Tuberkulose

Objectives

The WHO currently recommends stool testing using GeneXpert MTB/Rif (Xpert) for the diagnosis of paediatric tuberculosis (TB). The simple one-step (SOS) stool method enables processing for Xpert testing at the primary healthcare (PHC) level. We modelled the impact and cost-effectiveness of implementing the SOS stool method at PHC for the diagnosis of paediatric TB in Ethiopia and Indonesia, compared with the standard of care.

Setting

All children (age <15 years) presenting with presumptive TB at primary healthcare or hospital level in Ethiopia and Indonesia.

Primary outcome

Cost-effectiveness estimated as incremental costs compared with incremental disability-adjusted life-years (DALYs) saved.

Methods

Decision tree modelling was used to represent pathways of patient care and referral. We based model parameters on ongoing studies and surveillance, systematic literature review, and expert opinion. We estimated costs using data available publicly and obtained through in-country expert consultations. Health outcomes were based on modelled mortality and discounted life-years lost.

Results

The intervention increased the sensitivity of TB diagnosis by 19–25% in both countries leading to a 14–20% relative reduction in mortality. Under the intervention, fewer children seeking care at PHC were referred (or self-referred) to higher levels of care; the number of children initiating anti-TB treatment (ATT) increased by 18–25%; and more children (85%) initiated ATT at PHC level. Costs increased under the intervention compared with a base case using smear microscopy in the standard of care resulting in incremental cost-effectiveness ratios of US$132 and US$94 per DALY averted in Ethiopia and Indonesia, respectively. At a cost-effectiveness threshold of 0.5xgross domestic product per capita, the projected probability of the intervention being cost-effective in Ethiopia and Indonesia was 87% and 96%, respectively. The intervention remained cost-effective under sensitivity analyses.

Conclusions

The addition of the SOS stool method to national algorithms for diagnosing TB in children is likely to be cost-effective in both Ethiopia and Indonesia.

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American Journal of Respiratory and Critical Care Medicine, Volume 206, Issue 1, Page 94-104, July 1, 2022. …

American Journal of Respiratory and Critical Care Medicine, Volume 206, Issue 1, Page 10-12, July 1, 2022. …

Objective

Tuberculosis (TB) and HIV/AIDS are public health concerns in Papua New Guinea (PNG). This study examines TB and HIV/AIDS mortalities and associated sociodemographic factors in PNG.

Method

As part of a longitudinal study, verbal autopsy (VA) interviews were conducted using the WHO 2016 VA Instrument to collect data of 926 deaths occurred in the communities within the catchment areas of the Comprehensive Health and Epidemiological Surveillance System from 2018 to 2020.

InterVA-5 cause of deaths analytical tool was used to assign specific causes of death (COD). Multinomial logistic regression analyses were conducted to identify associated sociodemographic factors, estimate adjusted ORs (AOR), 95% CIs and p values.

Result

TB and HIV/AIDS were the leading CODs from infectious diseases, attributed to 9% and 8% of the total deaths, respectively.

Young adults (25–34 years) had the highest proportion of deaths from TB (20%) and the risk of dying from TB among this age group was five times more likely than those aged 75+ years (AOR: 5.5 (95% CI 1.4 to 21.7)). Urban populations were 46% less likely to die from this disease compared rural ones although the difference was not significant (AOR: 0.54 (95% CI 0.3 to 1.0)). People from middle household wealth quintile were three times more likely to die from TB than those in the richest quintile (AOR: 3.0 (95% CI 1.3 to 7.4)).

Young adults also had the highest proportion of deaths to HIV/AIDS (18%) and were nearly seven times more likely to die from this disease compared with those aged 75+years (AOR: 6.7 (95% CI 1.7 to 25.4)). Males were 48% less likely to die from HIV/AIDS than females (AOR: 0.52 (95% CI 0.3 to 0.9)). The risk of dying from HIV/AIDS in urban population was 54% less likely than their rural counterparts (AOR: 0.46 (95% CI 0.2 to 0.9)).

Conclusion

TB and HIV/AIDS interventions are needed to target vulnerable populations to reduce premature mortality from these diseases in PNG.

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Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Abstract

Background

Mycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery.

Study design and methods

In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses.

Results

Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders.

Conclusions

Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.

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Abstract

Background

Mycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery.

Study design and methods

In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses.

Results

Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders.

Conclusions

Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.

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Science Advances, <a href='https://www.science.org/toc/sciadv/8/25'>Volume 8, Issue 25</a>, June 2022. …

Introduction

Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem globally. Long, complex treatment regimens coupled with frequent adverse events have resulted in poor treatment adherence and patient outcomes. Smartphone-based mobile health (mHealth) technologies offer national TB programmes an appealing platform to improve patient care and management; however, clinical trial evidence to support their use is lacking. This trial will test the hypothesis that an mHealth intervention can improve treatment success among patients with MDR-TB and is cost-effective compared with standard practice.

Methods and analysis

A community-based, open-label, parallel-group randomised controlled trial will be conducted among patients treated for MDR-TB in seven provinces of Vietnam. Patients commencing therapy for microbiologically confirmed rifampicin-resistant or multidrug-resistant tuberculosis within the past 30 days will be recruited to the study. Participants will be individually randomised to an intervention arm, comprising use of an mHealth application for treatment support, or a ‘standard care’ arm. In both arms, patients will be managed by the national TB programme according to current national treatment guidelines. The primary outcome measure of effectiveness will be the proportion of patients with treatment success (defined as treatment completion and/or bacteriological cure) after 24 months. A marginal Poisson regression model estimated via a generalised estimating equation will be used to test the effect of the intervention on treatment success. A prospective microcosting of the intervention and within-trial cost-effectiveness analysis will also be undertaken from a societal perspective. Cost-effectiveness will be presented as an incremental cost per patient successfully treated and an incremental cost per quality-adjusted life-year gained.

Ethics

Ethical approval for the study was granted by The University of Sydney Human Research Ethics Committee (2019/676).

Dissemination

Study findings will be disseminated to participants and published in peer-reviewed journals and conference proceedings.

Trial registration number

ACTRN12620000681954.

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New England Journal of Medicine, Volume 386, Issue 25, Page 2438-2440, June 2022. …

AbstractBackgroundTreatment of rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) requires multiple drugs and outcomes remain suboptimal. Some drugs are associated with improved outcome, however whether particular pharmacokinetic-pharmacodynamic relationships predict outcome is unknown.MethodsAdults with pulmonary RR/MDR-TB in Tanzania, Bangladesh and Russian Federation receiving therapy with local regimens were enrolled from June, 2016 to July, 2018. Serum was collected after two, four, and eight weeks for each drug’s area under the concentration-time curve (AUC0-24) and quantitative susceptibility of the Mycobacterium tuberculosis isolate measured by minimum inhibitory concentrations (MIC). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (OR) for association with favorable treatment outcome and hazard ratios (HR) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into four clusters by AUC0-24/MIC exposures.ResultsAmong 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome [OR 3.75 (1.21, 11.56), p = 0·022], while levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg*h/L were associated with faster culture conversion [HR > 1·0, p < 0.05]. Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed those with lowest multidrug exposures had slowest culture conversion.ConclusionAmidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs – fluoroquinolones, pyrazinamide, clofazimine – were predictive and should be optimized to improve clinical outcome.

Abstract

Background

Although the World Health Organization reports that the incidence of tuberculosis in China is decreasing every year, the burden of tuberculosis in China is still very heavy. Understanding the spatial and temporal distribution pattern of tuberculosis in China and its influencing environmental factors will provide effective reference for the prevention and treatment of tuberculosis.

Methods

Data of TB incidence from 2010 to 2017 were collected. Time series and global spatial autocorrelation were used to analyze the temporal and spatial distribution pattern of tuberculosis incidence in China, Geodetector and Geographically Weighted Regression model were used to analyze the environmental factors affecting the TB incidence.

Results

In addition to 2007 and 2008, the TB incidence decreased in general. TB has a strong spatial aggregation. Cities in Northwest China have been showing a trend of high-value aggregation. In recent years, the center of gravity of high-value aggregation area in South China has moved further south. Temperature, humidity, precipitation, PM10, PM2.5, O3, NO2 and SO2 have impacts on TB incidence, and in different regions, the environmental factors show regional differences.

Conclusions

Residents should pay more attention to the risk of developing TB caused by climate change and air pollutant exposure. Increased efforts should be placed on areas with high-value clustering in future public resource configurations.

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Abstract

Background

Although the World Health Organization reports that the incidence of tuberculosis in China is decreasing every year, the burden of tuberculosis in China is still very heavy. Understanding the spatial and temporal distribution pattern of tuberculosis in China and its influencing environmental factors will provide effective reference for the prevention and treatment of tuberculosis.

Methods

Data of TB incidence from 2010 to 2017 were collected. Time series and global spatial autocorrelation were used to analyze the temporal and spatial distribution pattern of tuberculosis incidence in China, Geodetector and Geographically Weighted Regression model were used to analyze the environmental factors affecting the TB incidence.

Results

In addition to 2007 and 2008, the TB incidence decreased in general. TB has a strong spatial aggregation. Cities in Northwest China have been showing a trend of high-value aggregation. In recent years, the center of gravity of high-value aggregation area in South China has moved further south. Temperature, humidity, precipitation, PM10, PM2.5, O3, NO2 and SO2 have impacts on TB incidence, and in different regions, the environmental factors show regional differences.

Conclusions

Residents should pay more attention to the risk of developing TB caused by climate change and air pollutant exposure. Increased efforts should be placed on areas with high-value clustering in future public resource configurations.

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Introduction

Previous studies indicate people with diabetes mellitus (DM) may have varying treatment outcomes when receiving treatment for tuberculosis (TB) and that TB infection or its treatment may predispose them to develop an abnormal blood glucose or type 2 DM. This has implications for Eswatini which is a high TB burden country and with increasing cases of non-communicable diseases including DM. This study will describe the epidemiology of DM-TB comorbidity in a prospective cohort of patients receiving TB treatment and identify best practices for integration of care for non-communicable diseases into TB services in Eswatini.

Methods and analysis

This study will employ a mixed-methods approach. Data from a prospective cohort of newly enrolled patients with TB at 12 health facilities from 1 June 2022 to 30 September 2022, and followed up to 30 April 2023, will be used. For the qualitative, key informants who provide TB services at the health facilities will be interviewed. Quantitative data from patients will be analysed descriptively and by tests of association and multivariate modelling. Key informant interviews from healthcare workers will be analysed using content analysis.

Ethics and dissemination

This research has been approved by the Eswatini Health and Human Research Review Board and participant confidentiality will be maintained. COVID-19 safety measures to reduce the risk of infection or transmission by researchers and participants have been instituted. Key programmatic findings and how they can impact healthcare delivery and access will be presented to the specific programme in the Eswatini Ministry of Health and other relevant stakeholders.

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Antimicrobial Agents and Chemotherapy, Ahead of Print. …

Introduction

The COVID-19 outbreak poses a significant threat to the patients with tuberculosis (TB). TB and COVID-19 (TB–COVID) coinfection means the disease caused by both Mycobacterium tuberculosis and SARS-CoV-2 infection. Currently, the prevalence status, treatment and outcomes of the coinfection are poorly characterised. We aimed to systematically review the evidence on this topic and provide comprehensive information to guide the control and treatment of TB–COVID coinfection.

Methods

An extensive screening was conducted using six electronic databases to search eligible studies from 1 November 2019 to 19 March 2021. Prevalence rate, treatment and outcomes of TB–COVID coinfection were extracted. Random-effects models were used to calculate mean fatality rates of coinfection with 95% CIs. The risks of bias were assessed with the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Study Reporting Prevalence Data and JBI Critical Appraisal Checklist for Case Report. A meta-analysis was conducted for subgroups on in-hospital fatality rate.

Results

Forty-two studies were included into the analysis (35 case reports and 7 retrospective cohort studies). Nineteen countries reported coinfected patients, including high and low TB prevalence countries. The only study revealing prevalence rate came from West Cape Province, South Africa (people aged above 20 years, 0.04% until 1 June 2020 and 0.06% until 9 June 2020). The treatment regimens for coinfected patients were highly heterogeneous. The mean overall and in-hospital fatality rates of coinfection were 13.9% (95% CI: 1.6% to 26.2%) and 17.5% (95% CI: 8.9% to 26.0%). The mean in-hospital fatality rates for high-income countries (Italy and Argentina) and low/middle-income countries (LMICs) (India, Philippines, South Africa) were 6.5% (95% CI: –0.8% to ~13.9%) and 22.5% (95% CI: 19.0% to ~26.0%).

Conclusion

TB–COVID coinfection is common globally, and the coinfected patients suffer from higher fatality risk than patients with normal COVID-19. Outcomes shared significant differences between high-income countries and LMICs.

PROSPERO registration number

CRD42021253660.

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Abstract

Background

There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB).

Methods

We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed.

Results

PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02–1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95%CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels.

Conclusion

In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.

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Abstract

Background

There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB).

Methods

We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed.

Results

PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02–1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95%CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels.

Conclusion

In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.

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Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.

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.