The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically-identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% CI 8.0-29.2) among child contacts, 4.8% (3.0-7.7) among adult contacts, 5.0% (1.6-14.5) among migrants, and 4.8%(1.5-14.3) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk-stratification. We thus developed a personalised risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T-cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random-effects meta-analysis C-statistic of 0.88 (0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the crude current approach to TB risk estimation among people with LTBI, in favour of our evidence-based and patient-centered method, in settings aiming towards pre-elimination worldwide. J.S.D.'s institution receives investigator-initiated research grants and consultancy income from GileadSciences, AbbVie, Bristol Myers Squibb and Merck. The Burnet Institute receives funding from the Victorian Government Operational Infrastructure Fund. C.L. reports honoraria from Chiesi, Gilead, Insmed, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie (for participation at sponsored symposia) and from Oxford Immunotec (to attend a scientific advisory board meeting), all outside the submitted work. M.S. reports receipt of test kits free of charge from Qiagen and from Oxford Immunotec for investigator-initiated research projects. I.A. reports receiving free test kits from Qiagen for an

Disease caused by nontuberculous mycobacteria (NTM) is reported to increase due to an ageing population and a rise in the proportion of immunosuppressed patients. We did a retrospective cohort study of NTM-disease in the Danish population through a quarter-century to determine the disease burden and trends in annual incidence rates. 524,119 clinical specimens were cultured for mycobacteria from 1991 through 2015 at the International Reference Laboratory of Mycobacteriology in Denmark. Among these, 8,227 NTM strains were identified from 3,462 patients and distributed according to microbiological disease criteria. We observed no increase in NTM disease incidence or proportion of patients with positive NTM cultures during the study period (Quasi-Poisson regression, p = 0.275 and 0.352 respectively). Annual incidence rates were 1.20/105 for definite NTM disease, 0.49/105 for possible NTM disease and 0.88/105 for NTM colonization. The incidence rate of NTM disease was highest in children aged 0-4 years (5.36/105/year), predominantly with cervical Mycobacterium avium complex (MAC) adenitis. Surprisingly, based on more than half a million clinical specimens cultured for mycobacteria in Denmark through 25 years, the NTM disease burden and trend in incidence in the Danish population has not increased opposed to numerous internationals reports.

BackgroundThe QuantiFERON-TB-Gold Test (QFT) is more specific than the Mantoux skin-test to discriminate between Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacterial (NTM) infections. Here we study the performance of the QFT in patients with NTM disease.MethodsFrom 2005 to 2011, nationwide patient data on positive NTM cultures (n = 925) were combined with nationwide data on QFT results (n = 16,133), both retrieved from the International Reference Laboratory of Mycobacteriology, Denmark. A total of 112 patients with NTM infections had a QFT performed, 53 patients had definite NTM disease, 10 had possible disease and 49 had NTM colonization.ResultsQFT was positive in 8% (4/53) of patients with definite disease, 40% (4/10) with possible disease and 31% (15/49) with colonization. Positivity rate was lowest among patients with definite disease infected with NTM without the RD1 region 4% (2/50). None of the 15 children with MAC lymphadenitis had a positive QFT.ConclusionThis study is one of the largest assessing IGRAs in patients with NTM disease in a TB low-incidence setting. Our study showed that the QFT holds potential to discriminate between NTM and MTB infections. We found no positive IGRA test results among children with NTM not sharing the RD1-region of MTB resulting in a 100% specificity and we suggest that a QFT in a child presenting with cervical lymphadenitis may be helpful in distinguishing NTM from TB lymphadenitis.

BackgroundFalse negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively.MethodsPatients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results.ResultsSmokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02).ConclusionsCigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status.

BackgroundAntigen specific release of IP-10 is the most promising alternative marker to IFN-γ for infection with M. tuberculosis. Compared to Interferon-γ release assays (IGRA), IP-10 is released in high levels enabling novel approaches such as field friendly dried blood spots (DBS) and molecular detection.AimTo develop a robust IP-10 based molecular assay for the diagnosis of infection with M. tubercuolsis from whole blood and DBS.MethodWe developed a one-step probe based multiplex RT-qPCR assay for detecting IP-10 and IFN-γ mRNA expression from whole blood and DBS samples. The assay was validated and applied for the diagnosis of M. tuberculosis infection in DBS samples from 43 patients with confirmed TB, 13 patients with latent TB and 96 presumed uninfected controls. In parallel, IP-10 and INF-γ levels were measured in Quantiferon (QFT-TB) plasma supernatants.ResultsIP-10 mRNA upregulation was detectable at 4 hours after stimulation (6 fold upregulation) peaking at 8 hours (108 fold upregulation). IFN-γ expression occurred in concert but levels were lower (peak 6.7 fold upregulation). IP-10 gene expression level was significantly higher in patients with tuberculosis (median 31.2, IQR 10.7–67.0) and persons with latent tuberculosis infection (LTBI) (41.2, IQR 9.8–64.9) compared to healthy controls (1.6, IQR 1.1–2.4; p<0.0001). The IP-10 mRNA and protein based tests had comparable diagnostic accuracy to QFT-TB, sensitivity (85% and 88% vs 85%) and specificity (96% and 96% vs 97%, p = ns.).ConclusionWe developed a rapid, robust and accurate molecular immunodiagnostic test for M. tuberculosis infection. By combining DBS based sample acquisition, mail or currier based sample transport with centralized molecular detection, this immunodiagnostic test concept can reduce the local technological requirements everywhere and make it possible to offer highly accurate immunodiagnostic tests in low resource settings.

We confirmed a high NPV of the QFT and found positive QFT associated with a higher risk of subsequent incident TB. Overall, the PPV for incident cases was 1.32%, and development of incident TB was associated with time interval after the QFT, but not with age.

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