study and 55% had been vaccinated against tuberculosis. After the first purified protein derivative (PPD) test, 55.1% of the patients showed a positive reaction, ultimately reaching a total of 68.4% following the second test. Cumulative positive TST results were significantly correlated with male gender (P ⫽ .001, r ⫽ .352), previous tuberculosis history (P ⫽ .013, r ⫽ .183) positively, whereas with the ferritin level (P ⫽ .001, r ⫽ ⫺.233) negatively; but there were no significant relationships between TST results and other data. Conclusions. Impairment of delayed-type hypersensitivity reaction is frequent in dialysis patients, but we observed high rates of positivity with the two-step TST which could be attributed to tuberculosis being endemic in Turkey. Further comparative studies with more specific diagnostic methods will be helpful to evalute the importance of TST positivity in identifying tuberculosis-infected HD patients.
T
HE INCIDENCE OF tuberculosis (TB) is higher in patients with end-stage renal disease (ESRD) than in the general population.1–3 The main reason for the increased incidence of TB in that particular group of patients is cellular immune dysfunction caused by uremia; other factors include nosocomial exposure, advanced age, and immunosuppressive drug usage.1,2,4 The relative risk of active TB is 10 to 25.3 times higher in patients with ESRD and 37 times higher in renal transplantation patients than that in the general population.5 For those reasons, the tuberculin skin test (TST) should be performed in all ESRD patients and renal transplantation candidates, and individuals with latent TB infection (LTBI) should receive treatment.6 TST is still the most widely used screening test for TB. However, the high prevalence of anergy that is characteristic of patients with chronic renal failure makes the inter© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 883– 886 (2007)
pretation of the TST difficult in those individuals.2–5 A single TST may elicit little response in those whose TB infection occurred many years ago or in patients with history of BCG vaccination, because delayed-type hypersensitivity diminishes with time. But an initially falsenegative TST result can be boosted to a true positive result by repeating the test 1 week to 1 year after its first administration. That technique, which is referred to as the From the Departments of Pulmonary Disease (M.A.H., M.K., N.S., H.E., F.O.E.), Nephrology (D.T., N.O.), and Infectious Diseases and Clinical Microbiology (Y.Z.D.), Faculty of Medicine, Baskent University, Ankara, Turkey. Address reprint requests to Dr Mehmet Ali Habesog˘lu, Baskent University Adana Teaching and Medical Research Center, Dadaloglu M, 39 S, No 6 Yüregir, 01250 Adana, Turkey. E-mail: [email protected] 0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.02.035 883
884
“booster phenomenon,” helps to decrease the number of false-negative TST results.7 The aims of this prospective study were to evaluate the value of the 2-step TST in screening for TB infection and to analyze the compounding factors that can affect the results of that test in patients treated with hemodialysis (HD) in areas of Turkey that are endemic for TB. MATERIALS AND METHODS One hundred eighty-seven of 218 patients in the HD program at the Adana Teaching and Training Hospital of Baskent University, Faculty of Medicine, Ankara, Turkey, were included in this study. Patients with acute renal failure, those with an unconfirmed diagnosis, all hospitalized HD patients, and those who refused the skin test were excluded. All patients were from a similar low-tomoderate socioeconomic background. Three times per week, all subjects underwent dialysis for an average of 4 to 5 hours. The study protocol was approved by the ethics committee, and each patient provided informed consent. Age, sex, cause of renal failure, and the duration and frequency of HD were recorded. The patients were questioned about their history of pulmonary TB and their contact with any individual infected with TB. BCG vaccination scars were detected and counted; the scars were always positioned over the left deltoid muscle. The results of each patient’s most recent laboratory tests (hemoglobin and white blood cell counts, erythrocyte sedimentation rate, and levels of albumin, total cholesterol, and ferritin) were recorded. The efficacy of HD was measured with PRU. Hepatitis B surface antibody levels were combined with the dose of hepatitis B vaccination administered within the last 2 years to identify the patients’ response to vaccination and to compare it with the response to the TST. A chest radiograph performed within the last 3 months was evaluated for the presence of TB lesions by an independent pulmonologist, and the findings of that evaluation were scored blindly as “positive,” “possible,” or “negative.” Dense pulmonary nodules with or without calcification in the hilar area or upper lobes and pleural scarring were scored as a positive result. Lesions that could not undoubtedly be attributed to the result of prior TB infection were considered to be a possible result. The skin test was performed by means of the Mantoux technique with the injection of 0.1 mL (5 tuberculin units) of purified protein derivative (PPD; Tween 80, BB-NCIPP Ltd, Sofia, Bulgaria) into the volar surface of the forearm that did not have the arteriovenous shunt. Administering the PPD by intradermal injection with a standard 26-gauge 1-mL needle and plastic syringe was considered to be correctly done only if a 6- to 10-mm wheal was observed at the injection site. Areas of skin with scars, lesions, or visible veins that might interfere with test interpretation were avoided by a minimum distance of 30 mm. Responses to the test were read on the patient’s next regularly scheduled HD day, 72 hours after the injection of PPD had been administered. The transverse axis of induration was measured with a flexible ruler by an experienced physician. TSTnegative patients received a booster TST that was administered 7 to 10 days after the first test and was placed approximately 10 cm away from the site of the previous injection. The second TST was performed and interpreted in a manner identical to that used for the first test. The result of the second TST was defined as positive (the booster phenomenon) if the induration from the second test was 10 mm or more in diameter and measured at least 6 mm greater in diameter than the induration from the first TST. Data were analyzed with SPSS software (Statistical Package for the
HABESOGLU, TORUN, DEMIROGLU ET AL Social Sciences, version 11.0, SSPS Inc, Chicago, III, USA). Statistical comparisons were performed with the Mann-Whitney nonparametric analysis and Pearson correlation test. A value of P ⬍ .05 was considered significant.
RESULTS
A total of 187 patients (96 female, 91 male) were included in the study. None of the subjects had active TB during the study. BCG vaccine had been administered to 103 patients (55.1%) in their neonatal period or childhood, and the presence of a characteristic scar on the left shoulder was considered evidence of vaccination. The demographic characteristics of the study subjects are shown in Table 1. After the administration of the first TST, 55.1% (103/ 187) of the patients demonstrated a positive reaction. Twenty-five of the 84 patients (29.7%) whose TST result was initially negative (ie, an induration size ⬍10 mm) exhibited a positive result from the second TST; thus a total of 68.4% (128/187) of the patients studied had a positive TST result. The mean size of the induration of a positive TST result was 15 ⫾ 4 mm from the first test and 11 ⫾ 2 mm from the second test; therefore, the overall mean size of the indurations was 13.6 ⫾ 3.6 mm. Table 2 shows that cumulative positive TST results had a significantly positive correlation with male sex (P ⫽ .0001, r ⫽ .352) and the anamnestic data of a previous TB infection (P ⫽ .012, r ⫽ .183), but a negative correlation with the ferritin level (P ⫽ .001, r ⫽ ⫺.233). There was no significant relationship with other data. With respect to the cumulative results from the 2 tests, there was no significant difference between the negative and positive TST groups in terms of age, previous BCG vaccination, TST history, prior exposure to TB, response to dialysis, primary renal disease, nutritional status, laboratory findings, vitamin D intake, and response to hepatitis B vaccination (Table 3, 4). There was no significant correlation between a positive TST result and the results of chest radiographs. Although chest radiographs of the 93 patients with a positive TST result were within normal limits, radiographic signs of prior Table 1. Demographic Data of the Study Subjects Patients (N) Age (y; mean ⫾ SD) Sex (F/M) BCG vaccination (yes/no) Duration of dialysis (months; mean ⫾ SD) Cause of renal disease Diabetic nephropathy Renovascular disease Glomerulonephritis Infection Obstructive Polycystic kidney Other Unknown
187 50.0 ⫾ 15.9 96/91 103/84 53.1 ⫾ 54.9 48 29 15 16 10 3 3 63
TST IN SCREENING FOR TB IN HD PATIENTS
885 Table 4. Comparison of TST Negative Vs Positive Groups (Mean): Cumulative Results of the 2 Tests
Table 2. Correlation Between Positive TST Results (Cumulative) and Risk Factors
Sex Age Prior TB Prior TB contact Prior BCG vaccination Prior positive TST result Renal diagnosis Duration of dialysis PRU Albumin Ferritin Vitamin D Hepatitis B vaccination Cholesterol Triglyceride BMI Hb Leukocyte CRP ESR
r
P
.352 .140 .183 .030 .080 .131 ⫺.03 ⫺.01 ⫺.101 ⫺.07 ⫺.233 ⫺.91 .044 ⫺.127 ⫺.062 ⫺.123 .07 .006 .05 ⫺.58
.0001 .84 .012 .68 .27 .07 .60 .99 .14 .92 .001 .21 .56 .08 .40 .15 .34 .93 .51 .44
TB infection was noted in 4 of 59 patients with a negative TST result. DISCUSSION
In HD patients who are candidates for transplantation as in the general population, active TB most often develops from the reactivation of LTBI.6 It is essential to detect and treat LTBI before transplantation is performed,8,15 and TST is the most widely used method for the diagnosis of LTBI.2,3,5 In this study, we evaluated the role of TST in the diagnosis of LTBI in HD patients living in southern and southeastern Turkey, which are geographic areas in which Table 3. Comparison of TST Negative Vs Positive Groups (Number of Patients): Cumulative results of the 2 Tests
Patients (n) Sex (male/female) Renal disease Glomerulonephritis Diabetic nephropathy Renovascular disease Obstructive Infection Polycystic kidney Other Unknown Prior TB infection (no/yes) Prior TB contact (no/yes) BCG vaccination (no/yes) Prior positive TST result (no/yes) Thoracic radiograph (negative/ possible/positive)
Negative
Positive
59 15/44
128 81/47
2 12 8 4 8 2 1 22 58/1 52/7 30/29 55/4 43/12/4
13 36 21 6 8 1 2 41 111/17 110/18 54/74 107/21 93/18/17
P
.0001 .50
.013 .68 .34 .87 .37
Patients (n) Age (y) Duration of dialysis (months) PRU BMI (kg/m2) Albumin (g/dL) Cholesterol (g/dL) TG (g/dL) Hb (g/dL) Leukocyte ESR CRP Ferritin
Negative
Positive
P
61 49.7 ⫾ 17.4 53.1 ⫾ 42.6 63.4 ⫾ 6.8 25.5 ⫾ 6.0 3.9 ⫾ 0.4 160 ⫾ 47 197 ⫾ 102 10.0 ⫾ 1.6 7612 ⫾ 2478 54.9 ⫾ 30.8 12.98 ⫾ 18.6 723 ⫾ 583
126 50.3 ⫾ 15.3 53.0 ⫾ 59.9 61.7 ⫾ 7.6 24.1 ⫾ 4.6 3.9 ⫾ 0.5 161 ⫾ 47 183 ⫾ 108 10.3 ⫾ 1.6 7643 ⫾ 2283 51.0 ⫾ 31.6 15.3 ⫾ 23.7 488 ⫾ 387
.79 .34 .83 .46 .52 .08 .32 .48 .80 .38 .95 .008
that disease is endemic. In that population 55.1% of the first TST were positive, whereas totally 68.4% of patients showed a significant TST reaction at the end of the second TST. To our knowledge, those are the highest rates of positive reaction to a TST in HD patients that has been published in the literature. Some authors have reported that the percentage of TST positivity in their subjects varied between 16% and 54.7%.2,9 –11 The high rate of positive TST results in those areas of Turkey, which is not surprising, could be attributed to several factors. The evaluation of the booster phenomenon increased the rate of TST positivity 13.3%. In addition, including the patients with a history of active TB in this study may have resulted in a high rate of TST positivity. Fifteen of 16 patients with a history of TB had a positive TST result, and a statistically significant correlation was detected between a history of TB and a positive TST result. Nosocomial exposure is another possible reason for the high rate of TST positivity.2,5 Active TB developed after the beginning of the HD program in 4 of 16 patients with a history of TB. The nonspecific signs and symptoms that develop in HD patients with TB constitute a risk factor for delayed diagnosis and increase the risk of nosocomial exposure to TB.1 BCG vaccination is one of the most common causes of a positive TST result and the booster phenomenon. Although 55.1% of our subjects had been vaccinated, there was no correlation between TST positivity and BCG vaccination. That result is similar to those of other studies in HD patients.2,10,11 According to a meta-analysis published in 2002, the effect of BCG vaccination on the result of TST lasts fewer than 15 years.12 Because the mean age of our patients was 50 ⫾ 15 years, TST positivity may be attributed more often to LTBI than to the effect of BCG. In our study, TST positivity was significantly higher in male subjects than in female subjects, as it was in 2 other studies in Turkey (one of which involved health care workers and the other, the general Turkish population).13,14 In another study from Mexico, the higher TST positivity in men was attributed to environmental exposure and the dynamics of local spread.15 The biologic, socioeconomic,
886
and cultural factors that may cause this gender-based difference were not evaluated in our study. We found no correlation between the factors that can influence TST positivity, such as primary renal disease, the duration and efficacy of dialysis, nutritional status, BMI, vitamin D intake, and response to hepatitis B vaccination. Among laboratory parameters, only the serum level of ferritin was negatively correlated with the TST result (r ⫽ ⫺.233, P ⫽ .001). High serum ferritin levels may indicate iron overload, which alters T-cell function as well as the chemotactic and phagocytic properties of neutrophils, thereby reducing their ability to kill invading pathogens.16,17 Immune dysfunction that is due to iron overload may lead to TST anergy. The relationship between levels of serum ferritin, iron overload, and TST response requires further investigation. We found no correlation between the results of chest radiography and the TST result. Normal chest radiographs in TST-positive patients may be attributed to a high incidence of extrapulmonary TB, which was reported to vary between 36% and 80% in those individuals.1 On the other hand, pulmonary TB may resolve without sequelae. Radiographic findings of TB sequelae in TST-negative patients may be attributed to anergy and a history of extrapulmonary TB. However, chest radiography is valuable in the diagnosis of patients infected with TB in geographic areas of endemic infection, and in our opinion, it is a useful diagnostic tool in screening HD patients for TB. We concluded that although the impairment of delayedtype hypersensitivity reaction is frequent in HD patients, we observed high rates of positivity with the 2-step TST, perhaps because TB is endemic in some areas of Turkey.18 TST, which is an appropriate screening method for TB, is available and relatively inexpensive. However, to determine the importance of TST positivity in identifying TB-infected HD patients, especially renal transplantation candidates, further comparative studies with more specific diagnostic methods are required. REFERENCES 1. Hussein MM, Mooij JM, Roujouleh H: Tuberculosis and chronic renal disease. Semin Dial 16:38, 2003
HABESOGLU, TORUN, DEMIROGLU ET AL 2. Wauters A, Peetermans WE, Van den Brande P, et al: The value of tuberculin skin testing in haemodialysis patients. Nephrol Dial Transplant 19:433, 2004 3. Fang HC, Chou KJ, Chen CL, et al: Tuberculin skin test and anergy in dialysis patients of a tuberculosis-endemic area. Nephron 91:682, 2002 4. Centers for Disease Control and Prevention (CDC): Tuberculosis transmission in a renal dialysis center—Nevada, 2003. MMWR Morb Mortal Wkly Rep 53:873, 2004 5. American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 49:1, 2000 6. EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. IV. Long-term management of the transplant recipient. IV.7.2. Late infections. Tuberculosis. Nephrol Dial Transplant 17:39, 2002 7. Menzies D: Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med 159:15, 1999 8. Kantarci G, Altinoz H, Sahin S, et al: Tuberculin positivity: a serious problem before transplantation in Turkey. Transplant Proc 38:646, 2006 9. Smirnoff M, Patt C, Seckler B, et al: Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest 113:25, 1998 10. Cengiz K, Seker A: Boosted tuberculin skin testing in hemodialysis patients. Am J Infect Control 34:383, 2006 11. Akcay A, Erdem Y, Altun B, et al: The booster phenomenon in 2-step tuberculin skin testing of patients receiving long-term hemodialysis. Am J Infect Control 31:371, 2003 12. Wang L, Turner MO, Elwood RK, et al: A meta-analysis of the effect of Bacille Calmette Guerin vaccination on tuberculin skin test measurements. Thorax 57:804, 2002 13. Ucan ES, Sevinc C, Abadoglu O, et al: Interpretation of tuberculin test results, standards of our country and new needs. J Thorax 1:25, 2000 14. Keskiner R, Ergonul O, Demiroglu Z, et al: Risk of tuberculous infection among healthcare workers in a tertiary-care hospital in Ankara, Turkey. Infect Control Hosp Epidemiol 25:1067, 2004 15. Jimenez-Corona ME, Garcia-Garcia L, DeRiemer K, et al: Gender differentials of pulmonary tuberculosis transmission and reactivation in an endemic area. Thorax 61:348, 2006 16. Hoen B: Iron and infection: clinical experience. Am J Kidney Dis 34:S30, 1999 17. Cohen G, Haag-Weber M, Horl WH: Immune dysfunction in uremia. Kidney Int Suppl 62:S79, 1997 18. Ergin F, Eyuboglu FO, Akcay S, et al: Tuberculosis in renal transplant recipients. Transplant Proc 35:2680, 2003
T
HE INCIDENCE OF tuberculosis (TB) is higher in patients with end-stage renal disease (ESRD) than in the general population.1–3 The main reason for the increased incidence of TB in that particular group of patients is cellular immune dysfunction caused by uremia; other factors include nosocomial exposure, advanced age, and immunosuppressive drug usage.1,2,4 The relative risk of active TB is 10 to 25.3 times higher in patients with ESRD and 37 times higher in renal transplantation patients than that in the general population.5 For those reasons, the tuberculin skin test (TST) should be performed in all ESRD patients and renal transplantation candidates, and individuals with latent TB infection (LTBI) should receive treatment.6 TST is still the most widely used screening test for TB. However, the high prevalence of anergy that is characteristic of patients with chronic renal failure makes the inter© 2007 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 39, 883– 886 (2007)
pretation of the TST difficult in those individuals.2–5 A single TST may elicit little response in those whose TB infection occurred many years ago or in patients with history of BCG vaccination, because delayed-type hypersensitivity diminishes with time. But an initially falsenegative TST result can be boosted to a true positive result by repeating the test 1 week to 1 year after its first administration. That technique, which is referred to as the From the Departments of Pulmonary Disease (M.A.H., M.K., N.S., H.E., F.O.E.), Nephrology (D.T., N.O.), and Infectious Diseases and Clinical Microbiology (Y.Z.D.), Faculty of Medicine, Baskent University, Ankara, Turkey. Address reprint requests to Dr Mehmet Ali Habesog˘lu, Baskent University Adana Teaching and Medical Research Center, Dadaloglu M, 39 S, No 6 Yüregir, 01250 Adana, Turkey. E-mail: [email protected] 0041-1345/07/$–see front matter doi:10.1016/j.transproceed.2007.02.035 883
884
“booster phenomenon,” helps to decrease the number of false-negative TST results.7 The aims of this prospective study were to evaluate the value of the 2-step TST in screening for TB infection and to analyze the compounding factors that can affect the results of that test in patients treated with hemodialysis (HD) in areas of Turkey that are endemic for TB. MATERIALS AND METHODS One hundred eighty-seven of 218 patients in the HD program at the Adana Teaching and Training Hospital of Baskent University, Faculty of Medicine, Ankara, Turkey, were included in this study. Patients with acute renal failure, those with an unconfirmed diagnosis, all hospitalized HD patients, and those who refused the skin test were excluded. All patients were from a similar low-tomoderate socioeconomic background. Three times per week, all subjects underwent dialysis for an average of 4 to 5 hours. The study protocol was approved by the ethics committee, and each patient provided informed consent. Age, sex, cause of renal failure, and the duration and frequency of HD were recorded. The patients were questioned about their history of pulmonary TB and their contact with any individual infected with TB. BCG vaccination scars were detected and counted; the scars were always positioned over the left deltoid muscle. The results of each patient’s most recent laboratory tests (hemoglobin and white blood cell counts, erythrocyte sedimentation rate, and levels of albumin, total cholesterol, and ferritin) were recorded. The efficacy of HD was measured with PRU. Hepatitis B surface antibody levels were combined with the dose of hepatitis B vaccination administered within the last 2 years to identify the patients’ response to vaccination and to compare it with the response to the TST. A chest radiograph performed within the last 3 months was evaluated for the presence of TB lesions by an independent pulmonologist, and the findings of that evaluation were scored blindly as “positive,” “possible,” or “negative.” Dense pulmonary nodules with or without calcification in the hilar area or upper lobes and pleural scarring were scored as a positive result. Lesions that could not undoubtedly be attributed to the result of prior TB infection were considered to be a possible result. The skin test was performed by means of the Mantoux technique with the injection of 0.1 mL (5 tuberculin units) of purified protein derivative (PPD; Tween 80, BB-NCIPP Ltd, Sofia, Bulgaria) into the volar surface of the forearm that did not have the arteriovenous shunt. Administering the PPD by intradermal injection with a standard 26-gauge 1-mL needle and plastic syringe was considered to be correctly done only if a 6- to 10-mm wheal was observed at the injection site. Areas of skin with scars, lesions, or visible veins that might interfere with test interpretation were avoided by a minimum distance of 30 mm. Responses to the test were read on the patient’s next regularly scheduled HD day, 72 hours after the injection of PPD had been administered. The transverse axis of induration was measured with a flexible ruler by an experienced physician. TSTnegative patients received a booster TST that was administered 7 to 10 days after the first test and was placed approximately 10 cm away from the site of the previous injection. The second TST was performed and interpreted in a manner identical to that used for the first test. The result of the second TST was defined as positive (the booster phenomenon) if the induration from the second test was 10 mm or more in diameter and measured at least 6 mm greater in diameter than the induration from the first TST. Data were analyzed with SPSS software (Statistical Package for the
HABESOGLU, TORUN, DEMIROGLU ET AL Social Sciences, version 11.0, SSPS Inc, Chicago, III, USA). Statistical comparisons were performed with the Mann-Whitney nonparametric analysis and Pearson correlation test. A value of P ⬍ .05 was considered significant.
RESULTS
A total of 187 patients (96 female, 91 male) were included in the study. None of the subjects had active TB during the study. BCG vaccine had been administered to 103 patients (55.1%) in their neonatal period or childhood, and the presence of a characteristic scar on the left shoulder was considered evidence of vaccination. The demographic characteristics of the study subjects are shown in Table 1. After the administration of the first TST, 55.1% (103/ 187) of the patients demonstrated a positive reaction. Twenty-five of the 84 patients (29.7%) whose TST result was initially negative (ie, an induration size ⬍10 mm) exhibited a positive result from the second TST; thus a total of 68.4% (128/187) of the patients studied had a positive TST result. The mean size of the induration of a positive TST result was 15 ⫾ 4 mm from the first test and 11 ⫾ 2 mm from the second test; therefore, the overall mean size of the indurations was 13.6 ⫾ 3.6 mm. Table 2 shows that cumulative positive TST results had a significantly positive correlation with male sex (P ⫽ .0001, r ⫽ .352) and the anamnestic data of a previous TB infection (P ⫽ .012, r ⫽ .183), but a negative correlation with the ferritin level (P ⫽ .001, r ⫽ ⫺.233). There was no significant relationship with other data. With respect to the cumulative results from the 2 tests, there was no significant difference between the negative and positive TST groups in terms of age, previous BCG vaccination, TST history, prior exposure to TB, response to dialysis, primary renal disease, nutritional status, laboratory findings, vitamin D intake, and response to hepatitis B vaccination (Table 3, 4). There was no significant correlation between a positive TST result and the results of chest radiographs. Although chest radiographs of the 93 patients with a positive TST result were within normal limits, radiographic signs of prior Table 1. Demographic Data of the Study Subjects Patients (N) Age (y; mean ⫾ SD) Sex (F/M) BCG vaccination (yes/no) Duration of dialysis (months; mean ⫾ SD) Cause of renal disease Diabetic nephropathy Renovascular disease Glomerulonephritis Infection Obstructive Polycystic kidney Other Unknown
187 50.0 ⫾ 15.9 96/91 103/84 53.1 ⫾ 54.9 48 29 15 16 10 3 3 63
TST IN SCREENING FOR TB IN HD PATIENTS
885 Table 4. Comparison of TST Negative Vs Positive Groups (Mean): Cumulative Results of the 2 Tests
Table 2. Correlation Between Positive TST Results (Cumulative) and Risk Factors
Sex Age Prior TB Prior TB contact Prior BCG vaccination Prior positive TST result Renal diagnosis Duration of dialysis PRU Albumin Ferritin Vitamin D Hepatitis B vaccination Cholesterol Triglyceride BMI Hb Leukocyte CRP ESR
r
P
.352 .140 .183 .030 .080 .131 ⫺.03 ⫺.01 ⫺.101 ⫺.07 ⫺.233 ⫺.91 .044 ⫺.127 ⫺.062 ⫺.123 .07 .006 .05 ⫺.58
.0001 .84 .012 .68 .27 .07 .60 .99 .14 .92 .001 .21 .56 .08 .40 .15 .34 .93 .51 .44
TB infection was noted in 4 of 59 patients with a negative TST result. DISCUSSION
In HD patients who are candidates for transplantation as in the general population, active TB most often develops from the reactivation of LTBI.6 It is essential to detect and treat LTBI before transplantation is performed,8,15 and TST is the most widely used method for the diagnosis of LTBI.2,3,5 In this study, we evaluated the role of TST in the diagnosis of LTBI in HD patients living in southern and southeastern Turkey, which are geographic areas in which Table 3. Comparison of TST Negative Vs Positive Groups (Number of Patients): Cumulative results of the 2 Tests
Patients (n) Sex (male/female) Renal disease Glomerulonephritis Diabetic nephropathy Renovascular disease Obstructive Infection Polycystic kidney Other Unknown Prior TB infection (no/yes) Prior TB contact (no/yes) BCG vaccination (no/yes) Prior positive TST result (no/yes) Thoracic radiograph (negative/ possible/positive)
Negative
Positive
59 15/44
128 81/47
2 12 8 4 8 2 1 22 58/1 52/7 30/29 55/4 43/12/4
13 36 21 6 8 1 2 41 111/17 110/18 54/74 107/21 93/18/17
P
.0001 .50
.013 .68 .34 .87 .37
Patients (n) Age (y) Duration of dialysis (months) PRU BMI (kg/m2) Albumin (g/dL) Cholesterol (g/dL) TG (g/dL) Hb (g/dL) Leukocyte ESR CRP Ferritin
Negative
Positive
P
61 49.7 ⫾ 17.4 53.1 ⫾ 42.6 63.4 ⫾ 6.8 25.5 ⫾ 6.0 3.9 ⫾ 0.4 160 ⫾ 47 197 ⫾ 102 10.0 ⫾ 1.6 7612 ⫾ 2478 54.9 ⫾ 30.8 12.98 ⫾ 18.6 723 ⫾ 583
126 50.3 ⫾ 15.3 53.0 ⫾ 59.9 61.7 ⫾ 7.6 24.1 ⫾ 4.6 3.9 ⫾ 0.5 161 ⫾ 47 183 ⫾ 108 10.3 ⫾ 1.6 7643 ⫾ 2283 51.0 ⫾ 31.6 15.3 ⫾ 23.7 488 ⫾ 387
.79 .34 .83 .46 .52 .08 .32 .48 .80 .38 .95 .008
that disease is endemic. In that population 55.1% of the first TST were positive, whereas totally 68.4% of patients showed a significant TST reaction at the end of the second TST. To our knowledge, those are the highest rates of positive reaction to a TST in HD patients that has been published in the literature. Some authors have reported that the percentage of TST positivity in their subjects varied between 16% and 54.7%.2,9 –11 The high rate of positive TST results in those areas of Turkey, which is not surprising, could be attributed to several factors. The evaluation of the booster phenomenon increased the rate of TST positivity 13.3%. In addition, including the patients with a history of active TB in this study may have resulted in a high rate of TST positivity. Fifteen of 16 patients with a history of TB had a positive TST result, and a statistically significant correlation was detected between a history of TB and a positive TST result. Nosocomial exposure is another possible reason for the high rate of TST positivity.2,5 Active TB developed after the beginning of the HD program in 4 of 16 patients with a history of TB. The nonspecific signs and symptoms that develop in HD patients with TB constitute a risk factor for delayed diagnosis and increase the risk of nosocomial exposure to TB.1 BCG vaccination is one of the most common causes of a positive TST result and the booster phenomenon. Although 55.1% of our subjects had been vaccinated, there was no correlation between TST positivity and BCG vaccination. That result is similar to those of other studies in HD patients.2,10,11 According to a meta-analysis published in 2002, the effect of BCG vaccination on the result of TST lasts fewer than 15 years.12 Because the mean age of our patients was 50 ⫾ 15 years, TST positivity may be attributed more often to LTBI than to the effect of BCG. In our study, TST positivity was significantly higher in male subjects than in female subjects, as it was in 2 other studies in Turkey (one of which involved health care workers and the other, the general Turkish population).13,14 In another study from Mexico, the higher TST positivity in men was attributed to environmental exposure and the dynamics of local spread.15 The biologic, socioeconomic,
886
and cultural factors that may cause this gender-based difference were not evaluated in our study. We found no correlation between the factors that can influence TST positivity, such as primary renal disease, the duration and efficacy of dialysis, nutritional status, BMI, vitamin D intake, and response to hepatitis B vaccination. Among laboratory parameters, only the serum level of ferritin was negatively correlated with the TST result (r ⫽ ⫺.233, P ⫽ .001). High serum ferritin levels may indicate iron overload, which alters T-cell function as well as the chemotactic and phagocytic properties of neutrophils, thereby reducing their ability to kill invading pathogens.16,17 Immune dysfunction that is due to iron overload may lead to TST anergy. The relationship between levels of serum ferritin, iron overload, and TST response requires further investigation. We found no correlation between the results of chest radiography and the TST result. Normal chest radiographs in TST-positive patients may be attributed to a high incidence of extrapulmonary TB, which was reported to vary between 36% and 80% in those individuals.1 On the other hand, pulmonary TB may resolve without sequelae. Radiographic findings of TB sequelae in TST-negative patients may be attributed to anergy and a history of extrapulmonary TB. However, chest radiography is valuable in the diagnosis of patients infected with TB in geographic areas of endemic infection, and in our opinion, it is a useful diagnostic tool in screening HD patients for TB. We concluded that although the impairment of delayedtype hypersensitivity reaction is frequent in HD patients, we observed high rates of positivity with the 2-step TST, perhaps because TB is endemic in some areas of Turkey.18 TST, which is an appropriate screening method for TB, is available and relatively inexpensive. However, to determine the importance of TST positivity in identifying TB-infected HD patients, especially renal transplantation candidates, further comparative studies with more specific diagnostic methods are required. REFERENCES 1. Hussein MM, Mooij JM, Roujouleh H: Tuberculosis and chronic renal disease. Semin Dial 16:38, 2003
HABESOGLU, TORUN, DEMIROGLU ET AL 2. Wauters A, Peetermans WE, Van den Brande P, et al: The value of tuberculin skin testing in haemodialysis patients. Nephrol Dial Transplant 19:433, 2004 3. Fang HC, Chou KJ, Chen CL, et al: Tuberculin skin test and anergy in dialysis patients of a tuberculosis-endemic area. Nephron 91:682, 2002 4. Centers for Disease Control and Prevention (CDC): Tuberculosis transmission in a renal dialysis center—Nevada, 2003. MMWR Morb Mortal Wkly Rep 53:873, 2004 5. American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 49:1, 2000 6. EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. IV. Long-term management of the transplant recipient. IV.7.2. Late infections. Tuberculosis. Nephrol Dial Transplant 17:39, 2002 7. Menzies D: Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med 159:15, 1999 8. Kantarci G, Altinoz H, Sahin S, et al: Tuberculin positivity: a serious problem before transplantation in Turkey. Transplant Proc 38:646, 2006 9. Smirnoff M, Patt C, Seckler B, et al: Tuberculin and anergy skin testing of patients receiving long-term hemodialysis. Chest 113:25, 1998 10. Cengiz K, Seker A: Boosted tuberculin skin testing in hemodialysis patients. Am J Infect Control 34:383, 2006 11. Akcay A, Erdem Y, Altun B, et al: The booster phenomenon in 2-step tuberculin skin testing of patients receiving long-term hemodialysis. Am J Infect Control 31:371, 2003 12. Wang L, Turner MO, Elwood RK, et al: A meta-analysis of the effect of Bacille Calmette Guerin vaccination on tuberculin skin test measurements. Thorax 57:804, 2002 13. Ucan ES, Sevinc C, Abadoglu O, et al: Interpretation of tuberculin test results, standards of our country and new needs. J Thorax 1:25, 2000 14. Keskiner R, Ergonul O, Demiroglu Z, et al: Risk of tuberculous infection among healthcare workers in a tertiary-care hospital in Ankara, Turkey. Infect Control Hosp Epidemiol 25:1067, 2004 15. Jimenez-Corona ME, Garcia-Garcia L, DeRiemer K, et al: Gender differentials of pulmonary tuberculosis transmission and reactivation in an endemic area. Thorax 61:348, 2006 16. Hoen B: Iron and infection: clinical experience. Am J Kidney Dis 34:S30, 1999 17. Cohen G, Haag-Weber M, Horl WH: Immune dysfunction in uremia. Kidney Int Suppl 62:S79, 1997 18. Ergin F, Eyuboglu FO, Akcay S, et al: Tuberculosis in renal transplant recipients. Transplant Proc 35:2680, 2003