Etanercept therapy in patients with a positive tuberculin skin test

INTRODUCTION: Etanercept (Enbrel), a tumor necrosis factor-alpha (TNF-alpha) antagonist, is commonly used for the treatment of a variety of rheumatic diseases. Tuberculosis (TB) infections have been associated with chronic TNF-alpha blocking therapy, and there is concern that such therapy may predispose patients to TB reactivation. In this study, we attempted to evaluate the frequency of latent TB reactivation among patients treated with etanercept. METHODS: All patients with either a positive purified protein derivative (PPD) for TB or a previous history of therapy for latent TB infection (LTBI) who were prescribed etanercept in the division of rheumatology at John H. Stroger Jr Hospital of Cook County prior to November 2005 were enrolled in this study. A retrospective chart review was performed looking for evidence of active TB infection during etanercept treatment. RESULTS: Forty-eight patients with a positive PPD were treated with etanercept, and followed for an aggregate of 818 patient-months of etanercept exposure, with a mean follow-up period of 17 months (range 5 to 48 months); all patients had at least one follow-up visit. Forty-four patients (92%) were fully or partially treated with LTBI therapy prior to initiation of etanercept. Chest roentgenograms were available for review in 43 patients, ten of which had evidence of old granulomatous disease. No cases of active TB were described during the study period. CONCLUSIONS: In this small retrospective analysis, none of the 48 patients with positive PPDs who were treated with etanercept for average of 17 months developed active TB.     

Effect of anti-tuberculosis treatment on the tuberculin interferon-gamma response in tuberculin skin test (TST) positive health care workers and patients with tuberculosis.

SETTING: Public hospital, Victoria, Australia. OBJECTIVE: To evaluate the effect of multidrug treatment and isoniazid (INH) chemoprophylaxis on the tuberculin interferon-y assay (QIFN) in 19 patients with culture-confirmed Mycobacterium tuberculosis and 119 health care workers (HCWs) with tuberculin skin tests (TST) > or =15 mm. DESIGN: Patients with M. tuberculosis were treated with standard medication and tested with QIFN at diagnosis and at regular intervals over a 12-month period. All HCWs, 59 (50%) of whom were prescribed INH chemoprophylaxis, were tested with QIFN at baseline, 2, 4, 6 and 12 months. RESULTS: QIFN results in patients with tuberculosis were consistent and reproducible. At the initial time point QIFN assays were positive for M. tuberculosis in 67%, and once positive, the QIFN assay remained so over the 12-month period. In the HCWS, initial QIFN assays were positive in 73 (61%). During the 12-month study, 91 HCWs had a QIFN assay on at least two occasions. The overall reproducibility between tests was fair (kappa statistic = 0.45), and was little affected by administration of INH. CONCLUSION: These data suggest that although the QIFN assay is generally positive in patients with proven tuberculosis, it does not provide clinically useful information during the first 12 months of treatment with multidrug chemotherapy or INH chemoprophylaxis.     

Characteristics of children with positive tuberculin skin test

The aim of the study was to define the characteristics of children with latent tuberculosis diagnosed with positive tuberculin skin test (TST) and evaluate potential risk factors in children with positive TST. Children followed with the diagnosis of latent tuberculosis infection were included in the study retrospectively. Demographic characteristics of patients including history of atopy, respiratory infections, family history of tuberculosis and atopy, number of BCG vaccinations, findings of physical examination and laboratory data were extracted from patient's file. Eighty-one children (51 male, 30 female) who had positive TST were retrospectively evaluated in the study. Mean age of the patients was 8.00 ± 4.00 years. Only 13 (16%) of the children had contact with a case who had active tuberculosis. It was shown that the age of the patients, number of BCG scars and BCG vaccination significantly affected TST reaction size. TST size was not affected with time passed after last dose of BCG vaccination, family history of tuberculosis, presence of TST positive case in the family, exposure to cigarette smoke, number of household family members and presence of respiratory allergic disease. The patient's age, numbers of BCG vaccination and BCG scars significantly affect TST results in childhood. This may cause difficulty in diagnosing latent tuberculosis infection and in decision of initiating prophylactic treatment. The results of this study may show that recently developed, more accurate and convenient in vitro tests that they have higher costs and require sophisticated laboratory, can be used to diagnose latent tuberculosis.     

T-lymphocyte subgroups and tuberculin skin test reactivity in patients with chronic renal failure

As anergy is common in patients with chronic renal failure (CRF), the use of tuberculin skin test (TST) is controversial. Therefore, determination of the factors that affect the TST reactivity would increase the diagnostic value of the test. The aim of the present study was to investigate the factors affecting TST reactivity and evaluate the relationship between T-lymphocyte subsets and TST reactivity. We thus examined 44 patients (mean age 46.6 +/- 15.6 years, 25 males, duration of CRF 5.6 +/- 5.2 years), performed TST (an induration with a diameter of 5 mm or more was considered as positive) and measured Tlymphocyte subsets and biochemical parameters. Twenty-three patients were on hemodialysis, six were on peritoneal dialysis, seven were transplant recipients, and eight were on medical treatment. Eleven patients (25%) had immunosuppressive treatment. Eleven patients (25%) had two, 29 patients (66%) had one, and four patients (9%) had no BCG scars. Five patients (11%) had low body mass index (BMI). T-lymphocyte subsets were as follows: CD4= 40.7 +/- 7.6%, CD8= 32 +/- 8.9%, CD4/CD8= 1.7 +/- 2.5%, CD3= 71.4 +/- 9.4%, CD19= 6.3 +/- 5.1%, NK= 9.7 +/- 5.9. Twenty-two patients had positive TST reactivity. No relation was found between TST reactivity and age, gender, co-morbidity, BCG vaccination, BMI, immunosuppressive therapy, duration and treatment of CRF. Similarly, TST reactivity was not related to the biochemical parameters and Tlymphocyte subsets. These data provide that tuberculin reactivity does not seem to be associated with T-lymphocyte dysfunction and clinical features in patients with chronic renal failure.     

Replacing the tuberculin skin test with a specific blood test

For almost 100 years has the tuberculin skin test (TST) been used for the support the diagnosis of active and latent TB infection. The TST test has, however, a number of limitations most notable low specificity in BCG vaccinated individuals due to cross-reactive components in PPD and the M. bovis BCG vaccine strain and an intensive search for new and more specific diagnostic antigens has therefore be ongoing. In this review we describe the discovery process leading to the identification of the M. tuberculosis specific antigens ESAT6 and CFP10; two low molecular weight proteins which are highly sensitive and specific for detection of a M. tuberculosis infection.     

The significance of the tuberculin skin test in elderly persons

Study of 49,467 persons over age 50 in Arkansas nursing homes afforded insight into the significance of the tuberculin skin test in the elderly. Whereas only 15% to 20% of persons showed a significant (10 mm or more) reaction to tuberculin on admission, 2% to 3% of these developed tuberculosis. Persons having no reactions comprised two subsets: a small group who died at an increased rate and were probably anergic, and a larger group who survived as well as persons who had reactions. Minor increases in reaction size with repeated testing appeared to be due to immunologic recall. However, conversions of 12 mm or more from a documented negative result indicated spread of infection. When not treated preventively, 7.6% (women) to 12.7% (men) of definite converters developed tuberculosis. The increase in number of persons showing positive reactions after entry may have been due to rapid demise of the anergic subset, improvement in nutrition of survivors, or unsuspected spread of tuberculous infection.     

Two-step tuberculin skin test in nurse students

The tuberculin skin test (TST) was conducted in 243 nurse students (19.4 +/- 1.3 years old). The second TST were carried out in 240 students who did not show blister or necrosis in the first TST. The size of erythema was 16.5 +/- 9.4 mm in the first TST (T1) and 24.3 +/- 15.6 mm in the second TST (T2). The negative reactors, whose size of erythema was below 10 mm, were decreased from 53 to 25, whereas, the strong reactors, whose size of erythema was more than 30 mm, were increased from 11 to 71. The difference of the size of erythema (T2-T1) was 9.7 +/- 11.9 mm in the group I (190 students) who received the latest TST in junior high school, whereas, that was 0.5 +/- 9.2 mm in the group II (50 students) who received the latest TST 14 months before this study. T2-T1 in the group I was weakly correlated with T1. Twenty-four negative reactors received BCG vaccination, and 23 of them converted to positive. Seventy-one strong reactors were checked by chest X-ray, and none showed the findings of tuberculosis, and required the administration of anti-TB drug. The two-step TST is an essential means to know the baseline reactivity to TST, and to distinguish newly infected tuberculosis from booster phenomenon.     

Infliximab does not suppress the tuberculin skin test (purified protein derivative)

OBJECTIVE: Tuberculin skin testing with purified protein derivative (PPD) is part of tuberculosis (TB) screening in patients receiving infliximab. We assessed whether infliximab, a strong inhibitor of inflammation, suppressed dermal induration, the outcome of this test. We also reassessed the booster phenomenon and the interobserver variability in tuberculin testing. METHODS: Forty-seven patients with various diagnoses, who had had a PPD test before infliximab use, were retested after infliximab treatment. The test was also assessed cross-sectionally among 31 patients with rheumatoid arthritis (RA) after 8.6 [+/- 4.1 standard deviation (SD)] months of infliximab use and in 82 patients with RA who had never used this agent. Booster phenomenon and the interobserver variability of reading the test were reassessed among 163 infliximab-naive patients with RA and Behcet's disease (BD) and 47 healthy controls. RESULTS: Among the 47 patients who received infliximab, and for whom sequential data were available, the mean skin induration was 5.9 +/- 8.0 SD mm before and 6.1 +/- 7.5 mm after 4.8 +/- 3.7 months of treatment (p = 0.890). In the cross-sectional study the mean PPD induration was 7.8 +/- 8.4 mm among infliximab-naive patients with RA, while it was 6.6 +/- 2.1 mm in those receiving infliximab (p = 0.271). Booster phenomenon was observed in 14/49 (29%) of patients with RA, 7/31 (23%) of those with BD, and 1/10 of healthy controls. Interobserver variability of PPD reading was good (kappa = 0.92). CONCLUSION: Infliximab use does not suppress the skin reaction to tuberculin. We confirm the booster phenomenon and that the PPD skin test has an acceptable interobserver reliability for an in vivo test.     

The tuberculin reaction two years after the initial two-step tuberculin skin test in our hospital

The tuberculin skin test was carried out to employees of our hospital one and two years later after the initial two-step tuberculin skin test in 1999 to examine the possibility of new tuberculosis infection. Nineteen weakly positive reactors aged 39-year-old or less in 1999 were followed up by tuberculin reaction for two years. The significant changes were not recognized in either the size of erythema or the size of induration, examined by one-way ANOVA and Tukey-Kramer multiple comparison procedure. Among weakly positive reactors aged 39-year-old or less, it seemed that there had been no new tuberculosis infection during 2 years follow-up.     

Usefulness of skin tests (tuberculin and delayed-type hypersensitivity reaction) in patients with HIV infection

The aim of this study is to asses the management and application of skin tests (tuberculin and delayed-type hypersensitivity reaction) in patients with HIV-infection.     

Phytohemagglutinin (PHA) skin test in patients with sarcoidosis.

A group of 17 patients with histologically confirmed sarcoidosis were examined for the presence of anergy and the intracutaneous response to 2 mug of purified phytohemagglutinin (PHA); lymphocytes of 15 of these patients were studied for in vitro blastic response to PHA-M. Although 8 of the patients were anergic and 8 had impaired in vitro response to PHA, all patients showed a normal response to intradermal injection of PHA. It was concluded that patients with sarcoidosis have an intact intradermal response to PHA, suggesting that the anergy seen in this disease results from impaired initiation of the delayed hypersensitivity reaction and not from impaired mononuclear cell responsiveness. The PHA skin test may be a useful adjunct in the evaluation of anergic patients.     

The effect of bacille Calmette-Guérin vaccination at birth on tuberculin skin test reactivity in Ugandan children.

SETTING: In Uganda, bacille-Calmette Guerin (BCG) vaccination coverage at birth is between 82 and 84%. OBJECTIVE: To evaluate the effect of neonatal BCG vaccination on tuberculin skin test positivity in Ugandan children exposed to infectious cases. DESIGN: As part of an ongoing prevalence study of household contacts of new tuberculosis cases, 365 children were evaluated to determine if BCG vaccination at birth had an impact on tuberculin skin testing. The children were classified as contacts (179) and non-contacts (186) depending on the presence of a sputum acid-fast bacilli (AFB) smear-positive adult tuberculosis case in the household. RESULTS: Regardless of prior BCG vaccination, children exposed to a smear-positive adult were more likely to have a positive skin test (purified protein derivative >5mm) (68% versus 36%, P < 0.01). BCG-vaccinated children below 1 year of age without a known household contact with active tuberculosis had a lower frequency of tuberculin skin reactions (29%) compared to their counterparts in the contact households (65%, P = 0.031). CONCLUSION: BCG vaccination at birth had no important effect on the interpretation of the tuberculin skin test reactivity in this group of Ugandan children. The tuberculin skin test remains a valuable tool for the evaluation of household contacts and suspected cases of tuberculosis in BCG-vaccinated children.