Persistent High Incidence of Tuberculosis in Immigrants in a Low-Incidence Country

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

Tracing <i>Mycobacterium tuberculosi</i>s transmission by whole genome sequencing in a high incidence setting:A retrospective population-based study in East Greenland

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

Migrant tuberculosis: the extent of transmission in a low burden country

<p>Abstract</p> <p>Background</p> <p>Human migration caused by political unrest, wars and poverty is a major topic in international health. Infectious diseases like tuberculosis follow their host, with potential impact on both the migrants and the population in the recipient countries. In this study, we evaluate <it>Mycobacterium tuberculosis </it>transmission between the national population and migrants in Denmark.</p> <p>Methods</p> <p>Register study based on IS<it>6110</it>-RFLP results from nationwide genotyping of tuberculosis cases during 1992 through 2004. Cases with 100% identical genotypes were defined as clustered and part of a transmission chain. Origin of clusters involving both Danes and migrants was defined as Danish/migrant/uncertain. Subsequently, the proportion of cases likely infected by the "opposite" ethnic group was estimated.</p> <p>Results</p> <p>4,631 cases were included, representing 99% of culture confirmed cases during 1992 through 2004. Migrants contributed 61.6% of cases. Up to 7.9% (95% CI 7.0-8.9) of migrants were infected by Danes. The corresponding figure was 5.8% (95% CI 4.8-7.0) for Danes. Thus, transmission from Danes to migrants occurred up to 2.5 (95% CI 1.8-3.5) times more frequent than vice versa (OR = 1). A dominant strain, Cluster-2, was almost exclusively found in Danes, particular younger-middle-aged males.</p> <p>Conclusions</p> <p>Transmission between Danes and migrants is limited, and risk of being infected by the "opposite" ethnic group is highest for migrants. TB-control efforts should focus on continues micro-epidemics, e.g. with Cluster-2 in Danes, prevention of reactivation TB in high-risk migrants, and outbreaks in socially marginalized migrants, such as Somalis and Greenlanders. Fears that TB in migrants poses a threat for resident Danes seem exaggerated and unjustified. We believe this to be true for other low incidence countries as well.</p

Evidence for waning of latency in a cohort study of tuberculosis

<p>Abstract</p> <p>Background</p> <p>To investigate how the risk of active tuberculosis disease is influenced by time since original infection and to determine whether the risk of reactivation of tuberculosis increases or decreases with age.</p> <p>Methods</p> <p>Cohort analysis of data for the separate ten year birth cohorts of 1876-1885 to 1959-1968 obtained from Statistics Norway and the National Tuberculosis Registry. These data were used to calculate the rates and the changes in the rates of bacillary (or active) tuberculosis. Data on bacillary tuberculosis for adult (20+) age groups were obtained from the National Tuberculosis Registry and Statistics Norway from 1946 to 1974. Most cases during this period arose due to reactivation of remote infection. Participants in this part of the analysis were all reported active tuberculosis cases in Norway from 1946 to 1974 as recorded in the National Tuberculosis Registry.</p> <p>Results</p> <p>Tuberculosis decreased at a relatively steady rate when following individual birth cohorts, but with a tendency of slower decline as time passed since infection. A mean estimate of this rate of decline was 57% in a 10 year period.</p> <p>Conclusions</p> <p>The risk of reactivation of latent tuberculosis decreases with age. This decline may reflect the rate at which latent tuberculosis is eliminated from a population with minimal transmission of tubercle bacilli. A model for risk of developing active tuberculosis as a function of time since infection shows that the rate at which tuberculosis can be eliminated from a society can be quite substantial if new infections are effectively prevented. The findings clearly indicate that preventative measures against transmission of tuberculosis will be the most effective. These results also suggest that the total population harbouring live tubercle bacilli and consequently the future projection for increased incidence of tuberculosis in the world is probably overestimated.</p

Long-term risk of tuberculosis among migrants according to migrant status: a cohort study.

BACKGROUND: The majority of tuberculosis (TB) cases in low-incidence countries occur in migrants. Only few studies have assessed the long-term TB risk in migrants after immigration, and datasets have not considered this across a range of diverse migrant groups. This nationwide study aimed to investigate long-term TB risk among migrants according to migrant status and region of origin. METHODS: This cohort study included all migrants aged  ≥ 18 years who obtained residence in Denmark from 1993 to 2015, with a mean follow-up of 10.8 years [standard deviation (SD) 7.3]. Migrants were categorized based on legal status of residence and region of origin. Incidence rates (IR) and rate ratios (IRR) were estimated by Poisson regression. RESULTS: A total of 142 314 migrants were included. Across all migrants, the TB risk was highest during year 1 of residence (IR 275/100 000 person-years; 95% CI 249-305) followed by a gradual decline, though TB risk remained high for over a decade. Compared with the Danish-born population, the IRRs after 7-8 years were particularly higher among former asylum seekers (IRR 31; 95% CI 20-46), quota refugees (IRR 31; 95% CI 16-71), and family-reunified with refugees (IRR 22; 95% CI 12-44). Sub-Saharan African migrants also experienced elevated risk (IRR 75; 95% CI 51-109). The proportion of migrants with pulmonary TB was 52.4%. CONCLUSION: All migrant groups experienced an initial high TB risk, but long-term risk remained high in key migrant groups. Most European countries focus TB screening on or soon after arrival. Our study suggests that approaches to TB screening should be adapted, with migrant populations benefiting from long-term access to preventive health services

First-in-Man Open Clinical Trial of a Combined rdESAT-6 and rCFP-10 Tuberculosis Specific Skin Test Reagent

Tuberculin is still the only available skin test reagent for the diagnosis of mycobacterial infection. The product has a remarkable sensitivity, but poor specificity. Previous studies, including two human phase I clinical trials, have indicated that rdESAT-6 has a potential as an improved skin test reagent. Animal studies have shown that the sensitivity may be increased by inclusion of the genetically related CFP-10 antigen in the preparation without loosing specificity.In this study a Lactococcus fermented, recombinant skin test reagent consisting of a 1ratio1 wt/wt of rdESAT-6 and CFP-10 was manufactured according to GMP standards and tested for the first time in 42 healthy adult volunteers. The two doses of 0.01 microg or 0.1 microg were injected intradermally by the Mantoux technique with 6 or 12 weeks interval. No serious adverse events and only mild adverse reactions were reported. The reagent elicited a positive skin test reaction after the first injection in one participant, who most likely was latently infected with M. tuberculosis as indicated by an appreciable IFN gamma response just below the Quantiferon(R) cut-off level at the screening visit. None of the remaining participants in the four groups had any skin test reactions and sensitisation by the reagent could therefore be excluded.The investigational skin test reagent rdESAT-6 and CFP-10 appeared safe and non-sensitising in this first-in-man clinical trial in human volunteers and can now be tested in larger clinical trials involving individuals with latent M. tuberculosis infection or active TB disease.ClinicalTrials.gov NCT00793702

First insights into the phylogenetic diversity of Mycobacterium tuberculosis in Nepal

BACKGROUND: Tuberculosis (TB) is a major public health problem in Nepal. Strain variation in Mycobacterium tuberculosis may influence the outcome of TB infection and disease. To date, the phylogenetic diversity of M. tuberculosis in Nepal is unknown. METHODS AND FINDINGS: We analyzed 261 M. tuberculosis isolates recovered from pulmonary TB patients recruited between August 2009 and August 2010 in Nepal. M. tuberculosis lineages were determined by single nucleotide polymorphisms (SNP) typing and spoligotyping. Drug resistance was determined by sequencing the hot spot regions of the relevant target genes. Overall, 164 (62.8%) TB patients were new, and 97 (37.2%) were previously treated. Any drug resistance was detected in 50 (19.2%) isolates, and 16 (6.1%) were multidrug-resistant. The most frequent M. tuberculosis lineage was Lineage 3 (CAS/Delhi) with 106 isolates (40.6%), followed by Lineage 2 (East-Asian lineage, includes Beijing genotype) with 84 isolates (32.2%), Lineage 4 (Euro-American lineage) with 41 (15.7%) isolates, and Lineage 1 (Indo-Oceanic lineage) with 30 isolates (11.5%). Based on spoligotyping, we found 45 different spoligotyping patterns that were previously described. The Beijing (83 isolates, 31.8%) and CAS spoligotype (52, 19.9%) were the dominant spoligotypes. A total of 36 (13.8%) isolates could not be assigned to any known spoligotyping pattern. Lineage 2 was associated with female sex (adjusted odds ratio [aOR] 2.58, 95% confidence interval [95% CI] 1.42-4.67, p = 0.002), and any drug resistance (aOR 2.79; 95% CI 1.43-5.45; p = 0.002). We found no evidence for an association of Lineage 2 with age or BCG vaccination status. CONCLUSIONS: We found a large genetic diversity of M. tuberculosis in Nepal with representation of all four major lineages. Lineages 3 and 2 were dominating. Lineage 2 was associated with clinical characteristics. This study fills an important gap on the map of the M. tuberculosis genetic diversity in the Asian reg

Genomic Diversity of Mycobacterium tuberculosis Complex Strains in Cantabria (Spain), a Moderate TB Incidence Setting

Background Tuberculosis (TB) control strategies are focused mainly on prevention, early diagnosis, compliance to treatment and contact tracing. The objectives of this study were to explore the frequency and risk factors of recent transmission of clinical isolates of Mycobacterium tuberculosis complex (MTBC) in Cantabria in Northern Spain from 2012 through 2013 and to analyze their clonal complexity for better understanding of the transmission dynamics in a moderate TB incidence setting. Methods DNA from 85 out of 87 isolates from bacteriologically confirmed cases of MTBC infection were extracted directly from frozen stocks and genotyped using the mycobacterial interspersed repetitive units-variable number tandem repeat (MIRU-VNTR) method. The MIRUVNTRplus database tool was used to identify clusters and lineages and to build a neighbor joining (NJ) phylogenetic tree. In addition, data were compared to the SITVIT2 database at the Pasteur Institute of Guadeloupe. Results The rate of recent transmission was calculated to 24%. Clustering was associated with being Spanish-born. A high prevalence of isolates of the Euro-American lineage was found. In addition, MIRU-VNTR profiles of the studied isolates corresponded to previously found MIRU-VNTR types in other countries, including Spain, Belgium, Great Britain, USA, Croatia, South Africa and The Netherlands. Six of the strains analyzed represented clonal variants. Conclusion Transmission of MTBC is well controlled in Cantabria. The majority of TB patients were born in Spain. The population structure of MTBC in Cantabria has a low diversity of major clonal lineages with the Euro-American lineage predominating

Clinical presentation, demographics and outcome of Tuberculosis (TB) in a low incidence area: a 4-year study in Geneva, Switzerland

<p>Abstract</p> <p>Background</p> <p>The incidence of tuberculosis (TB) in developed countries has decreased since the 1990s, reflecting worldwide efforts to identify and treat TB according to WHO recommendations. However TB remains an important public health problem in industrialized countries with a high proportion of cases occurring among subjects originating from high prevalence countries. The aim of this study was to describe clinical and social characteristics of patients with TB and their outcome in a low incidence area with a high immigration rate.</p> <p>Methods</p> <p>Four-year retrospective study based on a computerized database and subsequent review of medical records of all patients with TB followed at the outpatient section of the Division of Pulmonary Diseases, Geneva University Hospital, Switzerland.</p> <p>Results</p> <p>252 patients (84% foreigners, 25% asylum seekers) aged 38 ± 19 yrs were studied (11% co-infected with HIV). TB was intrapulmonary (TBP) in 158 cases (63%), extrapulmonary (TBE) in 137 (54%), and both in 43 cases (17%). TBP was smear (S)+/culture (C)+ in 59%, S-/C+ in 37%, S-/C- in 4%. Smoking was significantly associated with cavitary disease.</p> <p>Time from onset of symptoms to diagnosis was 2.1 ± 3.1 months. Initially, 10% were asymptomatic; 35% had no general symptoms. Despite systematic sputum analysis (induced or spontaneous), TBP was confirmed only by bronchoscopy in 38 subjects (24% of TBP). Side effects requiring changes in treatment occurred in 38 cases (11%).</p> <p>Treatment was completed in 210 (83%) patients. In 42 cases, follow up was unsuccessful; causes were: failure (n = 2; 0.8%), defaulters (n = 8; 3%), transfer out (n = 28; 11%) and death (n = 4; 1.6%). Relapse rate was 0.24 per 100 patient-years. Considering S+ TBP only, success rate was 87%.</p> <p>Conclusion</p> <p>TB in our area is predominantly a disease of young foreign-born subjects. Smoking appears as a possible risk factor for cavitary TBP. Time to diagnosis remains long. Compliance to treatment is satisfactory. Success rate for S+ TBP is within WHO objectives.</p

The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.

BACKGROUND: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. METHODS AND FINDINGS: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. CONCLUSIONS: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached