A cluster of multidrug-resistant Mycobacterium tuberculosis among patients arriving in Europe from the Horn of Africa: a molecular epidemiological study.

BACKGROUND: The risk of tuberculosis outbreaks among people fleeing hardship for refuge in Europe is heightened. We describe the cross-border European response to an outbreak of multidrug-resistant tuberculosis among patients from the Horn of Africa and Sudan. METHODS: On April 29 and May 30, 2016, the Swiss and German National Mycobacterial Reference Laboratories independently triggered an outbreak investigation after four patients were diagnosed with multidrug-resistant tuberculosis. In this molecular epidemiological study, we prospectively defined outbreak cases with 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) profiles; phenotypic resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, and capreomycin; and corresponding drug resistance mutations. We whole-genome sequenced all Mycobacterium tuberculosis isolates and clustered them using a threshold of five single nucleotide polymorphisms (SNPs). We collated epidemiological data from host countries from the European Centre for Disease Prevention and Control. FINDINGS: Between Feb 12, 2016, and April 19, 2017, 29 patients were diagnosed with multidrug-resistant tuberculosis in seven European countries. All originated from the Horn of Africa or Sudan, with all isolates two SNPs or fewer apart. 22 (76%) patients reported their travel routes, with clear spatiotemporal overlap between routes. We identified a further 29 MIRU-VNTR-linked cases from the Horn of Africa that predated the outbreak, but all were more than five SNPs from the outbreak. However all 58 isolates shared a capreomycin resistance-associated tlyA mutation. INTERPRETATION: Our data suggest that source cases are linked to an M tuberculosis clone circulating in northern Somalia or Djibouti and that transmission probably occurred en route before arrival in Europe. We hypothesise that the shared mutation of tlyA is a drug resistance mutation and phylogenetic marker, the first of its kind in M tuberculosis sensu stricto. FUNDING: The Swiss Federal Office of Public Health, the University of Zurich, the Wellcome Trust, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), the Medical Research Council, BELTA-TBnet, the European Union, the German Center for Infection Research, and Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG).

Systematic review on tuberculosis transmission on aircraft and update of the European Centre for Disease Prevention and Control risk assessment guidelines for tuberculosis transmitted on aircraft (RAGIDA-TB).

As a setting for potential tuberculosis (TB) transmission and contact tracing, aircraft pose specific challenges. Evidence-based guidelines are needed to support the related-risk assessment and contact-tracing efforts. In this study evidence of TB transmission on aircraft was identified to update the Risk Assessment Guidelines for TB Transmitted on Aircraft (RAGIDA-TB) of the European Centre for Disease Prevention and Control (ECDC). Electronic searches were undertaken from Medline (Pubmed), Embase and Cochrane Library until 19 July 2013. Eligible records were identified by a two-stage screening process and data on flight and index case characteristics as well as contact tracing strategies extracted. The systematic literature review retrieved 21 records. Ten of these records were available only after the previous version of the RAGIDA guidelines (2009) and World Health Organization guidelines on TB and air travel (2008) were published. Seven of the 21 records presented some evidence of possible in-flight transmission, but only one record provided substantial evidence of TB transmission on an aircraft. The data indicate that overall risk of TB transmission on aircraft is very low. The updated ECDC guidelines for TB transmission on aircraft have global implications due to inevitable need for international collaboration in contract tracing and risk assessment.

Tracking a tuberculosis outbreak over 21 years: strain-specific single-nucleotide polymorphism typing combined with targeted whole-genome sequencing.

BACKGROUND: Whole-genome sequencing (WGS) is increasingly used in molecular-epidemiological investigations of bacterial pathogens, despite cost- and time-intensive analyses. We combined strain-specific single-nucleotide polymorphism (SNP) typing and targeted WGS to investigate a tuberculosis cluster spanning 21 years in Bern, Switzerland. METHODS: On the basis of genome sequences of 3 historical outbreak Mycobacterium tuberculosis isolates, we developed a strain-specific SNP-typing assay to identify further cases. We screened 1642 patient isolates and performed WGS on all identified cluster isolates. We extracted SNPs to construct genomic networks. Clinical and social data were retrospectively collected. RESULTS: We identified 68 patients associated with the outbreak strain. Most received a tuberculosis diagnosis in 1991-1995, but cases were observed until 2011. Two thirds were homeless and/or substance abusers. Targeted WGS revealed 133 variable SNP positions among outbreak isolates. Genomic network analyses suggested a single origin of the outbreak, with subsequent division into 3 subclusters. Isolates from patients with confirmed epidemiological links differed by 0-11 SNPs. CONCLUSIONS: Strain-specific SNP genotyping allowed rapid and inexpensive identification of M. tuberculosis outbreak isolates in a population-based strain collection. Subsequent targeted WGS provided detailed insights into transmission dynamics. This combined approach could be applied to track bacterial pathogens in real time and at high resolution.

Treatment outcomes of multidrug-resistant tuberculosis in Switzerland.

OBJECTIVE: To assess outcomes 24 months after treatment start for multidrug-resistant tuberculosis (MDR-TB). METHODS: Cohort study of all culture-positive MDR-TB cases notified in Switzerland from 01/2003 to 07/2010. RESULTS: Fifty-one cases were observed, with a median age of 26 years (range 2-56). Twenty-seven were male, five of Swiss origin, 46 of foreign origin (Asia 18, Africa 13, former Soviet Union 8), including 21 asylum seekers and refugees. Twelve had received a previous treatment for TB and 24 had not (15 unknown). Forty-four cases were pulmonary of which 25 were known to be sputum smear positive. All but two strains showed additional resistances: 29 to ethambutol, 27 to pyrazinamide, 6 to a fluoroquinolone, 5 to amikacin. None was resistant to both of the latter two classes. Molecular analyses showed three pairs of identical strains. Fluoroquinolones were used in 48 patients and second-line injectable drugs in 37. The median duration of MDR treatment was 18 months (range 1-26). The outcome after 24 months was successful in 39 (76%) and unsatisfactory in 12 (24%) patients: two deaths from TB; two treatments terminated owing to side effects of drugs and one owing to pregnancy; four defaults from treatment at months 0, 4, 8, and 21; two transfers abroad with unknown outcome; one outcome unknown. There was no significant association of unfavourable outcomes with age, sex, origin, previous treatment, treatment delay, resistance pattern, and classes of drugs used. CONCLUSIONS: MDR-TB in Switzerland occurs mostly in persons of foreign origin. Results of decentralised treatments were satisfactory.

HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis.

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5-20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV-infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.

Tuberculosis in HIV-negative and HIV-infected patients in a low-incidence country: clinical characteristics and treatment outcomes.

BACKGROUND: In Switzerland and other developed countries, the number of tuberculosis (TB) cases has been decreasing for decades, but HIV-infected patients and migrants remain risk groups. The aim of this study was to compare characteristics of TB in HIV-negative and HIV-infected patients diagnosed in Switzerland, and between coinfected patients enrolled and not enrolled in the national Swiss HIV Cohort Study (SHCS). METHODS AND FINDINGS: All patients diagnosed with culture-confirmed TB in the SHCS and a random sample of culture-confirmed cases reported to the national TB registry 2000-2008 were included. Outcomes were assessed in HIV-infected patients and considered successful in case of cure or treatment completion. Ninety-three SHCS patients and 288 patients selected randomly from 4221 registered patients were analyzed. The registry sample included 10 (3.5%) coinfected patients not enrolled in the SHCS: the estimated number of HIV-infected patients not enrolled in the SHCS but reported to the registry 2000-2008 was 146 (95% CI 122-173). Coinfected patients were more likely to be from sub-Saharan Africa (51.5% versus 15.8%, P<0.0001) and to present disseminated disease (23.9% vs. 3.4%, P<0.0001) than HIV-negative patients. Coinfected patients not enrolled in the SHCS were asylum seekers or migrant workers, with lower CD4 cell counts at TB diagnosis (median CD4 count 79 cells/µL compared to 149 cells/µL among SHCS patients, P = 0.07). There were 6 patients (60.0%) with successful outcomes compared to 82 (88.2%) patients in the SHCS (P = 0.023). CONCLUSIONS: The clinical presentation of coinfected patients differed from HIV-negative TB patients. The number of HIV-infected patients diagnosed with TB outside the SHCS is similar to the number diagnosed within the cohort but outcomes are poorer in patients not followed up in the national cohort. Special efforts are required to address the needs of this vulnerable population.

Mycobacterium tuberculosis transmission in a country with low tuberculosis incidence: role of immigration and HIV infection.

Immigrants from high-burden countries and HIV-coinfected individuals are risk groups for tuberculosis (TB) in countries with low TB incidence. Therefore, we studied their role in transmission of Mycobacterium tuberculosis in Switzerland. We included all TB patients from the Swiss HIV Cohort and a sample of patients from the national TB registry. We identified molecular clusters by spoligotyping and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) analysis and used weighted logistic regression adjusted for age and sex to identify risk factors for clustering, taking sampling proportions into account. In total, we analyzed 520 TB cases diagnosed between 2000 and 2008; 401 were foreign born, and 113 were HIV coinfected. The Euro-American M. tuberculosis lineage dominated throughout the study period (378 strains; 72.7%), with no evidence for another lineage, such as the Beijing genotype, emerging. We identified 35 molecular clusters with 90 patients, indicating recent transmission; 31 clusters involved foreign-born patients, and 15 involved HIV-infected patients. Birth origin was not associated with clustering (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 0.73 to 3.43; P = 0.25, comparing Swiss-born with foreign-born patients), but clustering was reduced in HIV-infected patients (aOR, 0.49; 95% CI, 0.26 to 0.93; P = 0.030). Cavitary disease, male sex, and younger age were all associated with molecular clustering. In conclusion, most TB patients in Switzerland were foreign born, but transmission of M. tuberculosis was not more common among immigrants and was reduced in HIV-infected patients followed up in the national HIV cohort study. Continued access to health services and clinical follow-up will be essential to control TB in this population.

A comparative examination of tuberculosis immigration medical screening programs from selected countries with high immigration and low tuberculosis incidence rates.

BACKGROUND: Tuberculosis (TB) in migrants is an ongoing challenge in several low TB incidence countries since a large proportion of TB in these countries occurs in migrants from high incidence countries. To meet these challenges, several countries utilize TB screening programs. The programs attempt to identify and treat those with active and/or infectious stages of the disease. In addition, screening is used to identify and manage those with latent or inactive disease after arrival. Between nations, considerable variation exists in the methods used in migration-associated TB screening. The present study aimed to compare the TB immigration medical examination requirements in selected countries of high immigration and low TB incidence rates. METHODS: Descriptive study of immigration TB screening programs. RESULTS: 16 out of 18 eligible countries responded to the written standardized survey and phone interview. Comparisons in specific areas of TB immigration screening programs included authorities responsible for TB screening, the primary objectives of the TB screening program, the yield of detection of active TB disease, screening details and aspects of follow up for inactive pulmonary TB. No two countries had the same approach to TB screening among migrants. Important differences, common practices, common problems, evidence or lack of evidence for program specifics were noted. CONCLUSIONS: In spite of common goals, there is great diversity in the processes and practices designed to mitigate the impact of migration-associated TB among nations that screen migrants for the disease. The long-term goal in decreasing migration-related introduction of TB from high to low incidence countries remains diminishing the prevalence of the disease in those high incidence locations. In the meantime, existing or planned migration screening programs for TB can be made more efficient and evidenced based. Cooperation among countries doing research in the areas outlined in this study should facilitate the development of improved screening programs.

[Epidemiogy and treatment of tuberculosis in Switzerland]. / Epidémiologie et prise en charge de la tuberculose en Suisse.

Problems in tuberculosis are its rarity, drug-resistant strains, and patients' social aspects. Knowing the epidemiology helps to "think tuberculosis" when some anamnestic and clinical findings are present. In a not too seriously ill patient, the emergency consists of excluding infectious tuberculosis by sputum smear examinations. A positive result will lead to the patient's isolation and the initiation of treatment. Negative smears allow to wait for culture results, while following the patient and repeating smears after a non-specific antibiotic treatment. In case of strong suspicion of tuberculosis or risk for a rapid progression, the treatment should begin without delay. Discussion with a specialist is often warranted. A follow-up by the Swiss Pulmonary Association is recommended to prevent the patient from defaulting from treatment.

Outcome of treatment of pulmonary tuberculosis in Switzerland in 1996.

PRINCIPLES: Adequate treatment of pulmonary tuberculosis cures patients and reduces transmission. The study assesses treatment outcomes under current conditions in Switzerland. METHODS: Retrospective cohort study including all TB cases with positive sputum cultures notified to the national surveillance system between July 1996 and June 1997. Ten months after notification, treating physicians reported the outcomes using WHO categories. RESULTS: Of 265 patients, 209 (79%) completed at least 6 months' treatment, 3 (1%) were treatment failures, 23 (9%) died, 8 (3%) defaulted from treatment and 22 (8%) left the country. The proportion of successful treatments did not significantly differ between the 103 Swiss-born (80%) and the 162 foreign-born (78%) patients. There were 19 deaths (18%) in the Swiss-born and 4 (2%) in the foreign-born groups; death was caused by TB in two patients, 10 died of other causes (cause unknown in 11). In the foreign-born group there were 31 (19%) potentially unsatisfactory outcomes (treatment failure, default from treatment, transfer abroad) and in the Swiss-born group 2 (2%). Default from treatment involved 8 patients, 6 of whom were asylum seekers. In a multivariate analysis potentially unsatisfactory outcomes were not significantly associated with foreign origin but with status as a foreigner of irregular or unknown legal status (adj. OR 8.8; 95% CI 1.4 to 53.7). CONCLUSIONS: Overall treatment success rates are satisfactory and similar to those of other western European countries. Potentially unsatisfactory outcomes are more common in foreign-born persons of irregular legal status. Tracking of non-adherent patients by health workers could further improve outcomes.

Screening and treatment for latent tuberculosis infection among asylum seekers entering Switzerland.

AIM OF THE STUDY: To evaluate the compliance of doctors and patients with the current recommendations for screening and preventive treatment of immigrants with a positive tuberculin skin test (TST) suggestive of latent tuberculosis infection (LTBI). METHODS: Retrospective cohort study of all asylum seekers entering Switzerland between 1 January 1993 and 31 December 1993 and assigned to the cantons of Aargau, Fribourg, Geneva, Neuchâtel, Valais and Vaud, who underwent a TST at the border. The medical documents of all individuals with a TST size suggestive of LTBI (> or = 10 mm in children <15 years, > or = 18 mm in young adults aged 15-25 years) were reviewed for final diagnosis, therapeutic decision, compliance with treatment if prescribed, and notification for tuberculosis within the next 3 years. RESULTS: Among 2515 asylum seekers, 172 had a positive TST suggestive of LTBI. The documents of 93 persons were available. The final diagnosis was LTBI in 71 cases, possible tuberculosis in 10 cases, an effect of BCG immunisation in 10 cases, and other diagnoses in 2 cases. Among 82 individuals with normal chest X-ray or no radiological examination, only 37 (46%) received a preventive treatment and one a full course of antituberculosis drugs. Among 11 persons with an abnormal chest X-ray, 2 received a full course of antituberculosis drugs, 7 a preventive therapy and 2 had no treatment prescribed. Among the 44 subjects in whom a preventive treatment was prescribed, 30 adhered to the treatment regimen. One case (without prescribed treatment) was notified for tuberculosis two years after entry. CONCLUSIONS: Compliance of doctors and patients with current recommendations for examination and treatment of immigrants with a TST suggestive of LTBI is unsatisfactory. New guidelines are needed to provide a clearer definition of the indications and explain the benefits of treating LTBI.