XpertMTB/RIF outperformed smear microscopy, established a diagnosis in a significant proportion of patients with smear-negative TB, detected many highly likely TB cases missed by culture, and accurately ruled out rifampicin-resistant TB. Sample-specific factors had limited impact on performance. Performance in patients infected with HIV, especially those with advanced immunosuppression, warrants further study.

Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasoneindacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM) IRIDIUM trial investigators; Kerstjens, Huib A

Lack of point-of-care tests for tuberculosis (TB) result in diagnostic delay, and increased mortality and healthcare-related costs. The urine Determine™ TB-LAM point-of-care strip-test was evaluated in 335 prospectively-recruited hospitalised patients with suspected TB-HIV co-infection (group 1) and from 88 HIV-infected hospitalised patients with non-TB diagnoses (group 2). Cut-off point-specific analyses were performed using: 1) a microbiological reference standard (culture positive versus.negative); and 2) a composite reference standard (exclusion of patients with clinical-TB from the culture-negative group). Using the microbiological reference and the manufacturer-recommended grade-1 cut-off point, LAM sensitivity and specificity was 66% (95% CI 57–74%). By contrast, using the composite reference sensitivity was 60% (95% CI 53–67%) and specificity improved to 96% (95% CI 89–100%) (p=0.001). The same pattern was seen when the grade-2 cut-off point was used (specificity 75% versus 96%; p=0.01). In group two patients specificity was poor using the grade-1 cut-off point, but improved significantly when the grade-2 cut-off point was used (90% versus 99%; p=0.009). The grade-2 cut-off point also offered superior inter-reader reliability (p=0.002). Sensitivity was highest in those with a CD4 <200 cells per mL. LAM combined with smear-microscopy was able to rule-in TB in 71% of Mycobacterium tuberculosis culture-positive patients. This preliminary study indicates that the LAM strip-test may be a potentially useful rapid rule-in test for TB in hospitalised patients with advanced immunosuppression. The grade 2, but not the manufacturer-recommended grade 1 cut-off point, offered superior rule-in utility and inter-reader reliability. Larger studies to evaluate cut-off points and diagnostic accuracy are urgently required.

BackgroundVariability in interferon-gamma release assays (IGRAs) results for tuberculosis has implications for interpretation of results close to the cut-point, and for defining thresholds for test conversion and reversion. However, little is known about the within-subject variability (reproducibility) of IGRAs. Several national guidelines recommend a two-step testing procedure (tuberculin skin test [TST] followed by IGRA) for the diagnosis of LTBI. However, the effect of a preceding TST on subsequent IGRA results has been reported in studies with apparently conflicting results.Methodology/FindingsWe conducted a systematic review to synthesize evidence on within-subject variability of IGRA results and the potential boosting effect of TST. We searched several databases and reviewed citations of previous reviews on IGRAs. We included studies using commercial IGRAs, in addition to non-commercial versions of the ELISPOT assay. Four studies, fulfilling our predefined criteria, examined within-subject variability and 13 studies evaluated TST effects on subsequent IGRA responses. Meta-analysis was not considered appropriate because of heterogeneity in study methods, assays, and populations. Although based on limited data, within-subject variability was present in all studies but the magnitude varied (16-80%) across studies. A TST induced “boosting” of IGRA responses was demonstrated in several studies and although more pronounced in IGRA-positive (i.e. sensitized) individuals, also occurred in a smaller but not insignificant proportion of IGRA-negative subjects. The TST appeared to affect IGRA responses only after 3 days and may apparently persist for several months, but evidence for this is weak.Conclusions/SignificanceAlthough reproducibility data are scarce, significant within person IGRA variability has been reported. If confirmed in more studies, this has implications for the interpretation of results close to the cut-point and for definition of conversions and reversions. Although the effect of TST on IGRA results is likely to be inconsequential in IGRA-positive subjects, in IGRA-negative subjects, the interpretation of results may be confounded by a preceding TST if administered more than 3 days prior to an IGRA.

IGRAs may still be useful in high-burden settings in specific subgroups at high risk of progression, including young children, HIV-infected individuals and healthcare workers, but this requires confirmation. Although the IGRAs cannot distinguish between latent and active TB, their utility as rule-out tests, when combined with smear microscopy or the TST, requires further study. Prospective studies are required in high-burden settings to confirm whether IFN-gamma responses are predictive of high risk of progression to active TB, particularly in HIV-infected individuals.

Tuberculosis (TB), smoking, HIV and chronic obstructive pulmonary disease (COPD) are burgeoning epidemics in developing countries. The link between TB and HIV is well established. Less well recognised is the strong relationship between tobacco smoking and the development and natural history of TB. These associations are of considerable relevance to public health and disease outcomes in individuals with TB. Moreover, tobacco smoking, a modifiable risk factor, is associated with poorer outcomes in HIV-associated opportunistic infections, of which TB is the commonest in developing countries. It is now also becoming clear that TB, like tobacco smoke, besides its known consequences of bronchiectasis and other pulmonary morbidity, is also a significant risk factor for the development of COPD. Thus, there is a deleterious and synergistic interaction between TB, HIV, tobacco smoking and COPD in a large proportion of the world’s population. Further work, specifically mechanistic and epidemiological studies, is required to clarify the role of tobacco smoke on the progression of TB and HIV infection, and to assess the impact of smoking cessation interventions. These interactions deserve urgent attention and have major implications for coordinated public health planning and policy recommendations in the developing world.

When using a two-step screening strategy it appears safe to perform a QuantiFERON-TB-GIT or T-SPOT.TB IGRA within 3 days of performing the TST. A 3-spot or 80% IFN-gamma response variation, on either side of baseline values, explains 95% of the short-term variability and may be useful for interpreting conversions and reversions, and values close to the cut-point.

No abstract