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AIM: The purpose of this viewpoint is to summarize the advantages and constraints of the tools and strategies available for reducing the annual incidence of tuberculosis (TB) by implementing the World Health Organization (WHO) End TB Strategy and the linked WHO TB Elimination Framework, with special reference to Oman. METHODS: The case-study was built based on the presentations and discussions at an international workshop on TB elimination in low incidence countries organized by the Ministry of Health, Oman, which took place from September 5 to September 7, 2019, and supported by the WHO and European Society of Clinical Microbiology and Infectious Diseases (ESCMID). RESULTS: Existing tools were reviewed, including the screening of migrants for latent TB infection (LTBI) with interferon-gamma release assays, clinical examination for active pulmonary TB (APTB) including chest X-rays, organization of laboratory services, and the existing centres for mandatory health examination of pre-arrival or arriving migrants, including examination for APTB. The need for public-private partnerships to handle the burden of screening arriving migrants for active TB was discussed at length and different models for financing were reviewed. CONCLUSIONS: In a country with a high proportion of migrants from high endemic countries, screening for LTBI is of high priority. Molecular typing and the development of public-private partnerships are needed.

BACKGROUND: Tuberculous lymphadenitis (TBLA) is the most common extrapulmonary manifestation of tuberculosis (TB), often claimed to be reactivation. We aimed to describe the epidemiology of TBLA in Denmark, as it has not previously been investigated specifically although extrapulmonary TB has been associated with an increased long-term mortality and delays in the diagnosis. METHODS: Register-based study of all patients notified with TBLA in Denmark from 2007 through 2016 utilizing six different nationwide registers. Patients were identified through the national TB surveillance register, and the diagnosis evaluated based on microbiology, pathology and/or clinical assessment. RESULTS: In total, 13.5% (n = 489) of all TB patients in Denmark had TBLA with annual proportions from 9.4 to 15.7%. Most patients were immigrants between 25-44 years. Incidence rates ranged from as high as 1,014/100,000 for Nepalese citizens to as a low as 0.06/100,000 for Danes. Danes had a significant higher median age and significant more risk factors and comorbidities, as well as an increased overall mortality, compared with immigrants (p<0.05). A significant and much higher proportion of unique MIRU-VNTR genotypes were seen among TBLA patients compared to other TB manifestations. CONCLUSION: In Denmark, TBLA is a common manifestation of TB, especially in young immigrants from high-incidence countries. In Danes, it is a rare disease manifestation and associated with higher morbidity and mortality. To our knowledge, this is the first study suggesting that TBLA is predominantly associated with reactivation of latent TB infection based on genotyping although this remains to be clarified.

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SETTING: The objective of tuberculosis (TB) screening in low-incidence countries is to identify TB patients earlier, ideally to improve health outcomes and reduce Mycobacterium tuberculosis transmission. In this retrospective study, we compare hospitalisation (morbidity) and smear positivity rates (infectiousness) in TB patients identified through active case finding (ACF) with patients identified through passive case finding (PCF). METHODS : ACF patients were identified by screening socially marginalised persons or through contact investigation. Logistic regression was used to model the associations between case-finding group (ACF/PCF) and hospitalisation, and between case-finding group and smear positivity rates. RESULT S : A total of 108 patients were identified through ACF and 332 through PCF. Thirty (27.8%) ACF patients and 153 (46.1%) PCF patients were hospitalised. In the adjusted models, ACF patients (OR 0.24, P < 0.001) and ACF subgroups identified using mobile X-ray screening, spot sputum culture screening and contact investigation were significantly less likely to be hospitalised than PCF patients. Thirty-one (34.4%) ACF patients and 127 (50.4%) PCF patients were smearpositive. ACF patients (OR 0.30, P < 0.001) and ACF subgroups identified through contact investigation and spot sputum culture screening were less likely to be smear-positive than PCF patients. CONCLUS IONS : These findings suggest that ACF reduces morbidity and infectiousness among TB patients, thereby potentially improving health outcomes and reducing transmission of M. tuberculosis.

In East Greenland, a dramatic increase of tuberculosis (TB) incidence has been observed in recent years. Classical genotyping suggests a genetically similar Mycobacterium tuberculosis (Mtb) strain population as cause, however, precise transmission patterns are unclear. We performed whole genome sequencing (WGS) of Mtb isolates from 98% of culture-positive TB cases through 21 years (n = 182) which revealed four genomic clusters of the Euro-American lineage (mainly sub-lineage 4.8 (n = 134)). The time to the most recent common ancestor of lineage 4.8 strains was found to be 100 years. This sub-lineage further diversified in the 1970s, and massively expanded in the 1990s, a period of lowered TB awareness in Greenland. Despite the low genetic strain diversity, WGS data revealed several recent short-term transmission events in line with the increasing incidence in the region. Thus, the isolated setting and the uniformity of circulating Mtb strains indicated that the majority of East Greenlandic TB cases originated from one or few strains introduced within the last century. Thereby, the study shows the consequences of even short interruptions in TB control efforts in previously TB high incidence areas and demonstrates the potential role of WGS in detecting ongoing micro epidemics, thus guiding public health efforts in the future.

Culturing before DNA extraction represents a major time-consuming step in whole-genome sequencing of slow-growing bacteria, such as Mycobacterium tuberculosis. We report a workflow to extract DNA from frozen isolates without reculturing. Prepared libraries and sequence data were comparable with results from recultured aliquots of the same stocks.

Transmission of Mycobacterium tuberculosis continues at high rates among Greenland-born persons in Greenland and Denmark, with 203 and 450 notified cases per 105 population, respectively, in the year 2010. Here, we document that the predominant M. tuberculosis outbreak strain C2/1112-15 of Danish origin has been transmitted to Greenland-born persons in Denmark and subsequently to Greenland, where it is spreading at worrying rates and adding to the already heavy tuberculosis burden in this population group. It is now clear that the C2/1112-15 strain is able to gain new territories using a new population group as the "vehicle." Thus, it might have the ability to spread even further, considering the potential clinical consequences of strain diversity such as that seen in the widely spread Beijing genotype. The introduction of the predominant M. tuberculosis outbreak strain C2/1112-15 into the Arctic circumpolar region is a worrying tendency which deserves attention. We need to monitor whether this strain already has, or will, spread to other countries.

Mycobacterium simiae is a slow-growing mycobacteria that in rare cases can cause chronic pulmonary infection. We report the first case of lung transplantation in a patient with active M simiae infection at the time of transplantation. A 56-year-old immunocompetent nonsmoking woman underwent bilateral lung transplantation for end-stage idiopathic bronchiectasis and chronic M simiae infection. The disease proved manageable on a regimen of clarithromycin, moxifloxacin, and cotrimoxazole with a successful outcome 1-year posttransplantation. There is increasing evidence that nontuberculous mycobacterium infection should no longer be an absolute contraindication for lung transplantation.

Molecular genotyping of Mycobacterium tuberculosis has proved to be a powerful tool in tuberculosis surveillance, epidemiology, and control. Based on results obtained through 15 years of nationwide IS6110 restriction fragment length polymorphism (RFLP) genotyping of M. tuberculosis cases in Denmark, a country on the way toward tuberculosis elimination, we discuss M. tuberculosis transmission dynamics and point to areas for control interventions. Cases with 100% identical genotypes (RFLP patterns) were defined as clustered, and a cluster was defined as cases with an identical genotype. Of 4,601 included cases, corresponding to 76% of reported and 97% of culture-verified tuberculosis cases in the country, 56% were clustered, of which 69% were Danes. Generally, Danes were more often in large clusters (= 50 persons), older (mean age, 45 years), and male (male/female ratio, 2.5). Also, Danes had a higher cluster frequency within a 2-year observation window (60.8%), and higher clustering rate of new patterns over time, compared to immigrants. A dominant genotype, cluster 2, constituted 44% of all clustered and 35% of all genotyped cases. This cluster was primarily found among Danish males, 30 to 59 years of age, often socially marginalized, and with records of alcohol abuse. In Danes, cluster 2 alone was responsible for the high cluster frequency level. Immigrants had a higher incidence of clustered tuberculosis at a younger age (0 to 39 years). To achieve tuberculosis elimination in Denmark, high-risk transmission environments, like the cluster 2 environment in Danes, and specific transmission chains in immigrants in the capital area, e.g., homeless/socially marginalized Somalis/Greenlanders, often with alcohol abuse, must be targeted, including groups with a high risk of reactivation.

Denmark, a country with a low-incidence of tuberculosis (TB).

Udgivelsesdato: 2009

OBJECTIVE: To describe the tuberculosis (TB) epidemiology in Greenland in 1998-2002 and to identify possible obstacles for reducing the TB incidence. STUDY DESIGN/METHODS: TB notification data were collected from the annual reports of the Chief Medical Officer, and culture verification data were collected from the International Reference Laboratory of Mycobacteriology at Statens Serum Institut, Denmark. RESULTS: The TB incidence in Greenland reached a peak of 185/100,000 in 2001. In 1999-2001, the majority of cases were related to an outbreak in the Southern districts. In 1998-2002, 0.5% drug-resistance was found among patients living in Greenland in contrast to 13.1% drug-resistance found previously among Inuit patients in Denmark. In 1998-2001, microscopy positive cases made up 65% of all culture confirmed cases and DNA subtyping demonstrated the emergence of Mycobacterium tuberculosis strains that were previously infrequently found. CONCLUSION: It is important to eliminate factors that fuel the epidemic and to improve general living conditions in Greenland. Treatment seems effective as limited drug-resistance is detected. TB reduction will therefore depend on early detection of active disease and thorough contact tracing. Greenland will face a pool of persons latently infected some of whom will progress to active disease. Sufficient resources need to be allocated for TB control in the years to come.

The subject of the investigation is a group of 27 strains of Mycobacterium tuberculosis isolated in 2000 from prisoners with the diagnosis of tuberculosis, 19 Czechs and 8 foreigners (mean age 41 and 35 years resp.). The molecular-epidemiological examination of these strains was made using the RFLP fingerprint technique (Restriction Fragment Length Polymorphism) with evidence of the insertive sequence IS6110 and the technique of spoligotyping, based on detection of hybridization of spacer oligonucleotides. DNA fingerprinting revealed a high polymorphism in the number and molecular weight of sequence IS6110 which is common in Czech and other European strains of M. tuberculosis. All strains with the exception of two had mutually different fingerprint profiles. In the two with identical fingerprints probably a duplicit examination of the same material was involved which occurred by mistake during transport or in the laboratory. The fingerprint method thus did not prove interhuman transmission of tuberculosis between the examined prisoners. The technique of spoligotyping revealed the finding of genotype Beijing M. tuberculosis in two sick prisoners, one Algerian and one Albanese, and in one Czech prisoner. This genotype found in a high percentage of patients in southeastern Asia and in migrants from this area was detected for the first time in the Czech Republic. The findings are evidence of a satisfactory standard of the programme of tuberculosis control in the Czech prison system and at the same time draw attention to the potential possibility of the spread of tuberculosis from migrants coming from areas with a high prevalence.

SETTING: Predominant genotypes of Mycobacterium tuberculosis include the Beijing family, which has caused large tuberculosis outbreaks and has been associated with increased virulence and multidrug resistance (MDR). OBJECTIVE: To search for the Beijing genotype among Latvian MDR patients to characterise their DNA isolates at the molecular level. DESIGN: MDR isolates were spoligotyped and tested for gene mutations by automatic nucleotide sequencing. RESULTS: Of 109 isolates examined, 95 were located in six clusters of 2 to 63 isolates each. The 63 isolates in the largest cluster had an identical pattern corresponding to the Beijing genotype. The remaining isolates were of a non-Beijing genotype and formed another large group whose similarity ranged from 72% to 100%. Mutations in the rpoB and katG genes were compared in the Beijing and non-Beijing strains. In both groups, the rpoB gene mutations predominated in codons S531L (52.2%) and D516V (14.7%). Double mutations in the rpoB gene were observed in 8.2% of the isolates, most of them located among Beijing-type isolates. The katG gene mutation S315T (98.4%) was prevalent among all isolates. CONCLUSION: Molecular analysis of MDR isolates of M. tuberculosis demonstrates that the Beijing genotype, most likely due to recent transmission, is prevalent in Latvia among MDR patients and that this genotype can be associated with double mutations.

The subject of the investigation is a group of 27 strains of Mycobacterium tuberculosis isolated in 2000 from prisoners with the diagnosis of tuberculosis, 19 Czechs and 8 foreigners (mean age 41 and 35 years resp.). The molecular-epidemiological examination of these strains was made using the RFLP fingerprint technique (Restriction Fragment Length Polymorphism) with evidence of the insertive sequence IS6110 and the technique of spoligotyping, based on detection of hybridization of spacer oligonucleotides. DNA fingerprinting revealed a high polymorphism in the number and molecular weight of sequence IS6110 which is common in Czech and other European strains of M. tuberculosis. All strains with the exception of two had mutually different fingerprint profiles. In the two with identical fingerprints probably a duplicit examination of the same material was involved which occurred by mistake during transport or in the laboratory. The fingerprint method thus did not prove interhuman transmission of tuberculosis between the examined prisoners. The technique of spoligotyping revealed the finding of genotype Beijing M. tuberculosis in two sick prisoners, one Algerian and one Albanese, and in one Czech prisoner. This genotype found in a high percentage of patients in southeastern Asia and in migrants from this area was detected for the first time in the Czech Republic. The findings are evidence of a satisfactory standard of the programme of tuberculosis control in the Czech prison system and at the same time draw attention to the potential possibility of the spread of tuberculosis from migrants coming from areas with a high prevalence.

Spacer oligonucleotide typing (spoligotyping) is widely used for differentiation of bacteria of the Mycobacterium tuberculosis complex. However, the absence of any standardised method for concise description of spoligotypes makes it difficult to compare the results from different laboratories. This paper describes unambiguous, interconvertible systems for the designation of spoligotype patterns, the adoption of which will be beneficial to mycobacterial research.

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.

Increased rates of multidrug-resistant (MDR) tuberculosis (TB) has been reported from countries close to Denmark. This study evaluated the incidence of drug resistance in Denmark in order to determine the magnitude of the problem. Susceptibility testing was performed in isolates from 85.4% of all notified patients during 1991-1998. Epidemiological information was retrieved from the mandatory notification forms. Total drug resistance remained largely constant, although a minor increase was observed in 1997-1998. Monoresistance was observed in 7.3%, of the isolates. Among 3.6% polyresistant isolates, resistance to isoniazid and streptomycin accounted for 2.8%, whereas MDR accounted for 0.5%. The MDR strains displayed different restriction fragment length polymorphism (RFLP) patterns, and no matches were identified in the international MDR database. Drug resistance in untreated Danes and foreigners were 5.9% and 14.6%, respectively. Among Danes and foreigners with previous TB, 6.2% and 22.7% had drug resistance, respectively. Increased drug-resistance was found among untreated Danes aged 25-54 yrs mainly due to a single isoniazid and streptomycin-resistant RFLP-cluster. Among all patients with isoniazid and streptomycin-resistance, 77.0% had clustered strains. In conclusion, although drug resistance among untreated Danes was close to the rate estimated in good national programmes, close monitoring is needed in future years, as active transmission of isoniazid- and streptomycin-resistant Mycobacterium tuberculosis was demonstrated.

In Western Europe, awareness of tuberculous lymphadenitis (TLA) has declined. This report describes a patient who had suspected sarcoidosis for 3.5 y, who eventually died from miliary tuberculosis due to delay in diagnosis. The report includes a discussion of the differential diagnosis of TLA and sarcoidosis.