Tuberculin Skin Test Results and the Booster Phenomenon in Two-Step Tuberculin Skin Testing in Hemodialysis Patients

Abstract

Patients with chronic renal failure are at increased risk for tuberculosis (TB). Centers for Disease Control and Prevention (CDC) have recommended annual skin testing for TB, with tuberculin-purified protein derivative (PPD), in patients with chronic renal failure. Uremia alters the macrophage function, which can lead to anergy for skin tests. The aim of this prospective study was to determine the prevalence of positive tuberculin skin test (TST) and the booster effect of TST in hemodialysis patients living in a relatively underdeveloped portion of the country. Material and Methods. Patients were recruited from Van (Yuzuncu Yil University Hospital, Yuksek Ihtisas Hospital) and the Mus State Hospital). At the time of this study, a total of 143 patients were under hemodialysis treatment in these hemodialysis centers, and among them, 124 were included in the study. Informed consent was obtained before inclusion in the study. A positive PPD was an induration of >10 mm in response to five tuberculin units of PPD (RT23-Tween 80), at 72 h. TST-negative patients received a booster TST 10 days later, ~ 10 cm away from the previous intracutaneous injection. The test dose could not be increased due to unavailability of this kind of preparation. The test was performed and interpreted in the same way. Skin testing was performed in June and December 2003. Patients with known active TB are not included in the study. Testing was not done in hospitalized patients to rule out effects of other disease states. Results. Mean age of the patients was 45.3 ± 16 (range 13–82) years. All patients were on HD treatment twice (n: 14) or three times (n: 110) weekly. Duration of dialysis before TST was 30 ± 17 (12–84) months. With the first test (n: 14), 11.3% of the patients showed a positive reaction; the second test added (n: 15) 12.1% more TST-positive patients, reaching a total of (n: 29) 23.4% of the patients with a positive TST. The mean induration of the positive TST was 16 ± 4 mm in the first test and 15 ± 3 mm in the second. Five (17.2%) of the patients with positive PPD and two of the patients (2.1%) with negative PPD results subsequently developed active TB within 12 months. Conclusion. We found a significant booster effect in our hemodialysis patients using TST-2. Repeat PPD test with the same dosage could detect positive patients more than twofold higher. Among positive PPD patients, TB incidence is considerably high.

• PPD
• booster phenomenon
• tuberculosis
• hemodialysis

Introduction

Chronic hemodialysis patients are at increased risk for developing tuberculosis (TB). Investigations from several countries have shown that the incidence of active TB among patients on long-term dialysis is 6.9 to 52.5 times higher than the rate in the general population.[1-3] Hemodialysis patients have an increased risk of developing active tuberculosis, either by reactivation of an old infection, or by horizontal acquisition during a contact with a contagious TB patient.[4]

The tuberculin skin test (TST) is an important method for detecting Mycobacterium tuberculosis infection. Centers for Disease Control and Prevention (CDC) have recommended annual skin testing for TB, with tuberculin-purified protein derivative (PPD) in patients with chronic renal failure. Tuberculin reaction is an invaluable instrument of epidemiologic investigation. Clinically, the value of the tuberculin test, though remarkable, is limited by the fact that its positivity is not necessarily a sign of active tuberculosis.[5&6] Repeat TST of uninfected people does not sensitize them to tuberculin. Although subsequent initial skin testing may be negative for TB, the stimulus of a first test may boost or increase the size of the reaction to a second test administered 1 week to 1 year later and thus may suggest an apparent-but-false tuberculin conversion. This phenomenon has come to be known as the booster effect.[7]

TB incidence is high in our region in hemodialysis patients due to low socioeconomic background (E8). The aim of this prospective study was to determine the prevalence of positive tuberculin skin test (TST) and booster effect of TST in hemodialysis patients living in a relatively underdeveloped portion of the country.

Methods

Patients were recruited from Van (Yuzuncu Yil University Hospital, Yuksek Ihtisas Hospital) and the Mus State Hospital. Testing was done between June and December 2003. At the time of this study, a total of 143 patients were under hemodialysis treatment in these hemodialysis centers, and among them, 124 were included in the study. All patients were on HD treatment twice (n: 14) or three times (n: 110) weekly. Our dialysis patients had similar social backgrounds. Patients were given an educational handout on TST days before testing began.

A brief TB and social history were obtained from each patient, and verbal consent for testing was obtained. Like some European countries, in Turkey, routine BCG vaccination of children is used for the prevention of TB. No systematic program of TST had previously been performed at this hospital in hemodialysis patients. Patient charts were reviewed for demographics (age), renal diagnosis, and for current/past medication (duration of hemodialysis), medical history, and certain laboratory values (HBsAg, HCV, Hgb, albumin, cholesterol, LDL, HDL,). Patients with a history of TB or a positive TST either documented in the medical record or per the patient's verbal history and patients with active infections were excluded from the study.

Skin test was performed by using the Mantoux technique with 0.1 mL (5 tuberculin units) of purified protein derivative (PPD) intradermally into the volar surface of the forearm that did not have the arteriovenous shunt. Administering the purified protein derivative 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 of 30 mm distance, and results were read 48 to 72 h later. TST-negative patients received a booster TST 7–10 days later, ~ 10 cm away from the previous intracutaneous injection. The test dose could not be increased due to unavailability of this kind of preparation. The test was performed and interpreted in the same way. The booster phenomenon was defined as positive if induration from the TST-2 was 10 mm or more and measured at least 6 mm more than that of the TST-1.[8] Chest roentgenograms of patients with positive tuberculin reactions did not reveal any patient with pulmonary TB.

Results

A total of 143 patients was receiving dialysis at the three centers at the time of testing. For 12 patients, the exclusion criteria was the history of TB disease. A total of 124 (56 male, 68 female) patients were included in the study. BCG vaccine had been given to 112 (90.3%) patients in the neonatal or childhood period as assessed by the presence of a characteristic scar located in the shoulder area. Main clinical characteristics were shown in Table 1.

Table 1 Characteristics of the patients

	Total	TST-1 (+)	TST-2 (+)	TST(−)
Number	124	14	15	95
Age (years) (mean ± SD)	45.3 ± 16.2	51.4 ± 13.6	52.4 ± 12.7	43.6 ± 16.4
Gender	56	8/6	8/7	40
Duration of dialysis (months) (mean ± SD)	30 ± 17	28 ± 23	29 ± 21	32.4 ± 22
Glomerulonephritis	37	4	5	28
DM	25	3	3	19
Hypertensive nephropathy	17	2	2	13
Other	12	2	3	7
Unknown origin	33	3	2	28
BCG (vaccinated)	112	13	14	85
BCG (not vaccinated)	12	1	1	10

Of the 124 available for evaluation (n: 14), 11.3% had positive results for PPD and 110 (88.7%) had negative results for PPD initially. The 110 patients with negative test results were eligible for the second, or booster, PPD; after administration of the booster (n: 15), 12.1% more patients had positive test results. TST-positive patients reached a total of (n: 29) 23.4% of the patients. The mean induration of the positive TST was 16 ± 4 mm in the first test and 15 ± 3 mm in the second. When all TST-positive and TST-negative patients were compared in terms of age, gender, time on dialysis, primary renal disease, nutritional state (by means of albumin and cholesterol), and hepatic markers (HBsAg and HCV antibody) no significant difference was observed. Main laboratory parameters were shown in Table 2.

Table 2 Laboratory parameters of patients.

	Total	TST-1 (+)	TST-2 (+)	TST(−)
Number	124	14	15	95
HBs Antigen (+)	12	2	2	8
HCV Antibody (+)	65	5	6	54
Hbg (g/dL)	9.1 ± 2.1	9.0 ± 1.9	9.1 ± 2.1	9.1 ± 2.2
Cholesterol	154 ± 74	135 ± 34	191 ± 69	149 ± 87
LDL (g/dL)	83 ± 57	70 ± 26	76 ± 42	61 ± 10
HDL (g/dL)	54 ± 45	53 ± 38	39 ± 6	84 ± 14
TG (g/dL)	167 ± 96	140 ± 84	115 ± 31	101 ± 12
Albumin (g/dL)	3.4 ± 0.6	3.5 ± 0.4	3.4 ± 0.4	3.4 ± 0.6

Five (17.2%) of the patients (four TST positive and one TST2 positive) with positive PPD results and two of the patients (2.1%) with negative results subsequently developed active TB within 12 months.

Discussion

Patients on hemodialysis are at high risk for developing TB, at least in part because of an increased risk of developing active TB from latent infection.[1-7] In our country, several studies have demonstrated that the incidence of active TB disease is high among chronic HD patients.[9-11]

Uremia induces a suppression of the immune status, and there is a decreased T-cell response, as indicated by the high rate of anergy to intracutaneously administered antigens. A reason for the decreased cellular immunity might be a defect in the costimulatory function of antigen-presenting cells, and a persistent inflammatory state of monocytes, which is caused by uremia and by the dialysis treatment.[1] Other factors that might contribute to the decreased immunity are malnutrition, vitamin D deficiency, and hyperparathyroidism.[12] TST remains the most useful screening tool, and it is also considered the “gold standard” for latent TB infection.[13&14] TST is neither 100% sensitive nor 100% specific because of faulty techniques of application, cross-reactivity of other mycobacterial antigens, and reading errors, or immunologic abnormalities of the host. Despite these difficulties, the TST is an important method for detecting M tuberculosis infection.[5], [7] Therefore, it is important to determine the significance of tuberculin reactions as much as possible. The two-step tuberculin skin test (TST) is an important part of tuberculosis surveillance program.[15] In the two-step TST, a second test is done 1–4 weeks after the first to identify those who have immunologic recall of the tuberculosis antigen. A positive result after an initial negative result is referred to as the “booster phenomenon.” The results of the second test are then taken as the baseline with which to compare future TST results. A subsequent positive TST result after a negative two-step TST result is assumed to represent a conversion, and then treatment of latent tuberculosis may be recommended. If a second TST result is negative for TB, the patients are probably not infected or are anergic.[5], [16]

We identified a low rate of PPD positive (11.3%) in the first test. This is comparable with PPD positive rates reported for hemodialysis patients.[15], [17] This low rate is not surprising, given that renal insufficiency is a well-recognized risk factor for anergy. Akcay et al. reported that the prevalence of first TST positive rate was 35.8% and 29% for the second TST test. These ratios are higher than ours, because we did not perform tests on patients with known active TB history.[18] But after second TST with the same dosage, positive patients (12.1%) could be detected at more than twofold higher rates. Five of the patients with positive PPD results and two of the patients with negative results subsequently developed active TB within 12 months.

One of the limitations of our study was that the majority of our patients had a history of BCG vaccination, because it is the most common factor on tuberculin reactivity and the development of booster phenomenon.[16] Another limitation of the study was that we could not detect the rate of anergy in our patients. Furthermore, the study was done in the HD population in a region with high prevalence of TB.

Conclusion

We found significant booster effect in our hemodialysis patients using TST-2. The positivity of TST was detected as being twofold higher. However, our results cannot be generalized for all HD patients due to the fact that our region is an endemic area for TB. We concluded that the TST-2 test should be performed in investigating latent TB infection.