Reader variability and validation of the Timika X-ray score during treatment of pulmonary tuberculosis.

SETTING: Chest radiographs (CXRs) are widely used for diagnosing pulmonary TB and assessing response to therapy. The Timika X-ray score has been proposed as a tool for measuring disease severity and predicting treatment outcome. OBJECTIVE: To evaluate inter- and intra-reader agreement of Timika scores and assess the ability of the score to predict microbiologic outcome at 2 months. DESIGN: Analytical validation study. Disease severity was measured by two readers using pretreatment radiographs and follow-up films taken at 2, 6 and 12 months after the start of treatment among 110 human immunodeficiency virus negative adults with pulmonary TB. One fourth of the films were reread to assess intra-reader agreement. RESULTS: The two-component Timika score had high inter- and intra-reader agreement (intraclass correlation (ICC)inter = 75%, ICCintra > 0.81). Baseline Timika score was associated with positive month 2 smear (P = 0.0004) and culture status (P = 0.03). The average Timika score declined significantly over the course of successful treatment. CONCLUSION: The Timika score showed good inter- and intra-reader agreement and a significant association with microbiological outcomes after 2 months of treatment. The results of this study strengthen the evidence supporting the use of the Timika score for measuring disease severity on CXR.

Prolonged positivity of sputum smears with negative cultures during treatment for pulmonary tuberculosis.

SETTING: Acid-fast bacilli (AFB) microscopy of sputum smears is the most widely used tool for both diagnosing pulmonary tuberculosis (PTB) and monitoring treatment response. It is not uncommon for patients who show clinical improvement to have prolonged positivity of sputum smears (i.e., ≥60 days after initiation of treatment) with corresponding negative cultures. OBJECTIVE: To assess treatment outcomes and characteristics associated with prolonged smear-positive, culture-negative status. DESIGN: A retrospective review was performed of all patients seen by the Cuyahoga County TB Program in Cleveland from 2000 to 2009. There were 159 consecutive smear-positive, drug-susceptible PTB cases with sufficient analyzable bacteriologic, clinical and radiographic data for study. RESULTS: A smear-positive, culture-negative pattern was seen in 51 patients (32.1%) ≥2 months after initiation of treatment. Age ≥46 years and extent of baseline chest X-ray abnormality were both significantly associated with a prolonged smear-positive, culture-negative pattern. No patients were culture-positive for Mycobacterium tuberculosis after ≥2 months. There was no increased risk of death in the prolonged smear-positive, culture-negative group, and no confirmed relapses. CONCLUSION: In our population of patients, in the absence of clinical or radiographic evidence of deterioration, late smear positivity usually has no clinical significance and requires no specific action.

Concordance of a positive tuberculin skin test and an interferon gamma release assay in bacille Calmette-Guérin vaccinated persons.

BACKGROUND: False-positive tuberculin skin test (TST) results due to prior bacille Calmette-Guérin (BCG) vaccination may lead to unnecessary treatment of presumed latent tuberculosis infection (LTBI). Recently approved interferon-gamma release assays (IGRAs) are more specific for LTBI in this group. METHODS: A total of 316 BCG-vaccinated foreign-born individuals with a positive TST had a commercially available IGRA (QuantiFERON®-TB Gold In-Tube) performed as part of a two-step procedure to determine the need for isoniazid therapy. Baseline demographic information and TST size were recorded and analyzed for characteristics associated with an increased likelihood of having a positive IGRA. RESULTS: Increasing age, male sex, origin from a country with a high prevalence of tuberculosis (TB), shorter time since arrival in the United States, and increasing TST size were all independently associated with a positive IGRA. CONCLUSION: Patient characteristics and TST size can help determine those at highest risk for LTBI. A two-step procedure for LTBI screening should be considered for foreign-born persons with prior BCG vaccination and a positive TST.

Transient normalization of lymphocyte blastogenic and specific antibody responses following boosting of healthy elderly subjects with tetanus toxoid.

The diminished in vitro blastogenic response of lymphocytes from the elderly to mitogenic stimuli is cited as evidence of immunosenescence, but the response to specific microbial antigens has not been well characterized. We measured the response to tetanus toxoid before and after boosting in young and elderly subjects. Elderly subjects (age > or = 70) and young controls (age < 35) were subjected to clinical, laboratory, and nutritional evaluation to ensure a cohort of healthy subjects. Responses of lymphocytes from the elderly to the mitogens phytohemagglutinin and concanavalin A were markedly diminished compared to those from the young. For all subjects, the average in vitro blastogenic response to tetanus toxoid of lymphocytes from elderly subjects (n = 23) was significantly diminished compared to young controls (n = 23; 31,985 +/- 4502 vs 14,411 +/- 3714 cpm, p < .01). Following boosting with tetanus in those subjects in whom boosting with tetanus toxoid was indicated, blastogenesis was comparable between elderly (n = 17) and young subjects (n = 7; 38,078 +/- 11,451 vs 42,103 +/- 9247 cpm). The boosted response to tetanus apparently was not sustained, since in the subset of subjects with a history of tetanus immunization in the past 10 years, the response of the elderly was much less than that of the young. Thus, a cohort of healthy elderly with diminished blastogenic responses to mitogens was capable of at least a transiently normal response to tetanus post boosting.

A 19-year follow-up of tuberculin reactors. Assessment of skin test reactivity and in vitro lymphocyte responses.

Tuberculin skin test reactivity decreases with time such that repeat PPD skin testing may result in reactions of less than 10 mm. This reactivity may be boosted in some individuals with a second tuberculin skin test. The immunologic basis of these observations remains unclear. We studied the relationship between skin-test reactivity and in vitro blastogenic response to PPD in a cohort of 22 individuals (aged 28 to 81 years) known to be tuberculin reactors (induration greater than or equal to 10 mm) in 1970. In 1989, 18 subjects remained reactive to PPD on the first skin test and responded to PPD in vitro (mean incorporation of 3H-thymidine by peripheral blood mononuclear cells, 22,650 cpm). Three subjects reverted (induration in response to PPD less than 10 mm) and lost in vitro reactivity to PPD (mean incorporation of 3H-thymidine, 2,205 cpm). One subject boosted (increase of induration of at least 6 mm to greater than or equal to 15 mm) on the second skin test and showed a concomitant in vitro boost in the blastogenic response to PPD (from 1,008 cpm to 47,837 cpm). In this cohort, interpretation of the two-step tuberculin skin test correlated closely with in vitro proliferative responses. Over a 19-year period, the majority of individuals maintained skin test reactivity and strong in vitro responses to PPD despite a lack of ongoing exogenous exposure to Mycobacterium tuberculosis. The immunologic basis for reversion appears to depend in part on a loss of lymphocyte blastogenic capacity. In the one individual who exhibited the booster phenomenon, repeat antigen stimulation resulted in a dramatic increase in the in vitro blastogenic responses.

Enzyme-linked immunosorbent assay using Mycobacterium tuberculosis antigen 5 and PPD for the serodiagnosis of tuberculosis.

Enzyme-linked immunosorbent assays (ELISA) of immunoglobulin G antibody to Mycobacterium tuberculosis antigen 5 and tuberculin purified protein derivative (PPD) were assessed for the serodiagnosis of tuberculosis in 41 patients with active tuberculosis, 19 patients with inactive tuberculosis, and 59 healthy control subjects. Patients with active tuberculosis were studied serially at monthly intervals following the initiation of therapy. When contrasted with our earlier studies of sera from patients in Bolivia and Argentina, serum titers in Cleveland patients with active tuberculosis were somewhat lower. Geometric mean titer in patients with active tuberculosis was 1:68 with antigen 5 and 1:46 with PPD. Titer was correlated with patient age, male sex, extent of tuberculosis, and history of prior tuberculosis. However, these associations were not statistically significant. During monthly follow-up for 16 months after the initiation of therapy, ELISA titers remained essentially stable. Thus, no convincing evidence was acquired to support the hypothesis that higher titers in sera from South American patients related to more chronic or more extensive disease. Receiver operating characteristics of ELISA with antigen 5 were better than those obtained using PPD and were similar to those reported by others for sputum smear. In a situation where tuberculosis screening is warranted, ELISA with antigen 5 might have a place if it recognizes a different population than does sputum smear.

Laryngeal tuberculosis presenting as carcinoma.

A typical patient had laryngeal tuberculosis (TB) mimicking carcinoma. The accompanying patient complaints from a representative literature survey are discussed. The difficulty of clinically differentiating laryngeal carcinoma from TB or another granulomatous process is stressed, as in the utility of obtaining a simple chest roentgenogram, a TB skin test, and, when indicated, a sputum examination. The pathogenesis of laryngeal TB and the treatment of health care personnel exposed to such a patient also is mentioned. The spectrum of TB, as well as the spectrum of physicians treating TB, is changing. The presence of a laryngeal process in a patient with active pulmonary TB is an important association that must not be overlooked.

Initial clinical trial of Mycobacterium tuberculosis antigen 5 in tuberculin-positive human subjects.

A single lot of Mycobacterium tuberculosis antigen 5 was used in graded doses to skin test 92 persons in a geographic area where nonspecific tuberculin reactivity is uncommon. In 47 tuberculin-positive subjects, antigen 5 was found to have a potency of 2.7 tuberculin units/micrograms. An intradermal dose of 0.50 microgram was found to give typical delayed skin test reactions in all of 15 tuberculin-positive subjects, with a mean reaction size of 15.17 mm. Some preparations of antigen 5 were found to be unstable during lyophilization and storage; solutions of antigen 5 in diluent containing Tween 80 were stable. Mycobacterium tuberculosis antigen 5 is a potent tuberculin skin test antigen deserving of further clinical evaluation.