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AbstractBackgroundThe lateral flow urine lipoarabinomannan assay, Determine TB-LAM (Determine LAM), offers the potential for timely tuberculosis (TB) treatment among people living with HIV (PWH).MethodsIn this cluster-randomized trial, Determine LAM was made available with staff training with performance feedback at three hospitals in Ghana. Newly admitted PWH with a positive WHO four-symptom screen for TB, severe illness, or advanced HIV were enrolled. The primary outcome was days from enrollment to TB treatment initiation. We also reported the proportion of patients with a TB diagnosis, initiating TB treatment, all-cause mortality, and Determine LAM uptake at 8 weeks.ResultsWe enrolled 422 patients including 174 (41.2%) in the intervention group. The median CD4 count was 87 cells/mm3 (IQR 25-205) and 138 patients (32.7%) were on antiretroviral therapy. More patients were diagnosed with TB in the intervention group compared with the control group, 59 (34.1%; 95%CI27.1-41.7) vs 46 (18.7%; 95%CI14.0-24.1), p

Abstract Background Immigration is considered as a risk factor of tuberculosis (TB). Qom province receives millions of pilgrims and significant numbers of immigrants each year. Most of the immigrants to Qom, arrive from neighboring TB-endemic countries. This study aimed to identify the current circulating Mycobacterium tuberculosis genotypes in Qom province using 24-locus MIRU-VNTR genotyping. Methods Eighty six M. tuberculosis isolates were collected during 2018–2022 from patients referring to Qom TB reference laboratory. The DNA of isolates was extracted and followed by 24 loci MIRU-VNTR genotyping which performed using the web tools available on MIRU-VNTRplus. Results Of 86 isolates, 39 (45.3%) were of Delhi/CAS genotype, 24 (27.9%) of NEW-1, 6 (7%) of LAM, 6 (7%) of Beijing, 2 (2.3%) of UgandaII, 2 (2.3%) of EAI, 1 of S (1.2%) and 6 (7%) did not match with profiles present in MIRUVNTRplus database. Conclusions About half of the isolates belong to Afghan immigrants; which warns health policy makers about the future situation of TB in Qom. Also, the similarity of Afghan and Iranian genotypes provides evidence that immigrants partake in the circulation of M. tuberculosis. This study underpin the studies about the circulating M. tuberculosis genotypes, their geographical distribution, the association of TB risk factors with these genotypes and the impact of immigration on the situation of TB in Qom province. …

AbstractBackgroundTuberculosis infection (TBI) and tuberculosis disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant tuberculosis exposure. We sought to characterize TBI and TBD incidence at one-year in HHCs and to evaluate tuberculosis preventive therapy (TPT) use in high-risk groups.MethodsWe previously conducted a cross-sectional study of HHCs of rifampin-/multidrug-resistant tuberculosis in 8 high-burden countries and re-assessed TBI (interferon-gamma release assay, HHCs ≥5 years) and TBD (HHCs all ages) at one-year. Incidence was estimated across age and risk groups (age

Abstract Background Immigration is considered as a risk factor of tuberculosis (TB). Qom province receives millions of pilgrims and significant numbers of immigrants each year. Most of the immigrants to Qom, arrive from neighboring TB-endemic countries. This study aimed to identify the current circulating Mycobacterium tuberculosis genotypes in Qom province using 24-locus MIRU-VNTR genotyping. Methods Eighty six M. tuberculosis isolates were collected during 2018–2022 from patients referring to Qom TB reference laboratory. The DNA of isolates was extracted and followed by 24 loci MIRU-VNTR genotyping which performed using the web tools available on MIRU-VNTRplus. Results Of 86 isolates, 39 (45.3%) were of Delhi/CAS genotype, 24 (27.9%) of NEW-1, 6 (7%) of LAM, 6 (7%) of Beijing, 2 (2.3%) of UgandaII, 2 (2.3%) of EAI, 1 of S (1.2%) and 6 (7%) did not match with profiles present in MIRUVNTRplus database. Conclusions About half of the isolates belong to Afghan immigrants; which warns health policy makers about the future situation of TB in Qom. Also, the similarity of Afghan and Iranian genotypes provides evidence that immigrants partake in the circulation of M. tuberculosis. This study underpin the studies about the circulating M. tuberculosis genotypes, their geographical distribution, the association of TB risk factors with these genotypes and the impact of immigration on the situation of TB in Qom province. …

Abstract Background The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. Methods We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. Results There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. Conclusion Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy. …

Abstract Introduction Tuberculosis (TB) is caused by M. tuberculosis complex (MTB) and pulmonary tuberculosis (PTB) is its classical manifestation. However, in some regions of the world, extrapulmonary TB (EPTB) seems to be more frequent. Methods We performed a retrospective cohort study of all TB patients treated at University Hospital Frankfurt, Germany, for the time period 2013–2018. Patient charts were reviewed and demographic, clinical, and microbiological data recorded. Patients were subdivided according to their geographic origins. Results Of the 378 included patients, 309 were born outside Germany (81.7%). Three WHO regions were significantly associated with the occurrence of isolated EPTB: the South-East Asian Region (OR 3.37, CI 1.74–6.66, p 

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Abstract Background The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. Methods We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. Results There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. Conclusion Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy. …

The global resurgence of tuberculosis following the COVID-19 pandemic has re-focused attention on strategies to achieve the World Health Organisation target of TB elimination by 2050 [1]. This target cannot be met without implementation of measures to prevent acquisition of M. tuberculosis infection [2]. In countries with a high TB burden, such measures will need to focus particularly on schoolchildren, a group at particularly high risk of tuberculosis infection [3, 4]. Existing efforts attempt to reduce transmission (e.g.

ObjectiveDescription of tuberculosis (TB)-focused point-of-care ultrasound (POCUS) findings for children with presumptive TB. DesignCross-sectional study (July 2019 to April 2020). SettingSimão Mendes hospital in Bissau, a setting with high TB, HIV, and malnutrition burdens. ParticipantsPatients aged between 6 months and 15 years with presumptive TB. InterventionsParticipants underwent clinical, laboratory and unblinded clinician-performed POCUS assessments, to assess subpleural nodules (SUNs), lung consolidation, pleural and pericardial effusion, abdominal lymphadenopathy, focal splenic and hepatic lesions and ascites. Presence of any sign prompted a POCUS positive result. Ultrasound images and clips were evaluated by expert reviewers and, in case of discordance, by a second reviewer. Children were categorised as confirmed TB (microbiological diagnosis), unconfirmed TB (clinical diagnosis) or unlikely TB. Ultrasound findings were analysed per TB category and risk factor: HIV co-infection, malnutrition and age. ResultsA total of 139 children were enrolled, with 62 (45%) women and 55 (40%) aged

ObjectivesTo understand the perspectives of adolescents (10–19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents. DesignWe conducted in-depth interviews using semistructured interview guides based on the World Health Organization (WHO)’s Five Dimensions of Adherence framework, which conceptualises adherence as being related to the health system, socioeconomic factors, patient, treatment and condition. We applied framework thematic analysis. SettingBetween August 2018 and May 2019, at 32 public health centres operated by the Ministry of Health in Lima, Peru. ParticipantsWe interviewed 34 adolescents who completed or were lost to follow-up from treatment for drug-susceptible pulmonary TB disease in the preceding 12 months; their primary caregiver during treatment; and 15 nurses or nurse technicians who had ≥6 months’ experience supervising TB treatment. ResultsParticipants reported numerous treatment barriers, the most common of which were the inconvenience of health facility-based directly observed therapy (DOT), long treatment duration, adverse treatment events and symptom resolution. The support of adult caregivers was critical for helping adolescents overcome these barriers and carry out the behavioural skills (eg, coping with the large pill burden, managing adverse treatment events and incorporating treatment into daily routines) needed to adhere to treatment. ConclusionOur findings support a three-pronged approach to improve TB treatment adherence among adolescents: (1) reduce barriers to adherence (eg, home-based or community-based DOT in lieu of facility-based DOT, reducing pill burden and treatment duration when appropriate), (2) teach adolescents the behavioural skills required for treatment adherence and (3) strengthen caregivers’ ability to support adolescents. …

ObjectiveWe described epidemiological characteristics of pulmonary tuberculosis (PTB) among students and evaluated susceptible populations and areas in Guizhou province and also to provide scientific suggestions for prevention and control. SettingGuizhou, China. DesignThis is a retrospective epidemiological study on PTB in students. MethodsData are from the China Information System for Disease Control and Prevention. We collected all PTB cases among the student population from 2010 to 2020 in Guizhou. Incidence, composition ratio and hotspot analysis were used to describe epidemiological and some clinical characteristics. ResultsA total of 37 147 new student PTB cases were registered among the population aged 5–30 years during 2010–2020. The proportions of men and women were 53.71% and 46.29%, respectively. Cases aged 15–19 years dominated (63.91%), and the proportion of ethnic groups was increasing during the period. Generally, the raw annual incidence of PTB among the population was increasing from 32.585 per 100 000 persons in 2010 to 48.872 per 100 000 persons in 2020 (c2trend=1283.230, p

by Temesgen Yihunie Akalu, Archie C. A. Clements, Adhanom Gebreegziabher Baraki, Kefyalew Addis Alene Introduction Multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are major public health threats that are significant causes of physical sequelae and financial consequences for infected people. Treatment for MDR- and XDR-TB are more toxic and take longer duration than for drug-susceptible-TB. As a result, the long-term sequelae are thought to be more common among patients with MDR- and XDR-TB than drug-susceptible-TB, but this is yet to be quantified. Hence, the aim of this systematic review and meta-analysis is to quantify the global burden and types of long-term physical sequelae and financial burden associated with both MDR- and XDR-TB. Method and analysis We will search CINHAL, MEDLINE, Embase, Scopus, and Web of science for studies that report physical and financial sequelae associated with rifampicin-resistant (RR), MDR- and XDR-TB or their treatments. The search will be conducted without time, language, and place restrictions. A random-effects meta-analysis will be conducted to estimate the pooled prevalence of each physical sequela. Heterogeneity will be measured using the Higgins I2 statistics. We will assess publication bias visually using the funnel plot and statistically using Egger’s test. Adjustments for publication basis will be made using Tweedie’s and Duval Trim and Fill analysis. Ethics and dissemination Since the study is based on published evidence, ethics approval is not required. The findings of the systematic review will be presented at various conferences and will be published in a peer-reviewed journal. Protocol registration The protocol is published in the PROSPERO with registration number CRD42021250909. …

by Temesgen Yihunie Akalu, Archie C. A. Clements, Adhanom Gebreegziabher Baraki, Kefyalew Addis Alene Introduction Multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are major public health threats that are significant causes of physical sequelae and financial consequences for infected people. Treatment for MDR- and XDR-TB are more toxic and take longer duration than for drug-susceptible-TB. As a result, the long-term sequelae are thought to be more common among patients with MDR- and XDR-TB than drug-susceptible-TB, but this is yet to be quantified. Hence, the aim of this systematic review and meta-analysis is to quantify the global burden and types of long-term physical sequelae and financial burden associated with both MDR- and XDR-TB. Method and analysis We will search CINHAL, MEDLINE, Embase, Scopus, and Web of science for studies that report physical and financial sequelae associated with rifampicin-resistant (RR), MDR- and XDR-TB or their treatments. The search will be conducted without time, language, and place restrictions. A random-effects meta-analysis will be conducted to estimate the pooled prevalence of each physical sequela. Heterogeneity will be measured using the Higgins I2 statistics. We will assess publication bias visually using the funnel plot and statistically using Egger’s test. Adjustments for publication basis will be made using Tweedie’s and Duval Trim and Fill analysis. Ethics and dissemination Since the study is based on published evidence, ethics approval is not required. The findings of the systematic review will be presented at various conferences and will be published in a peer-reviewed journal. Protocol registration The protocol is published in the PROSPERO with registration number CRD42021250909. …

ObjectiveTo demonstrate the impact of interventions on tuberculosis (TB) case detection in mining and pastoralist districts in southeastern Ethiopia over a 10-year period. DesignLongitudinal quasi-experimental study. SettingHealth centres and hospitals in six mining districts implemented interventions and seven nearby districts functioned as controls. ParticipantsData from the national District Health Information System (DHIS-2) were used for this study; therefore, people did not participate in this study. InterventionsDirected at training, active case finding and improving treatment outcomes. Primary and secondary outcome measuresPrimarily, trends in TB case notification and percentage of bacteriologically confirmed TB—as collected by DHIS-2—between pre-intervention (2012–2015) and post-intervention (2016–2021) were analysed. Secondarily, post-intervention was split into early post-intervention (2016–2018) and late post-intervention (2019–2021) to also study the long-term effects of the intervention. ResultsFor all forms of TB, case notification significantly increased between pre-intervention and early post-intervention (incidence rate ratio (IRR): 1.21, 95% CI: 1.13, 1.31; p

American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 10, Page 1376-1382, May 15, 2023.

by Afom T. Andom, Hannah N. Gilbert, Melino Ndayizigiye, Joia S. Mukherjee, Christina Thompson Lively, Jonase Nthunya, Tholoana A. Marole, Makena Ratsiu, Mary C. Smith Fawzi, Courtney M. Yuen Background Lesotho is one of the 30 countries with the highest tuberculosis incidence rates in the world, estimated at 650 per 100,000 population. Tuberculosis case detection is extremely low, particularly with the rapid spread of COVID-19, dropping from an estimated 51% in 2020 to 33% in 2021. The aim of this study is to understand the barriers to tuberculosis diagnosis and treatment completion. Methods We used a convergent mixed methods study design. We collected data on the number of clients reporting symptoms upon tuberculosis screening, their sputum test results, the number of clients diagnosed, and the number of clients who started treatment from one district hospital and one health center in Berea district, Lesotho. We conducted in-depth interviews and focus group discussions with 53 health workers and patients. We used a content analysis approach to analyze qualitative data and integrated quantitative and qualitative findings in a joint display. Findings During March-August, 2019, 218 clients at the hospital and 292 clients at the health center reported tuberculosis symptoms. The full diagnostic testing process was completed for 66% of clients at the hospital and 68% at the health center. Among clients who initiated tuberculosis treatment, 68% (61/90) at the hospital and 74% (32/43) at the health center completed treatment. The main barriers to testing and treatment completion were challenges at sample collection, lack of decentralized diagnostic services, and socioeconomic factors such as food insecurity and high patient movement to search for jobs. Conclusions Tuberculosis diagnosis could be improved through the effective decentralization of laboratory services at the health facility level, and treatment completion could be improved by providing food and other forms of social support to patients. …

AbstractBackgroundDespite data suggesting elevated morbidity and mortality among people who have survived tuberculosis disease, the impact of respiratory tuberculosis on healthcare utilization in the years following diagnosis and treatment remains unclear.MethodsUsing linked health administrative data from British Columbia, Canada, we identified foreign-born individuals treated for respiratory tuberculosis between 1990 and 2019. We matched each person with up to four people without a tuberculosis diagnosis from the same source cohort using propensity score matching. Then, using a controlled interrupted time series analysis, we measured outpatient physician encounters and in-patient hospital admissions in the five years following respiratory tuberculosis diagnosis and treatment.ResultsWe matched 1,216 individuals treated for respiratory tuberculosis to 4,864 non-tuberculosis controls. Immediately following the tuberculosis diagnostic and treatment period, the monthly rate of outpatient encounters in the tuberculosis group was 34.0% (95% CI 30.7, 37.2%) higher than expected, and this trend was sustained for the duration of the post-tuberculosis period. The excess utilization represented an additional 12.2 (95% CI 10.6, 14.9) outpatient encounters per person over the post-tuberculosis period, with respiratory morbidity a large contributor to the excess healthcare utilization. Results were similar for hospital admissions, with an additional 0.4 (95% CI 0.3, 0.5) hospital admissions per person over the post-tuberculosis period.DiscussionRespiratory tuberculosis appears to have long-term impacts on healthcare utilization beyond treatment. These findings underscore the need for screening, assessment, and treatment of post-tuberculosis sequelae, as it may provide an opportunity to improve health and reduce resource use.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Abstract Background Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs. Methods ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages. Discussion This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB. Trial registration The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071. …

Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1];  = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49];  = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56];  = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55];  = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9];  = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms;  = 0.01). Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).

Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

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.