Tuberkulose

Banurekha Velayutham, Mohideen Shaheed Jawahar, Dina Nair, Pooranagangadevi Navaneethapandian, Chinnaiyan Ponnuraja, Kandasamy Chandrasekaran, Gomathi Narayan Sivaramakrishnan, Marimuthu Makesh Kumar, Paramasivam Paul Kumaran, Santhanakrishnan Ramesh Kumar, Dhanaraj Baskaran, Daniel Bella Devaleenal, Devarajulu Reddy Sirasanambati, Mahalingam Vasantha, Paramasivam Palaniyandi, Geetha Ramachandran, Kadayam Ranganathan Uma Devi, Luke Elizabeth Hannah, Gomathi Sekar, Ammayappan Radhakrishnan

Tropical Medicine &International Health, Volume 0, Issue ja, -Not available-.

Abstract Background Compliance to anti-TB treatment is crucial in achieving cure and avoiding the emergence of drug resistance. Electronic health (eHealth) interventions are included in the strategy to end the global Tuberculosis (TB) epidemic by 2035. Evidences showed that mobile messaging systems could improve patient adherence to clinic appointment for diagnosis and treatment. This review aimed to assess the effect of mobile-phone messaging on anti-TB treatment success. Methods All randomized controlled trial (RCT) and quasi-experimental studies done prior to August 26, 2019 were included in the review. Studies were retrieved from PubMed, EMBASE, Cochrane and ScienceDirect databases including, grey and non-indexed literatures from Google and Google scholar. Quality of studies were independently assessed using Cochrane Risk of Bias Assessment Tool. A qualitative synthesis and quantitative pooled estimation were used to measure the effect of phone messaging on TB treatment success rate. PRISMA flow diagrams were used to summarize article selection process. Results A total of 1237 articles were identified, with 14 meeting the eligibility criteria for qualitative synthesis. Eight studies with a total of 5680 TB patients (2733 in intervention and 2947 in control groups) were included in meta-analysis. The pooled effect of mobile-phone messaging revealed a small increase in treatment success compared to standard of care (RR 1.04, 95% CI 1.02 to 1.06), with low heterogeneity (I2 = 7%, p 

Park J, Choi E, Park H, et al.

AbstractIn hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-gamma-releasing-assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative-or-indeterminate IGRA (1.15/100 person-years)(P=.01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years)(P=.09). The number needed to treat was 22 (95% CI 12-99) with positive IGRA results.

Abstract Background The WHO recently recommended the new Xpert MTB/RIF Ultra assay (Ultra) instead of the Xpert MTB/RIF assay because Ultra has improved sensitivity. We report the diagnostic accuracy of Ultra for tuberculous adenitis in a tuberculosis and HIV endemic setting. Methods We obtained fine-needle aspirates (FNA) and lymph node tissue by core-needle biopsy in adult patients with peripheral lymphadenopathy of >20 mm. Ultra and mycobacterial culture were performed on FNA and tissue specimens, with histological examination of tissue specimens. We assessed the diagnostic accuracy of Ultra against a composite reference standard of ‘definite tuberculosis’ (microbiological criteria) or ‘probable tuberculosis’ (histological and clinical criteria). Results We prospectively evaluated 99 participants of whom 50 were HIV positive: 21 had ‘definite tuberculosis’, 15 ‘probable tuberculosis’ and 63 did not have tuberculosis (of whom 38% had lymphoma and 19% disseminated malignancy). Using the composite reference standard the Ultra sensitivity on FNA was 70% (95% CI 51–85; 21 of 30), and on tissue was 67% (45–84; 16/24) these were far superior to the detection of acid-fast bacilli on an FNA (26%; 7/27); AFB on tissue (33%; 8/24); or tissue culture (39%; 9/23). The detection of granulomas on histology had high senstivity (83%) but the lowest specficity. When compared with culture the Ultra on FNA had a sensitvity of 78% (40-97; 7/9) and tissue 90% (55-100; 9/10). Conclusions Ultra performed on FNA or tissue of a lymph node had good sensitivity and high specificity. Ultra had a higher yield than culture and has the advantage of being a rapid test. Ultra on FNA would be an appropriate initial investigation for lymphadenopathy in tuberculosis endemic areas followed by a core biopsy for histopathology with a repeat Ultra on tissue if granulomas are present.…

Zhi-Bin Li, Yu-Shuai Han, Li-Liang Wei, Li-Ying Shi, Wen-Jing Yi, Jing Chen, Huai Huang, Ting-Ting Jiang, Ji-Cheng Li

In 2018, there were about 10 million new tuberculosis (TB) cases and 1.24 million TB deaths worldwide. China is ranked second for TB disease burden in the world with estimated 866,000 new TB patients and 37,000 TB related deaths annually (World Health Organization, 2019). One of the reasons for the high incidence of TB is the early discharge of uncured patients who can cause disease transmission. At present, cured TB is mainly evaluated by the following standards: ① Whether the patient has received standardized anti-TB treatment; ② Chest X-ray and/or CT scan results; ③ Sputum smear and sputum culture results.

Sossen B, Broger T, Kerkhoff A, et al.

AbstractReducing diagnostic delay is key towards decreasing tuberculosis-associated deaths in people living with HIV. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.

J. R. Campbell et al.

Xiaoxin Dong, Lingbo Zhao, Tongda Sun, Fei Yun and Lei Qiu

Abstract. There are hundreds of millions of internal migrants in China, and tuberculosis (TB) is an important health threat to them. However, the mental health problems of internal migrants with TB in China have been ignored. The present study aimed to determine the prevalence of depressive symptoms and its associated risk factors among internal migrants with TB in China. A cross-sectional survey was conducted between June 2018 and March 2019 in Shenzhen, southern China. Data were collected from 1,057 internal migrants with TB using a structured questionnaire. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Multinomial logistic regression analysis was used to identify risk factors for depressive symptoms. Of the 1,057 participants included in this study, 53.8% had depressive symptoms. Of these, 38.9% had mild, whereas 14.9% had moderate-to-severe depressive symptoms. Multinomial logistic regression analysis suggested that higher likelihoods of depressive symptoms were associated with female gender, lower education, family dysfunction, poor doctor–patient communication, and TB-related stigma. This study shows that the prevalence of depressive symptoms among internal migrants with TB is high in China. Targeting interventions and treatment of depressive symptoms among internal migrants with TB are needed.…

Bocar Baya, Bassirou Diarra, Seydou Diabate, Bourahima Kone, Drissa Goita, Yeya dit Sadio Sarro, Keira Cohen, Jane L. Holl, Chad J. Achenbach, Mohamed Tolofoudie, Antieme Combo Georges Togo, Moumine Sanogo, Amadou Kone, Ousmane Kodio, Djeneba Dabitao, Nadie Coulibaly, Sophia Siddiqui, Samba Diop, William Bishai, Sounkalo Dao, Seydou Doumbia, Robert Leo Murphy, Souleymane Diallo and Mamoudou Maiga

Abstract. Mycobacterium africanum (MAF) is known to endemically cause up to 40–50% of all pulmonary TB in West Africa. The aim of this study was to compare MAF with Mycobacterium tuberculosis (MTB) with regard to time from symptom onset to TB diagnosis, and clinical and radiological characteristics. A cross-sectional study was conducted in Bamako, Mali, between August 2014 and July 2016. Seventy-seven newly diagnosed pulmonary TB patients who were naive to treatment were enrolled at Mali’s University Clinical Research Center. Sputum cultures were performed to confirm the diagnosis and spoligotyping to identify the mycobacterial strain. Univariate and multivariate analyses were used to identify factors associated with disease progression. Overall, the frequency of female patients was 25% in MAF infection and only 10.0% in MTB infection (OR = 2.9), and MAF was more represented in patients aged ≥ 30 years (57.1% versus 36.7% [OR = 2.3]). More MAF- than MTB-infected patients had a history of a prior TB contact (32.1% versus 14.3% [OR = 2.8]). The mean duration between cough onset and TB diagnosis was 111 days (∼3.7 months) for MAF and 72 days (∼2.4 months) for MTB (P = 0.007). In a multivariate regression, weight loss (body mass index [BMI] < 18.5 kg/m2) and cough duration (> 4 months) were strongly associated with MAF infection (OR = 5.20 [1.49–18.26], P = 0.010, and 4.74 [1.2–18.58], P = 0.02), respectively. Our data show that MAF infection was significantly associated with lower BMI and a longer time between symptom onset and TB diagnosis than MTB. This supports the concept that MAF infection may have slower disease progression and less severe cough symptoms than MTB.…

Kishor Kumar Paul, Yosra M.A. Alkabab, Md Mahfuzur Rahman, Shahriar Ahmed, Md Jobaer Amin, Md Delwar Hossain, Scott K. Heysell, Sayera Banu

Abstract Background Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrug-resistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations. Methods MDR-TB isolates from the 2007 national drug resistance survey of China were sub-cultured and examined for pyrazinamide susceptibility by BACTEC MGIT 960 method. pncA mutations were identified by sequencing. Characteristics associated with pyrazinamide resistance were analyzed using univariable and multivariable log-binominal regression. Results Of 401 MDR-TB isolates, 324 were successfully sub-cultured and underwent drug susceptibility testing. Pyrazinamide resistance was prevalent in 40.7% of samples, similarly among new and previously treated MDR-TB patients. Pyrazinamide resistance in MDR-TB patients was associated with lower age (adjusted OR 0.54; 95% CI, 0.34–0.87 for those aged ≧60 years compared to

Li R, Nordio F, Huang C, et al.

AbstractBackgroundEfficient contact investigation strategies are needed for the early diagnosis of TB disease and treatment of latent TB infections.MethodsBetween September 2009 and August 2012, we conducted a prospective cohort study in Lima, Peru in which we enrolled and followed 14,044 household contacts of adult pulmonary TB patients. We used information from a subset of this cohort to derive two clinical prediction tools that identify contacts of TB patients at elevated risk of progressing to active disease by training multivariable models that predict (1) co-prevalent TB among all household contacts and (2) one-year incident TB among adult contacts. We validated the models in a geographically distinct sub-cohort and compared the relative utilities of clinical decisions based on these tools to existing strategies.ResultsIn our cohort, 296 (2.1%) household contacts had co-prevalent TB and 145 (1.9%) adult contacts developed incident TB within one year of index patient diagnosis. We predicted co-prevalent disease using information that could be readily obtained at the time an index patient was diagnosed and predicted one-year incident TB by including additional contact-specific characteristics. The area under the receiver-operating-characteristic curves for co-prevalent TB and incident TB were 0.86 (95%CI 0.83 – 0.89) and 0.72 (0.67 – 0.77). These clinical tools give 5-10% higher relative utilities than existing methods.ConclusionsWe present two tools that identify household contacts at high risk for TB disease based on reportable information from patient and contacts alone. The performance of these tools is comparable to biomarkers that are both more costly and less feasible than this approach.

Rens N, Uyl-de Groot C, Goldhaber-Fiebert J, et al.

ABSTRACTBackgroundThere is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N-acetyltransferase-2 (NAT2) gene explain over 88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) is unknown.MethodsWe constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 USD), quality adjusted life years (QALYs), and incremental cost-effectiveness ratios.ResultsIn Brazil, PGT gained 19 discounted life years (23 QALYs) and cost $11,064 per 1,000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life years (19 QALYs) and cost $33,182 per 1,000 patients, a value of $1,780 per QALY gained. In India, PGT gained 20 life years (24 QALYs) and cost $13,195 per 1,000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita GDP in all three countries in 99% of simulations.ConclusionsIsoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

Abstract Background Recurrence of drug-resistant tuberculosis (DR-TB) after treatment occurs through relapse of the initial infection or reinfection by a new drug-resistant strain. Outbreaks of DR-TB in high burden regions present unique challenges in determining recurrence status for effective disease management and treatment. In the Republic of Moldova the burden of DR-TB is exceptionally high, with many cases presenting as recurrent. Methods We performed a retrospective analysis of Mycobacterium tuberculosis from Moldova to better understand the genomic basis of drug resistance and its effect on the determination of recurrence status in a high DR-burden environment. To do this we analyzed genomes from 278 isolates collected from 189 patients, including 87 patients with longitudinal samples. These pathogen genomes were sequenced using Illumina technology, and SNP panels were generated for each sample for use in phylogenetic and network analysis. Discordance between genomic resistance profiles and clinical drug-resistance test results was examined in detail to assess the possibility of mixed infection. Results There were clusters of multiple patients with 10 or fewer differences among DR-TB samples, which is evidence of person-to-person transmission of DR-TB. Analysis of longitudinally collected isolates revealed that many infections exhibited little change over time, though 35 patients demonstrated reinfection by divergent (number of differences > 10) lineages. Additionally, several same-lineage sample pairs were found to be more divergent than expected for a relapsed infection. Network analysis of the H3/4.2.1 clade found very close relationships among 61 of these samples, making differentiation of reactivation and reinfection difficult. There was discordance between genomic profile and clinical drug sensitivity test results in twelve samples, and four of these had low level (but not statistically significant) variation at DR SNPs suggesting low-level mixed infections. Conclusions Whole-genome sequencing provided a detailed view of the genealogical structure of the DR-TB epidemic in Moldova, showing that reinfection may be more prevalent than currently recognized. We also found increased evidence of mixed infection, which could be more robustly characterized with deeper levels of genomic sequencing.…

Abstract Background The Xpert® MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA) is a cartridge-based nucleic acid amplification assay for rapidly diagnosing tuberculosis and assessing antibiotic sensitivity. Although previous evidence supports the use of Xpert for diagnosing extrapulmonary tuberculosis (EPTB) in adults, information regarding the accuracy of Xpert for EPTB only in children is lacking. This meta-analysis was performed to assess the accuracy of Xpert for detecting EPTB in children. Methods We searched the MEDLINE, EMBASE, and Cochrane Infectious Diseases Group Specialized Register from January 1, 2010 to July 16, 2019 for studies of the diagnostic performance wherein Xpert was analyzed against cultures or composite reference standards for

Jing, W., Zong, Z., Tang, B., Wang, J., Zhang, T., Wen, S., Xue, Y., Chu, N., Zhao, W., Huang, H.

Blood concentration of isoniazid (INH) is evidently affected by N-acetyltransferase-2 (NAT2) polymorphism, an enzyme that is primarily responsible for the tri-modal (i.e. fast, intermediate and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of uniform INH dosage in tuberculosis (TB) patients. Although, acetylator-specific INH dosing has long been suggested, their well-recognized dosages remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5-6 h after morning administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%) and 19 (21.3%) were fast, intermediate and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator-status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety Cmax serum concentration (3-6 μg/mL), the reported area under the concentration-time curve to infinity (AUC(0,)) (≥ 10.52μg/ml per hour), and the 2-h INH serum concentrations (≥ 2.19 μg/ml) that associated with the strongest early bactericidal activity. The optimal dosages, targeting different indicators, varied between 700-900 mg/day, 500-600 mg/day and 300 mg/day for rapid, intermediate and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time which suggested an approximated 800 mg/day, 500 mg/day or 300 mg/day dose for fast, intermediate and slow acetylators, respectively, after tradeoff between efficacy and the occurrence of side effects.…

Zhang, N., Strydom, N., Tyagi, S., Soni, H., Tasneen, R., Nuermberger, E. L., Savic, R. M.

TB drug, regimen and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics are essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection in BALB/c and athymic nude mice over time, which consisted of bacterial replication, bacterial death and adaptive immune effects. The adaptive immune effect was best described by a sigmoidal function on both bacterial load and incubation time. Applications to demonstrate the utility of this baseline model showed 1) the important influence of the adaptive immune response on PZA drug efficacy; 2) a persistent adaptive immune effect in mice relapsing after chemotherapy cessation; and 3) the protective effect of vaccines after M. tuberculosis challenge. These findings demonstrate the utility of our model for describing M. tuberculosis infection and corresponding adaptive immune dynamics for evaluating the efficacy of TB drugs, regimens and vaccines.…

Daniël Jacobus, Van Hoving,; Andre P, Kenge,; Gary, Maartens,; Graeme, Meintjes,

Background: The performance of point-of-care ultrasound (PoCUS) to diagnose HIV-associated tuberculosis has not been evaluated in large prospective studies. We determined the diagnostic accuracy of individual PoCUS features, performed an external validation of the Focused Assessment with Sonography for HIV/TB (FASH) protocol, and determined independent PoCUS predictors of HIV-associated tuberculosis appropriate for use by emergency center practitioners. Setting: A cross-sectional diagnostic study was performed at the emergency center of Khayelitsha Hospital (Cape Town, South Africa). Methods: HIV-positive adults with the suspicion of having tuberculosis were prospectively enrolled. PoCUS was performed according to a standardized protocol. Reference standard was the detection of Mycobacterium tuberculosis using Xpert MTB/RIF or culture. Results: We enrolled 414 participants: 243 female, median age 36 years, median CD4 cell count 86/mm3, and 172 (42%) had tuberculosis. Sensitivity and specificity were: ≥1 individual PoCUS feature (73% (95%CI 65-79), 54% (95%CI 47-60)), FASH protocol (71% (95%CI 64-78), 57% (95%CI 50-63)). Independent PoCUS predictors identified were intra-abdominal lymphadenopathy of any size (aDOR 3.7 (95%CI 2.0–6.7)), ascites (aDOR 3.0 (95%CI 1.5–5.7)), and pericardial effusion of any size (aDOR 1.9 (95%CI 1.2–3.0)). The c-statistic for the derivation model was 0.680 (95% CI 0.631 – 0.729), compared to 0.630 (95% CI 0.576-0.684) of the FASH protocol. Two or more independent PoCUS predictors had 91% (95%CI 86-94) specificity. Conclusion: The presence of two or more independent PoCUS predictors (intra-abdominal lymphadenopathy, ascites, pericardial effusion) had moderate discrimination for HIV-associated tuberculosis in patients presenting to the emergency center. Corresponding author: DJ van Hoving; Division of Emergency Medicine, PO Box 241, Cape Town, 8000. Tel: +27 0219389804; nvhoving@sun.ac.za Conflicts of Interest and Source of Funding: GrM was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). GaM was supported by NRF incentive funding (UID: 85810). DJvH received a Mindray ultrasound machine from the RCA division of Ascendis Medical to use in a part of the study. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. For the remaining author none were declared. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Meng-Rui Lee, Hung-Ling Huang, Lun-Che Chen, Han-Ching Yang, Jen-Chung Ko, Meng-Hsuan Cheng, Inn-Wen Chong, Li-Na Lee, Jann-Yuan Wang, George Dimopoulos

Chronic pulmonary aspergillosis (CPA) is an emerging global disease with tuberculosis (TB) being the most important risk factor. Epidemiologic data on the seroprevalence of Aspergillus IgG and prevalence of CPA in different areas, especially in country with intermediate burden of TB, are lacking.

Abstract Background In most developing countries, smear-negative pulmonary TB (SNPT) often gets missed from the diagnosis of consideration, though it accounts 30–65% of total PTB cases, due to deficient or inaccessible molecular diagnostic modalities. Methods The cross-sectional study enrolled 360 patients with clinical-radiological suspicion of SNPT in Tribhuvan University Teaching Hospital (TUTH). The patient selection was done as per the algorithm of Nepal’s National Tuberculosis Program (NTP) for Xpert MTB/RIF testing. Participants’ demographic and clinical information were collected using a pre-tested questionnaire. The specimens were collected, processed directly for Xpert MTB/RIF test according to the manufacturer’s protocol. The same samples were stained using the Ziehl-Neelsen technique then observed microscopically. Both findings were interpreted; rifampicin-resistant, if obtained, on Xpert testing was confirmed with a Line Probe Assay. Result Of 360 smear-negative sputum samples analyzed, 85(23.61%) found positive while 3(0.8%) of them were rifampicin resistance. The infection was higher in males, i.e. 60(25.3%) compared to female 25(20.3%). The age group, > 45(nearly 33%) with median age 42 ± 21.5, were prone to the infection. During the study period, 4.6% (515/11048) sputum samples were reported as smear-positive in TUTH. Consequently, with Xpert MTB/RIF assay, the additional case 16.5% (n = 85/515) from smear-negative presumptive TB cases were detected. Among the most occurring clinical presentations, cough and chest pain were positively associated with SNPT. While upper lobe infiltrates (36.4%) and pleural effusion (40.4%) were the most peculiar radiological impression noted in PTB patient. 94 multi-drug resistant(MDR) suspected cases were enrolled; of total suspects, 29(30.8%) samples were rifampicin sensitive, 1(1.06%) indeterminate, 3(3.19%) rifampicin-resistant while remaining of them were negative. 2(2.2%) MDR cases were recovered from the patient with a previous history of ATT, of total 89 previously treated cases enrolled However, a single rifampicin-resistant from the new suspects. Conclusion With an application of the assay, the additional cases, missed with smear microscopy, could be sought and exact incidence of the diseases could be revealed.…

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.