Background: Prevalence surveys have found a substantial burden of subclinical (asymptomatic but infectious) TB, from which individuals can progress, regress or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of TB disease. Methods: We created deterministic framework of TB disease with progression and regression between three states of pulmonary TB disease: minimal (non-infectious), subclinical, and clinical (symptomatic and infectious) disease. We estimated ranges for each parameter by considering all data from a systematic review in a Bayesian framework, enabling quantitative estimation of TB disease pathways. Findings: Twenty-four studies contributed data from 6030 individuals. Results suggested that, after five years, 24.7%(95% uncertainty interval, UI, 21.3%-28.6%) of individuals with prevalent subclinical disease at baseline had either progressed to clinical disease or died from TB, whereas 16.1%(95%UI, 13.8%-18.5%) had recovered after regressing to minimal disease. Over the course of five years 30% (95%UI, 27.2%-32.6%) of the subclinial cohort never developed symptoms. For those with clinical disease at baseline, 39%(95%UI, 35.8%-41.9%) and 10.3%(95%UI, 8.5%-12.4%) had died or recovered from TB, with the remainder in, or undulating between, the three disease states. The ten-year mortality of people with untreated prevalent infectious disease was 38%. Interpretation: Our results show that for people with subclinical disease, classic clinical disease is neither inevitable nor an irreversible outcome. As such, reliance on symptom- based screening means a large proportion of people with infectious disease may never be detected. Funding: TB Modelling and Analysis Consortium and European Research Council

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Background While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. Methods We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. Results 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. Conclusions The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term “real world” register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

ZusammenfassungZiel der Umgebungsuntersuchung bei Tuberkulose ist neben der aktiven Fallfindung das Aufdecken von Infektionsketten sowie die Verhütung der Weiterverbreitung der Erkrankung. Dabei ist eine sorgfältige Auswahl der Kontaktpersonen notwendig, die sich nach Art und Dauer des Kontaktes richtet, um möglichst frisch Infizierte zu identifizieren und so den Nutzen einer anschließenden präventiven Therapie zu erhöhen und unnötige Testungen von Personen ohne Ansteckungsrisiko zu vermeiden. Seit der letzten Überarbeitung der Empfehlungen zur Umgebungsuntersuchung hat sich die Datenlage zum Einsatz von Interferon-y release-Assays (IGRAs) bei Kindern weiterhin verbessert. Diese werden bevorzugt in der Umgebungsuntersuchung von erwachsenen Kontaktpersonen eingesetzt. Für Kinder unter 15 Jahren können sowohl IGRAs wie auch weiterhin der Tuberkulin-Hauttest gleichwertig verwendet werden. Als präventive Therapie bei nachgewiesener Infektion werden Rifampicin für 4 Monate, Rifampicin und Isoniazid für 3 Monate oder aber Isoniazid für 9 Monate empfohlen.Ausführlich wird auf die Durchführung der Umgebungsuntersuchung in verschiedenen Altersgruppen sowie rechtliche Rahmenbedingungen und sozialmedizinische Aspekte und Herausforderungen eingegangen. Zusätzlich werden Sonderfälle, wie die Umgebungsuntersuchung in Kitas, Schulen oder in anderen Gemeinschaftseinrichtungen, separat dargestellt.

BACKGROUNDKey stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up.METHODSWe searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585).FINDINGS10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71% (95% CI:6.17-13.34) with “active” TB imaging, and 1.06% (95% CI:0.31-1.82) with “inactive” TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40% (95% CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease.INTERPRETATIONWe present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions.