The QuantiFERON-TB Gold In-Tube Assay in Neuro-Ophthalmology.

BACKGROUND: Although QuantiFERON-TB Gold In-Tube (QFT-GIT) testing is regularly used to detect infection with Mycobacterium tuberculosis, its utility in a patient population with a low risk for tuberculosis (TB) has been questioned. The following is a cohort study analyzing the efficacy of QFT-GIT testing as a method for detection of active TB disease in low-risk individuals in a neuro-ophthalmologic setting. METHODS: Ninety-nine patients from 2 neuro-ophthalmology centers were identified as having undergone QFT-GIT testing between January 2012 and February 2016. Patients were divided into groups of negative, indeterminate, and positive QFT-GIT results. Records of patients with positive QFT-GIT results were reviewed for development of latent or active TB, as determined by clinical, bacteriologic, and/or radiographic evidence. RESULTS: Of the 99 cases reviewed, 18 patients had positive QFT-GIT tests. Of these 18 cases, 12 had documentation of chest radiographs or computed tomography which showed no evidence for either active TB or pulmonary latent TB infection (LTBI). Four had chest imaging which was indicative of possible LTBI. None of these 18 patients had symptoms of active TB and none developed active TB within the follow-up period. CONCLUSIONS: Based on our results, we conclude that routine testing with QFT-GIT in a low-risk cohort did not diagnose active TB infection. We do not recommend routine QFT-GIT testing for TB low-risk individuals, as discerned through patient and exposure history, ocular examination, and clinical judgment, in neuro-ophthalmology practice.

[COMPARISON OF QuantiFERON® TB GOLD TEST RESULTS BEFORE AND AFTER ENDOTOXIN CONTAMINATION].

PURPOSE: In response to a case of endotoxin contamination of tubes used in QuantiFERON® TB Gold (QFT-3G) testing in Japan in 2013, the effect of this contamination on QFT-3G test results was investigated. METHODS: We analyzed QFT-3G results from 4,258 participants in a tuberculosis contact investigation in Yamagata, Japan from September 2010 to April 2015. Of these, 2,488 samples were collected before the endotoxin contamination, while 1,770 samples were collected after the contamination. RESULTS: Negative control values in the group tested after the contamination were significantly lower than those in the group tested before the contamination (P < 0.0005). The proportion of positive controls that exceeded the calculated limit (10IU/ml) in the group tested after the contamination (87.8%) was lower than that in the group tested before the contamination (96.8%; P < 0.0005). The proportion of intermediate results in the group tested after the contamination (3.2%) was markedly lower than that in the group tested before the contamination (6.6%). DISCUSSION: Differences in QFT-3G test results were found to be related to a difference in blood collection before or after endotoxin contamination of blood collection tubes. Values resulting from QFT-3G testing were lower in blood samples that were collected after the contamination relative to those collected before the contamination.

Retrospective return on investment analysis of an electronic treatment adherence device piloted in the Northern Cape Province.

OBJECTIVE: The return on investment (ROI) for utilizing the SIMpill electronic treatment adherence solution as an adjunct to directly observed treatment short-course (DOTS) is assessed using data from a 2005 pilot of the SIMpill solution among new smear-positive tuberculosis (TB) patients in the Northern Cape Province. The value of this cost minimization analysis (CMA), for use by public health planners in low-resource settings as a precursor to more rigorous assessment, is discussed. MATERIALS AND METHODS: The retrospective analysis compares the costs and health outcomes of the DOTS-SIMpill cohort with DOTS-only controls. Hypothetical 5-year cash flows are generated and discounted to estimate net present values (NPVs). RESULTS: Comparison between the DOTS-SIMpill pilot cohort and DOTS-only supported controls, for a hypothetical implementation of 1,000 devices, over 5 years, demonstrates positive ROI for the DOTS-SIMpill cohort based on improved health outcomes and reduced average cost per patient. The net stream is shown to be positive from the first year. Discounted NPV is ZAR 3,255,256 (US$ 493,221) for a cohort that would have started mid 2005 and ZAR 3,747,636 (US$ 487,339) starting mid 2010. This is an ROI of 23% over the 5-year period. CONCLUSION: The addition of electronic treatment adherence support technology can help to improve TB outcomes and lower average cost per patient by reducing treatment failure and the associated higher cost and burden on limited resources. CMA is an appropriate initial analysis for health planners to highlight options that may justify more sophisticated methods such as cost effectiveness analysis or full cost benefit analysis where a preferred option is immediately revealed. CMA is proposed as a tool for use by public health planners in low-resource settings to evaluate the ROI of treatment adherence technology postpilot and prior to implementation.

Optimisation of the tuberculin skin test for detection of Mycobacterium bovis in African buffaloes (Syncerus caffer).

Effective screening methods are critical for preventing the spread of bovine tuberculosis (bTB) among livestock and wildlife species. The tuberculin skin test (TST) remains the primary test for bTB globally, although performance is suboptimal. African buffaloes (Syncerus caffer) are a maintenance host of Mycobacterium bovis in South Africa, tested using the single intradermal tuberculin test (SITT) or comparative test (SICTT). The interpretation of these tests has been based on cattle thresholds due to the lack of species-specific cut-off values for African buffaloes. Therefore, the aims of this study were to calculate buffalo-specific thresholds for different TST criteria (SITT, SICTT, and SICTT72h that calculates the differential change at 72 h only) and compare performance using these cut-off values. The results confirm that 3 mm best discriminates M. bovis-infected from unexposed control buffaloes with sensitivities of 69 % (95 % CI 60-78; SITT and SICTT) and 76 % (95 % CI 65-83; SICTT72h), and specificities of 86 % (95 % CI 80-90; SITT), 96 % (95 % CI 92-98; SICTT72h) and 97 % (95 % CI 93-99; SICTT), respectively. A comparison between TST criteria using buffalo-specific thresholds demonstrates that the comparative TST performs better than the SITT, although sensitivity remains suboptimal. Therefore, further research and the addition of ancillary tests, such as cytokine release assays, are necessary to improve M. bovis detection in African buffaloes.

Accuracy of tuberculosis diagnostic tests in small ruminants: A systematic review and meta-analysis.

Tuberculosis (TB) in small ruminants is a neglected disease despite its major impact on goat and sheep production and the global public health. The awareness of the role of small ruminants in the epidemiology of animal TB has increased in the last two decades, however, there is a lack of standardization of procedures and robust quantitative estimates on the accuracy of diagnostic TB tests in the scientific literature. To address this knowledge gap, all the available information regarding the use of ante-mortem diagnostic techniques in small ruminants was collected and summarized through a systematic review process. Furthermore, a random-effects meta-analysis was conducted to separately estimate the sensitivity (Se) and specificity (Sp) of cell-based tests among the retrieved studies in goats. Studies included in the meta-analysis were also evaluated using the Quality Assessment of Diagnostic Accuracy Studies included in systematic reviews adapted for animal diagnostic tests (VETQUADAS). Median pooled Se estimates of the single intradermal tuberculin (SIT) test (ranged from 0.51 to 0.59), the comparative intradermal tuberculin (CIT) test (ranged from 0.30 to 0.50) and the interferon-gamma (IFN-γ) release assay (IGRA) (ranged from 0.66 to 0.72) were lower than that reported previously in cattle, regardless the interpretation criteria and the reporting of MAP infection or vaccination. However, the specificity was adequate for all the tests (ranged from 0.95 to 0.99), except for the SIT test in MAP vaccinated herds (ranged from 0.78 to 0.90). This study provides an overview of the accuracy of diagnostic tests for TB in goats, however, the considerable between-study heterogeneity found hampered the conclusive interpretation of the pooled Se and Sp estimates. Therefore, further studies in small ruminants are necessary to optimize the diagnostic Se, which could help to design effective control strategies, accelerate the eradication of TB in these species and harmonize test procedures.

QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases.

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory prior to the initiation of tumour necrosis factor-alpha inhibitor therapy. However, no agreement exists on the best strategy for detecting LTBI in this population. The aim of the present study was to analyse the performance of the tuberculin skin test (TST) and QuantiFERON-TB Gold in-tube (QFT-GIT) on LTBI detection in subjects with immunomediated inflammatory diseases (IMID). The TST and QFT-GIT were prospectively performed in 398 consecutive IMID subjects, 310 (78%) on immunosuppressive therapy and only 16 (4%) had been bacillus Calmette-Guérin (BCG) vaccinated. Indeterminate results to QFT-GIT were found in five (1.2%) subjects. Overall, 74 (19%) out of 393 subjects were TST-positive and 52 (13%) were QFT-GIT-positive. Concordance between TST and QFT-GIT results was good (87.7%): 13 were QFT-GIT-positive/TST-negative and 35 QFT-GIT-negative/TST-positive. By multivariate analysis both tests were significantly associated with older age. Only the TST was associated with BCG vaccination and radiological lesions of past TB. Use of immunosuppressive drugs differently modulated QFT-GIT or TST scoring. Use of the QuantiFERON-TB Gold in-tube, as a screening tool for latent tuberculosis among immunomediated inflammatory disease subjects, is feasible. Until further data will elucidate discordant tuberculin skin test/QuantiFERON-TB Gold in-tube results, a strategy of simultaneous tuberculin skin and QuantiFERON-TB Gold in-tube testing in a low prevalence bacillus Calmette-Guérin vaccinated population, should maximise potentials of latent tuberculosis diagnosis.

Skin test of tuberculin purified protein derivatives with a dissolving microneedle-array patch.

BACKGROUND: The tuberculin skin test (TST) is a long-established screening method for tuberculosis. However, the Mantoux technique is often difficult to reliably perform, which affects testing results and safety, which causes local skin pain and pruritus. METHODS: In this study, dissolving microneedle-array patches (MNP) were used to deliver purified protein derivative (PPD) tuberculin into the skin. The skin reaction was compared between MNP delivery and conventional injection. RESULTS: The MNP penetrated the skin easily with a thumb press, and the microneedle dissolved into the skin completely after 1 h. The storage life of MNP loaded with PPD (MNP-PPD) was 7 weeks at atmospheric pressure and room temperature. Only 1/50 dosage of PPD (approximately 0.04 IU) was needed in MNP compared with conventional injection (2 IU) in terms of skin reactivity to TST. When TST was tested in volunteers, the redness and induration of the skin were 19.7 ± 5.6 mm in TB patients, 12.6 ± 4.4 mm in LTBI (latent TB infection) patients, and 5.8 ± 2.7 mm in BCG vaccination healthy volunteers and lasted approximately 26 ± 5.4 days. When applied with MNP-PPD, the redness and induration on the skin decreased significantly to 3.1 ± 0.7 mm in TB patients and 2.0 ± 0.5 mm in LTBI, and the duration time was only 8.5 ± 1.5 days. Moreover, despite the relatively mild skin reactivity in BCG vaccination healthy volunteers with conventional injection, there was no skin reactivity in BCG vaccination healthy volunteers with MNP-PPD. CONCLUSION: In addition to being minimally invasive, needle-free, and painless, no adverse effects were attributed to the new diagnostic method, which may be of value for the safe and effective clinical administration of TB screening. When applied with MNP-PPD, an area of redness and induration greater than 2.5 mm can identify a TB-positive patient.

Evaluation of the McLintock syringe as a cause of non-specific reactions in the intradermal tuberculin test used for the diagnosis of bovine tuberculosis.

The objective of this study was to elucidate whether the use of the McLintock syringe, used to inject tuberculin in cattle in several countries and based on an intradermal inoculation by needle, may, in itself, cause skin reactions that can be interpreted as positive reactions regardless of the real tuberculosis (TB) infection status of the animals. Forty-four cattle from an officially TB-free (OTF) herd were selected for the experiment. Each animal received four inoculations [one with sterile phosphate buffer saline (PBS) with 10% of glycerol and three with bovine purified protein derivative (PPD), as performed during the single intradermal tuberculin (SIT) test], two on each side of the neck (n = 176 inoculations). Three different McLintock syringes (n = 132 inoculations, PBS and bovine PPD) and one Dermojet syringe (n = 44 inoculations, PBS) were used to carry out the inoculations. No positive reactions (increase in skin-fold thickness > 3 mm) in response to the bovine PPD or PBS inoculations were observed regardless of the syringe used. No significant differences (p > 0.05) in the skin fold thickness increase (in mm) were observed between inoculation sites. Significant differences (p < 0.05) in the skin fold thickness were observed when PPD was injected in comparison to the PBS but no differences between McLintock and Dermojet were detected when PBS was injected. The McLintock syringe did not cause reactions per se that could be misunderstood as positive in TB-free cattle demonstrating that it is not a significant factor associated with the previously reported imperfect specificity of the SIT test.

Evaluation of the use of a needle-free injection syringe as a cause of non-specific reactions in the intradermal tuberculin test used for the diagnosis of bovine tuberculosis.

The objective of the study was to elucidate whether the use of the needle-free Dermojet syringe, which is based on a high pressure inoculation and is used to inject tuberculin in cattle in several countries, may, in itself, cause skin reactions that can be interpreted as positive reactions to the intradermal tests that are not, in fact, related to the real infection status of the animals. Forty-four cattle from an officially tuberculosis-free (OTF) herd were selected, and four single intradermal tuberculin (SIT) tests were performed on each animal, two on each side of the neck. Three different Dermojet (D1, D2 and D3) and one McLintock (M4) syringes were used to carry out sterile phosphate buffer saline (PBS) with 10% of glycerol and bovine PPD injections. No positive reactions to the SIT test were observed when using the D1-D3 syringes in the case of either bovine PPD or PBS. With regard to M4 (PBS), all the tests were negative when using a standard interpretation but three were positive in the case of the severe interpretation. Significant differences (p < 0.05) in the skin fold thickness measured were found only between certain Dermojet and McLintock syringes at certain inoculation sites. The results showed that the needle-free Dermojet syringe used for PPD intradermal testing in cattle did not cause significant reactions that could be misunderstood as positives.

Diagnostic usefulness of the QuantiFERON-TB gold in-tube test (QFT-GIT) for tuberculous vertebral osteomyelitis.

BACKGROUND: Interferon (IFN)-γ-releasing assay for diagnosing tuberculosis (TB) has shown promise; however, there are only a few reports on usefulness of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) for diagnosing TB vertebral osteomyelitis. METHODS: All patients presenting at a tertiary hospital between January 2010 and July 2016 with suspected TB vertebral osteomyelitis were retrospectively enrolled to evaluate the diagnostic performance of QFT-GIT. We used QFT-GIT to measure the IFN-γ response to ESAT-6, CFP-10 and TB7.7. RESULTS: A total of 141 patients were enrolled; 32 (23%) were categorized as having confirmed TB, (1%) as probable TB, 14 (10%) as possible TB and 93 (66%) as not TB. Of these, 16 patients with probable and possible TB were excluded from the final analysis. Chronic granulomas with/without necrosis, acid-fast bacilli stain, M. tuberculosis polymerase chain reaction and cultures for M. tuberculosis were positive in 14 (44%), 12 (38%), 22 (69%) and 28 (88%) patients, respectively, among the 32 patients with confirmed TB. The overall sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio for a positive result, and likelihood ratio for a negative result of the QFT-GIT for TB vertebral osteomyelitis were 91% (95% confidence interval [CI], 75-98%), 65% (95% CI, 54-75%), 50% (95% CI, 42-58%), 95% (95% CI, 86-98%), 2.59 (95% CI, 1.89-3.55) and 0.14 (95% CI, 0.05-0.43), respectively. CONCLUSION: The QFT-GIT appears to be a useful adjunct test for diagnosing TB vertebral osteomyelitis because the negative test results may be useful for excluding a diagnosis of active TB vertebral osteomyelitis.

Centrifugal Lithography: Self-Shaping of Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer Drops.

Polymeric microstructures encapsulating biopharmaceutics must be fabricated in a controlled environment to preserve the biological activity. There is increasing demand for simple methods designed to preserve the biological activity by utilizing the natural properties of polymers. Here, the paper shows that centrifugal lithography (CL) can be used for the fabrication of such microstructures in a single centrifugation, by engineering the self-shaping properties of hyaluronic acid (HA). In this method, HA drops are self-shaped into hourglass-microstructures to produce two dissolving microneedles (DMN), which facilitate transdermal delivery via implantation on the skin. In addition, tuberculin purified protein derivatives are encapsulated into HA DMNs under refrigerated conditions (4 °C) during CL. Therefore, the tuberculin skin test (TST) with the DMNs indicates minimal damage, as opposed to the case of TST with traditional hypodermic needles. These findings on the fabrication of polymeric microstructures with biopharmaceutics may trigger the development of various biomedical devices and therapies.

The importance of two-step tuberculin skin testing for newly employed healthcare workers.

At the time of hire, 4059 of 6522 healthcare workers required a 2-step tuberculin skin test; 114 workers (2.8%) demonstrated a boosted reaction after the second step. Boosted reactions were significantly associated with male sex and older age. A verbal history of previous tuberculin skin test results was not a reliable indicator of baseline tuberculin skin test status at the time of hire.

[Individual tuberculin diagnosis by the prick test].

The graded dermal tuberculin test, as described by N. N. Grinchar-Karpilovsky, which is carried out using 100%, 25%, 5%, and 1% tuberculin solution, is most commonly used for individual tuberculin diagnosis. The use of a prick lancet in a test (the prick test) makes the latter easier and standardized, ensures the equal depth of skin lesion, and requires the less surface of the skin. Assessment of the test (measurement of the diameter of a papule) becomes simpler and it is objective. The Grinchar-Karpilovsky prick test using a prick lancet significantly upgrades the quality of individual tuberculin diagnosis.

Safety and efficacy of tuberculin skin testing with microneedle MicronJet600™ in healthy adults.

SETTING: Intradermal injection using a syringe and needle is generally accepted as the most accurate method for the tuberculin skin test (TST). However, the Mantoux technique using a conventional needle is often difficult to perform reliably, affecting testing results and safety. OBJECTIVE: We evaluated the efficacy and safety of a novel intradermal injection device, the MicronJet600(TM) microneedle, compared with conventional injection in terms of skin reactivity to the TST. DESIGN: A prospective, open-label clinical study was conducted. The TST was administered by both methods in the same subject. For pain assessment, participants filled in a visual analogue scale (VAS) after each TST. Any side effects due to TST or injections were observed. RESULTS: TST reaction rates (cut-off ⩾5 mm) from microneedles and needles were respectively 44.0% and 47.2%, with no significant difference between the two. Furthermore, agreement of positivity between the two methods was excellent with both 5 mm and 10 mm cut-off values. However, the level of pain experienced when microneedles were used for TST was significantly lower than with conventional needles. No adverse effects were attributed to the MicronJet device. CONCLUSION: The novel microneedle device used for TST in this study was effective, safe and less painful in healthy adult volunteers.

Utility of QuantiFERON-TB Gold In-Tube Test in the Diagnosis of Latent TB in HIV-Positive Patients in a Medium-TB Burden Country.

BACKGROUND: The authors aimed to compare TST with QuantiFERON-TB Gold In-Tube (QFT) for detecting latent tuberculosis infection (LTBI) in HIV-infected patients in Iran as a TB-medium endemic country. METHODS: In a cross-sectional design,130 HIV-positive patients in HIV clinic of Tehran University were studied. Patients screened for LTBI with QFT and TST simultaneously. Concordance between 2 tests results and variables associated with tests discordance were assessed. RESULTS: Positive results found in 24.6% for TST and 7.7% for QFT. Overall agreement between them was 73.85% (Kappa = 0.083). History of imprisonment was associated with more positive TST (P = 0.014) and QFT (P = 0.01). Patients with intravenous drug use (IDU) history had significant discordant results (0.018). CONCLUSION: The authors recommend QFT for all negative cases of TST in HIV-positive patients especially who had history of IDU.

Plasma concentrations of isoniazid in children with tuberculous infections.

Six children with tuberculous infection were given their daily prescribed doses of isoniazid by the oral and the intramuscular route on different days. The plasma concentrations reached after both routes of administration were nearly equivalent. The plasma half-life of isoniazid ranged from 1.6 to 4.8 hours. The observed plasma concentrations in these children were higher than those reported in many adults. This difference is due to the larger doses of isoniazid prescribed for children.

Influence of needle gauge in Mantoux skin testing.

STUDY OBJECTIVE: To determine the influence of needle gauge in Mantoux skin testing for tuberculosis. DESIGN: Randomized selection of either a 27- or 30-gauge needle for Mantoux skin test placement; observer-blinded. SETTING: Annual hospital employee screening. PARTICIPANTS: Six hundred twenty-five employees working in clinical and laboratory research environments. RESULTS: Blinded observers found that the use of 27-gauge needles caused increased bleeding and bruising compared with 30-gauge needles (p < or = 0.007 for each). However, the 27-gauge needle produced larger blebs and less leakage of tuberculin solution (p < or = 0.0003). CONCLUSION: Smaller gauge needles could potentially cause false-negative screening results because of decreased antigen delivery. Use of needle gauges smaller than 27 gauge should be avoided until their reliability is validated.

Tuberculosis screening. Evaluation of a food handlers' program.

An evaluation of a tuberculosis screening program for food handlers revealed an unexpectedly low cost ($45) per identifiable candidate for preventive treatment (324 of 6,090 individuals screened). Four new active cases of tuberculosis were identified, and a risk/benefit analysis projected a potential reduction of 19.4 new active cases over the subsequent ten-year period.

Evaluation of the two-step tuberculin skin test in health care workers at an inner-city medical center.

The increased rate of tuberculosis (TB) infection and transmission from patients to health care workers (HCWs) has brought awareness of the need for better surveillance programs. The two-step purified protein derivative (PPD) skin test decreases the misinterpretation of a "boosted reaction" as a recent infection with Mycobacterium tuberculosis in HCWs. We reviewed the medical records of 4082 HCWs at an inner-city medical center who had PPD skin-testing performed as a component of the TB medical surveillance program during the years 1994 and 1995. Of those HCWs tested, 3896 (95.4%) returned for the PPD skin-test evaluation. Of those 3896 HCWs, 3659 (93.9%) had a negative baseline PPD skin test, and 237 (6.1%) had a positive skin test. Of those HCWs with a negative baseline skin test, 252 (6.9%) were eligible for the second PPD skin test. Of the 241 who returned for their second PPD skin-test reading, six (2.5%) had positive results. All six cases were foreign-born physician residents with a previous history of Bacille bilié de Calmette-Guérin (BCG) vaccination. We conclude that the two-step PPD skin test method is not indicted for HCWs at this urban medical facility.

[A new method of applying a tuberculin ointment for cutaneous use compared to the Mantoux test]. / Izuchenie novogo metoda applikatsii tuberkulinovoi mazi dlia nakozhnogo primeneniia v sravnenii s proboi Mantu.

The method for the applications of tuberculin ointment for the skin test by means of special aluminum chambers (Finn Chambers, obtained from Epitest Ltd. OY, Finland) was approved after trial. For control, the Mantoux test (intracutaneous tuberculin test) was used. The results of these two tests, made in parallel, were found to coincide in children with clinical symptoms of tuberculosis, or infected with Mycobacterium tuberculosis, in 84% of cases. The tuberculin skin test with the use of Finn Chambers proved to be more sparing, painless and safe. At the present stage of investigation, the new skin test may be recommended for children of preschool age.