Tuberkulose

tuberculosisdiabetes mellitusCOVID-19inflammationrisk factors…

AbstractBackgroundPeople with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity.MethodsWhole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to

AbstractBackgroundTransmission of Mycobacterium tuberculosis in healthcare settings is a preventable driver of the global tuberculosis epidemic. We aimed to assess the evidence for infection control interventions, including cough etiquette, engineering and personal respiratory protection measures, to prevent transmission of M. tuberculosis in healthcare settings.MethodsThree independent systematic reviews were performed using 6 databases and clinical trials websites. Randomized trials, cohort studies, before-after studies, and case-control studies were included. Searches were performed for controlled studies evaluating respiratory hygiene, engineering, and personal respiratory protection measures. Outcome measures included the incidence of tuberculosis infection and disease. Studies involving transmission to either humans or animals were included.ResultsEvaluation of respiratory hygiene and cough etiquette interventions identified 4 human studies, with 22 855 participants, and 1 guinea pig study. Studies in humans evaluated the effects of multiple concurrent interventions. Patient use of surgical masks reduced infection by 14.8%, and tuberculosis disease was reduced by between 0.5% and 28.9%. Engineering and environmental interventions were evaluated in 10 studies of humans, including 31 776 human participants, and 2 guinea pig studies. Mechanical ventilation was associated with between 2.9% and 14% less infection. Nine studies of personal respiratory protection were included, including 33 913 participants. Infection was reduced by between 0% and 14.8% in studies where particulate respirators were used. The quality of included studies was assessed as low.ConclusionsRespiratory hygiene, engineering, and environmental infection controls and personal respiratory protection interventions were associated with reduced transmission of M. tuberculosis and reduced tuberculosis disease in healthcare settings.

tuberculosishealthcare workerWorld Health OrganizationPICOCOVID-19…

AbstractEvidence is limited for infection prevention and control (IPC) measures reducing Mycobacterium tuberculosis (MTB) transmission in health facilities. This systematic review, 1 of 7 commissioned by the World Health Organization to inform the 2019 update of global tuberculosis (TB) IPC guidelines, asked: do triage and/or isolation and/or effective treatment of TB disease reduce MTB transmission in healthcare settings?Of 25 included articles, 19 reported latent TB infection (LTBI) incidence in healthcare workers (HCWs; absolute risk reductions 1%–21%); 5 reported TB disease incidence in HCWs (no/slight [high TB burden] or moderate [low burden] reduction) and 2 in human immunodeficiency virus-positive in-patients (6%–29% reduction). In total, 23/25 studies implemented multiple IPC measures; effects of individual measures could not be disaggregated.Packages of IPC measures appeared to reduce MTB transmission, but evidence for effectiveness of triage, isolation, or effective treatment, alone or in combination, was indirect and low quality. Harmonizing study designs and reporting frameworks will permit formal data syntheses and facilitate policy making.

Abstract Background Gene expression signatures have been used as biomarkers of tuberculosis (TB) risk and outcomes. Platforms are needed to simplify access to these signatures and determine their validity in the setting of comorbidities. We developed a computational profiling platform of TB signature gene sets and characterized the diagnostic ability of existing signature gene sets to differentiate active TB from LTBI in the setting of malnutrition. Methods We curated 45 existing TB-related signature gene sets and developed our TBSignatureProfiler software toolkit that estimates gene set activity using multiple enrichment methods and allows visualization of single- and multi-pathway results. The TBSignatureProfiler software is available through Bioconductor and on GitHub. For evaluation in malnutrition, we used whole blood gene expression profiling from 23 severely malnourished Indian individuals with TB and 15 severely malnourished household contacts with latent TB infection (LTBI). Severe malnutrition was defined as body mass index (BMI)

Abstract Background Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure. Methods Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda. Results Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7–99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort. Conclusions Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.…

Abstract Background Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. Methods An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid (‘intervention’) or a daily combination of rifampicin/isoniazid (‘standard’), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. Results Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7–91.4), compared with 19 of 25 (76.0%, CI 54.9–90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. Conclusion In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. Trial registration The trial was funded by the NIHR, UK and registered with ISRCTN (26/02/2013-No.04379941).…

by Olanrewaju Oladimeji, Victor Adepoju, Felix Emeka Anyiam, James Emmanuel San, Babatunde A. Odugbemi, Francis Leonard Mpotte Hyera, Maureen Nokuthula Sibiya, Sanni Yaya, Ayuba Ibrahim Zoakah, Lovett Lawson Background The Lagos State Tuberculosis, Buruli Ulcer, and Leprosy Control Program (LSTBLCP) started engaging private hospitals under the Public-Private Mix (PPM) Program in 2008. The study aimed to evaluate the trend and predictors of successful Tuberculosis (TB) treatment outcomes of patients managed across these private health facilities between 2010–2016 in Lagos, Nigeria. Methods Retrospective review of TB treatment register and treatment cards of patients commenced on TB treatment between January 2010 and December 2016 in 36 private health facilities engaged by the LSTBLCP. Between December 2016 and February 2017, data were collected and entered into Microsoft Excel by trained data entry clerks. The analysis was done using SPSS software. Independent predictors of successful treatment outcomes were determined using multivariate analysis at the statistical significance of p20years (aOR = 0.26, p = 0.001), receiving TB treatment in 2013 (aOR = 0.39, p = 0.001), having genexpert for TB diagnosis (aOR = 0.26, p = 0.031) and being HIV positive (aOR = 0.37, p = 0.001) significantly reduced likelihood of successful treatment outcome. The site of TB, being on ART or CPT, were confounding determinants of successful treatment outcomes as they became non-significant at the multivariate analysis level. Conclusion Treatment outcome among Lagos private hospitals was low compared with NTBLCP and World Health Organization (WHO) target. We urge the government and TB stakeholders to strengthen the PPM interventions to improve adherence, particularly among People Living with HIV (PLHIV) and older TB patients. Hence, promotion of early care-seeking, improving diagnostic and case holding efficiencies of health facilities, and TB/HIV collaborative interventions can reduce the risk of an unsuccessful outcome.…

An amendment to this paper has been published and can be accessed via the original article.…

The repurposed agent moxifloxacin has become an important addition to the physician’s armamentarium for the therapy of Mycobacterium tuberculosis. When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for Mycobacterium tuberculosis therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the Hollow Fiber Infection Model. We examined 12, 24 and 48 hr dosing intervals with doses of 200 mg, 400 mg and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8 and 4 hr were simulated. We attempted to keep the CAvg (AUC) constant across arms. We found that susceptible bacterial load decline was linked to CAvg, as we had indicated previously. Resistance suppression, a non-monotonic function, had CMin as the linked index. The 48 hr interval with the 4 hr half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (CPeak-linked) and adherence, we conclude that the 400 mg dose daily is optimal for moxifloxacin.…

Eradication of tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been a challenge due to its uncanny ability to survive dormantly inside the host granulomas for decades. Mtb rewires its metabolic and redox regulatory networks to survive in the hostile hypoxic and nutrient-limiting environment, facilitating the formation of the drug-tolerant persisters. Previously, we showed that Protein Kinase G (PknG), a virulence factor required for the lysosomal escape, aids in metabolic adaptation thereby promoting the survival of non-replicating mycobacterium. Here, we sought to investigate the therapeutic potential of PknG against latent mycobacterium. We show that inhibition of PknG by AX20017 reduces mycobacterial survival in vitro latency models such as hypoxia, persisters, and nutrient starvation. Targeting PknG enhances the bactericidal activity of the front-line anti-TB drugs in peritoneal macrophages. Deletion of pknG resulted in a five to fifteen-fold reduced survival of Mtb in chronically infected mice treated with anti-TB drugs. Importantly, in the Cornell mouse model of latent TB, the deletion of pknG drastically attenuated Mtb’s ability to resuscitate post antibiotics treatment when compared with wild type and complemented strains. This is the first study to investigate the sterilizing activity of pknG deletion and inhibition for adjunct therapy against latent TB in a preclinical model. Collectively, the results suggest PknG may be a promising drug target for adjunct therapy to shorten the treatment duration and lower disease relapse.…

Isoniazid dose proposal in Tunisian Tuberculosis patients based on a validated pharmacokinetic model: Proportion of simulated patients achieving target isoniazid concentraion (C3H) with various dosage regimens taking into account acetylator status.A. Rapid/intermediate acetylator status, B. Slow acetylators status.

Journal of Medical Virology, Accepted Article.

Abstract Tuberculosis (TB) is top infectious disease killer caused by a single organism responsible for 1.5 million deaths in 2018. Both COVID-19 and the pandemic response are risking to affect control measures for TB and continuity of essential services for people affected by this infection in western countries and even more in developing countries. Knowledge about concomitant pulmonary TB and COVID-19 is extremely limited. The double burden of these two diseases can have devastating effects. Here, we describe from both the clinical and the immunological point of view a case of a patient with in vitro immune cell anergy affected by bilateral cavitary pulmonary TB and subsequent COVID-19-associated pneumonia with a worst outcome. COVID-19 can be a precipitating factor in TB respiratory failure and, during ongoing SARS-COV-2 pandemic, clinicians must be aware of this possible co-infection in differential diagnosis of patients with active TB and new or worsening chest imaging. …

by Mulusew Andualem Asemahagn, Getu Degu Alene, Solomon Abebe Yimer Background Tuberculosis (TB) remains a key health menace in Ethiopia and its districts. This study aimed to assess the spatial-temporal clustering of notified pulmonary TB (PTB) cases in East Gojjam Zone, Northwest Ethiopia. Methods A retrospective study was conducted among all PTB cases reported from 2013–2019. Case notification rates (CNRs) of PTB cases at Kebele (the lowest administrative unit), woreda, and zone levels were estimated. The PTB clustering was done using global Moran’s I statistics on Arc GIS 10.6. We used Kulldorff SaTScan 9.6 with a discrete Poisson model to identify statistically significant spatial-temporal clustering of PTB cases at Kebele level. Similarly, a negative binomial regression analysis was used to identify factors associated with the incidence of PTB cases at kebele level. Results A total of 5340 (52%) smear-positive and 4928 (48%) smear-negative PTB cases were analyzed. The overall mean CNR of PTB cases at zone, woreda and Kebele levels were 58(47–69), 82(56–204), and 69(36–347) per 100,000 population, respectively. The purely spatial cluster analysis identified eight most likely clusters (one for overall and one per year for seven reporting years) and 47 secondary clusters. Similarly, the space-time scan analysis identified one most likely and seven secondary clusters. The purely temporal analysis also detected one most likely cluster from 2013–2015. Rural residence, distance from the nearest health facility, and poor TB service readiness were factors (p-value…

American Journal of Respiratory and Critical Care Medicine, Volume 203, Issue 2, Page 168-174, January 15, 2021. …

Nobel Prizes in science, technology, engineering, and mathematics-related fields have been overwhelmingly awarded to men.1 Similarly, major awards in global health, such as The John Dirks Canada Gairdner Global Health Award and the Prince Mahidol Award, have been awarded predominantly to men working in high-income countries (HICs). What about awards in tuberculosis, a key area of global health?…

Abstract Background Chest X-ray (CXR) interpretation remains a central component of the current World Health Organization recommendations as an adjuvant test in diagnosis of smear-negative tuberculosis (TB). With its low specificity, high maintenance and operational costs, utility of CXR in diagnosis of smear-negative TB in high HIV/TB burden settings in the Xpert MTB/RIF era remains unpredictable. We evaluated accuracy and additive value of CXR to Xpert MTB/RIF in the diagnosis of TB among HIV-positive smear-negative presumptive TB patients. Methods HIV co-infected presumptive TB patients were recruited from the Infectious Diseases Institute outpatient clinic and in-patient medical wards of Mulago Hospital, Uganda. CXR films were reviewed by two independent radiologists using a standardized evaluation form. CXR interpretation with regard to TB was either positive (consistent with TB) or negative (normal or unlikely TB). Sensitivity, specificity and predictive values of CXR and CXR combined with Xpert MTB/RIF for diagnosis of smear-negative TB in HIV-positive patients were calculated using sputum and/or blood mycobacterial culture as reference standard. Results Three hundred sixty-six HIV co-infected smear-negative participants (female, 63.4%; hospitalized, 68.3%) had technically interpretable CXR. Median (IQR) age was 32 (28–39) years and CD4 count 112 (23–308) cells/mm3. Overall, 22% (81/366) were positive for Mycobacterium tuberculosis (Mtb) on culture; 187/366 (51.1%) had CXR interpreted as consistent with TB, of which 55 (29.4%) had culture-confirmed TB. Sensitivity and specificity of CXR interpretation in diagnosis of culture-positive TB were 67.9% (95%CI 56.6–77.8) and 53.7% (95%CI 47.7–59.6) respectively, while Xpert MTB/RIF sensitivity and specificity were 65.4% (95%CI 54.0–75.7) and 95.8% (95%CI 92.8–97.8) respectively. Addition of CXR to Xpert MTB/RIF had overall sensitivity and specificity of 87.7% (95%CI 78.5–93.9) and 51.6% (95%CI 45.6–57.5) respectively; 86.2% (95%CI 75.3–93.5) and 48.1% (95%CI 40.7–55.6) among inpatients and 93.8% (95%CI 69.8–99.8) and 58.0% (95%CI 47.7–67.8) among outpatients respectively. Conclusion In this high prevalence TB/HIV setting, CXR interpretation added sensitivity to Xpert MTB/RIF test at the expense of specificity in the diagnosis of culture-positive TB in HIV-positive individuals presenting with TB symptoms and negative smear. CXR interpretation may not add diagnostic value in settings where Xpert MTB/RIF is available as a TB diagnostic tool.…

Clofazimine (CFZ) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising anti-tuberculosis activity in vitro and in animal models, is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacy of CFZ and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CFZ were dosed at 20 mg/kg daily for two weeks, followed by QD (once daily), TIW (thrice weekly) and BIW (twice weekly) for additional 10-weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW and BIW dosing regimens were determined after treatment. Once daily administration of CFZ and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once daily administration of TBI-166 increased the bactericidal activity by approximately 1 log10 CFU in the lung and spleen as compared with TIW or BIW dosing after 12 weeks of treatment, while once daily administration of CFZ increased the bactericidal activity by 1.27 to 1.90 log10 CFU/lung and by 1.61 to 2.22 log10 CFU/spleen in BALB/c mouse model, as compared to the intermittent therapies. The difference between QD and TIW and between QD and BIW were significant (P

Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis.

Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude of Mycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

The whole-genome fingerprinting technique, fluorescent amplified-fragment length polymorphism (FAFLP) analysis, was applied to Mycobacterium tuberculosis. Sixty-five clinical isolates were analyzed to determine the value of FAFLP as a stand-alone genotyping technique and to compare it with the well-established IS6110 typing system. The genome sequence of M. tuberculosis strain H37Rv (S. T. Cole et al., Nature 393:537-544, 1998) was used to model computer-generated informative primer combination(s), and the precision and reproducibility of FAFLP were evaluated by comparing the results of in vitro and computer-generated experiments. Multiplex FAFLP was used to increase resolving power in a predictable and systematic fashion. FAFLP analysis was broadly congruent with IS6110 typing for those strains with multiple IS6110 copies. It was also able to resolve an epidemiologically unlinked group of strains with only one copy of IS6110; up to 10% of clinical isolates may fall into this category. For certain epidemiological investigations, it was concluded that a combination of FAFLP and IS6110 typing would give higher resolution than would either alone. FAFLP data were digital, precise, reproducible, and suitable for rapid electronic dissemination, manipulation, interlaboratory comparison, and storage in national or international epidemiological databases. Because FAFLP samples and analyzes base substitution across the genome as a whole, FAFLP could generate new information about the microevolution of the M. tuberculosis complex.

To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

The present study is based on notified cases of tuberculosis (TB) in the National tbc. register 1972-1996. A decline in Tb incidence was seen from 1972 and until the mid-1980's. Subsequently the trend has reversed due to an increasing number of TB cases in foreigners. In 1996, 60% of all cases of TB in Denmark were found in foreigners reflecting the rising number of refugees and their families arriving in Denmark from highly endemic areas, mainly Somalia. Among native Danes the TB incidence fell from 14 per 100,000 in 1972 to 4 per 100,000 in the 1980's and stabilized at this very low level. The unchanged incidence in Danes covers a falling incidence in the older and a rising incidence in the younger and middle-aged adult population, mainly in the capital. Approximately half of the cases occur in high-risk groups. The TB-epidemic is close to elimination in the indigenous Danish population, but the disease is maintained at a low level probably due to increased patient and doctor delay and resulting microepidemics primarily in high-risk populations.