Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014.

INTRODUCTION: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome. AIM: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB. METHODS: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002-14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries. RESULTS: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6-0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2-1.5), male sex (OR: 1.3; 95% CI: 1.1-1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1-1.4), positive HIV status (OR: 3.3; 95% CI: 1.6-6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5-2.2). CONCLUSIONS: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.

Determinants of site of tuberculosis disease: An analysis of European surveillance data from 2003 to 2014.

BACKGROUND: We explored host-related factors associated with the site of tuberculosis (TB) disease using variables routinely collected by the 31 EU/EEA countries for national surveillance. METHODS: Logistic regression models were fitted to case-based surveillance data reported to the European Centre for Disease Prevention and Control for TB cases notified from 2003 to 2014. Missing data on HIV infection and on susceptibility to isoniazid and rifampicin for many patients precluded the inclusion of these variables in the analysis. Records from Finland, Lithuania, Spain and the United Kingdom were excluded for lack of exact details of disease localisation; other records without one or more variable (e.g. previous treatment history, geographical origin) or who had mixed pulmonary and extrapulmonary disease or more than one form of extrapulmonary disease were also removed (total exclusion = 38% of 913,637 notifications). RESULTS: 564,916 TB cases reported by 27 EU/EEA countries had exclusive pulmonary (PTB; 83%) or extrapulmonary (EPTB; 17%) disease. EPTB was associated with age <15 years (aOR: 5.50), female sex (aOR: 1.60), no previous TB treatment (aOR: 3.10), and geographic origin (aOR range: 0.52-3.74). Origin from the Indian subcontinent or Africa was most strongly associated with lymphatic, osteo-articular and peritoneal/digestive localization (aOR>3.7), and age <15 years with lymphatic (aOR: 17.96) and central nervous system disease (aOR: 11.41). CONCLUSIONS: Awareness of host-related determinants of site of TB is useful for diagnosis. The predilection for EPTB among patients originating from countries outside Europe may reflect strain preferences for disease localization, geographic/ethnic differences in disease manifestation and other factors, like HIV.

Health system factors influencing management of multidrug-resistant tuberculosis in four European Union countries - learning from country experiences.

BACKGROUND: In the European Union and European Economic Area only 38% of multidrug-resistant tuberculosis patients notified in 2011 completed treatment successfully at 24 months' evaluation. Socio-economic factors and patient factors such as demographic characteristics, behaviour and attitudes are associated with treatment outcomes. Characteristics of healthcare systems also affect health outcomes. This study was conducted to identify and better understand the contribution of health system components to successful treatment of multidrug-resistant tuberculosis. METHODS: We selected four European Union countries to provide for a broad range of geographical locations and levels of treatment success rates of the multidrug-resistant tuberculosis cohort in 2009. We conducted semi-structured interviews following a conceptual framework with representatives from policy and planning authorities, healthcare providers and civil society organisations. Responses were organised according to the six building blocks of the World Health Organization health systems framework. RESULTS: In the four included countries, Austria, Bulgaria, Spain, and the United Kingdom, the following healthcare system factors were perceived as key to achieving good treatment results for patients with multidrug-resistant tuberculosis: timely diagnosis of drug-resistant tuberculosis; financial systems that ensure access to a full course of treatment and support for multidrug-resistant tuberculosis patients; patient-centred approaches with strong intersectoral collaboration that address patients' emotional and social needs; motivated and dedicated healthcare workers with sufficient mandate and means to support patients; and cross-border management of multidrug-resistant tuberculosis to secure continuum of care between countries. CONCLUSION: We suggest that the following actions may improve the success of treatment for multidrug-resistant tuberculosis patients: deployment of rapid molecular diagnostic tests; development of context-specific treatment guidance and criteria for hospital admission and discharge in the European context; strengthening patient-centred approaches; development of collaborative mechanisms to ensure cross-border care, and development of long-term sustainable financing strategies.

Tuberculosis and HIV coinfection in Europe: looking at one reality from two angles.

OBJECTIVE: To better understand the epidemiology of tuberculosis (TB)/HIV coinfection in the European Union (EU) and European Economic Area (EEA) for planning of prevention and control measures. DESIGN: Analysis of surveillance data. METHODS: We performed an analysis of the 2014 TB and AIDS data to assess the burden of TB/HIV coinfection and we applied multivariable logistic regression to evaluate predictors for coinfection. RESULTS: Twenty-one of 31 EU/EEA countries reported HIV testing results for 64.6% of the 32 892 notified TB cases. Of those, 1051 (4.9%) were reported as HIV-positive. Males [adjusted odds ratio (aOR) 1.25; 95% confidence interval (CI) 1.07-1.46] and those in age group 25-44 years were more frequently coinfected. TB cases originating from the WHO African region had the highest proportion of coinfection (aOR 3.28 versus origin in EU/EEA; 95% CI 2.35-4.57). TB treatment was completed successfully by 57.9% of HIV-positive TB cases and 83.5% of HIV-negative cases. In 2014, 3863 cases of AIDS were reported by 29 EU/EEA countries; 691 (17.9%) of these cases presented with TB as an AIDS-defining illness. Persons who had acquired HIV through injecting drug use had higher odds of TB as an AIDS-defining illness (aOR 1.78 versus heterosexual route of transmission; 95% CI 1.37-2.32). CONCLUSION: TB/HIV coinfection is a substantial problem in the EU/EEA. The occurrence of TB in HIV-positive cases and the low TB treatment success rate suggest that international guidelines for prevention and treatment of TB in HIV-infected adults need to be better implemented.

The effect of migration within the European Union/European Economic Area on the distribution of tuberculosis, 2007 to 2013.

Immigration from tuberculosis (TB) high-incidence countries is known to contribute notably to the TB burden in low-incidence countries. However, the effect of migration enabled by the free movement of persons within the European Union (EU)/European Economic Area (EEA) on TB notification has not been analysed. We analysed TB surveillance data from 29 EU/EEA countries submitted for the years 2007-2013 to The European Surveillance System. We used place of birth and nationality as proxy indicators for native, other EU/EEA and non-EU/EEA origin of the TB cases and analysed the characteristics of the subgroups by origin. From 2007-2013, a total of 527,467 TB cases were reported, of which 129,781 (24.6%) were of foreign origin including 12,566 (2.4%) originating from EU/EEA countries other than the reporting country. The countries reporting most TB cases originating from other EU/EEA countries were Germany and Italy, and the largest proportion of TB cases in individuals came from Poland (n=1,562) and Romania (n=6,285). At EU/EEA level only a small proportion of foreign TB cases originated from other EU/EEA countries, however, the uneven distribution of this presumed importation may pose a challenge to TB programmes in some countries.

Impact of HIV infection on treatment outcome of tuberculosis in Europe.

BACKGROUND: The effect of HIV on tuberculosis (TB) treatment outcomes has not been well established. We aimed to assess the impact of HIV infection on TB treatment outcomes by using data from notifiable disease surveillance in Europe. METHODS: We analyzed the treatment outcomes of TB cases reported from nine European countries during 2010-2012. We investigate the effect of HIV on TB treatment outcomes using a multilevel and a multinomial logistic model, and considering the interaction between HIV and multidrug-resistant (MDR) TB. RESULTS: A total of 61,138 TB cases including 5.5% HIV-positive were eligible for our analysis. In the multilevel model adjusted for age and an interaction with MDR TB, HIV was significantly associated with lower treatment success in all MDR strata [non-MDR TB: odds ratio (OR) 0.24 CI (confidence interval) 0.20-0.29; unknown MDR TB status: OR 0.26 CI 0.23-0.30; MDR TB: OR 0.57 CI 0.35-0.91]. In the multinomial regression model, HIV-positive cases had significantly higher relative risk ratio (RRR) for death (non-MDR TB: RRR 4.30 CI 2.31-7.99; unknown MDR TB status: 5.55 CI 3.10-9.92; MDR TB: 3.59 CI 1.56-8.28) and being 'still on treatment' (non-MDR TB: RRR 7.27 CI 3.00-17.6; unknown MDR TB status: 5.36 CI 2.44-11.8; MDR TB: 3.76 CI 2.48-5.71). We did not find any significant association between HIV and TB treatment failure (non-MDR TB: RRR 0.50 CI 0.15-1.67; unknown MDR TB status: 1.51 CI 0.86-2.64; MDR TB: 0.51 CI 0.13-1.87). CONCLUSION: This large study confirms that HIV is a strong risk factor for an adverse TB treatment outcome, which is mainly manifested by an increased risk of death and still being on TB treatment.

Tuberculosis treatment outcome in the European Union and European Economic Area: an analysis of surveillance data from 2002-2011.

Monitoring the treatment outcome (TO) of tuberculosis (TB) is essential to evaluate the effectiveness of the intervention and to identify potential barriers for TB control. The global target is to reach a treatment success rate (TSR) of at least 85%. We aimed to assess the TB TO in the European Union and European Economic Area (EU/EEA) between 2002 and 2011, and to identify factors associated with unsuccessful treatment. Only 18 countries reported information on TO for the whole observation period accounting for 250,854 new culture-confirmed pulmonary TB cases. The 85% target of TSR was not reached in any year between 2002 and 2011 and was on average 78%. The TSR for multidrug-resistant (MDR)-TB cases at 24-month follow-up was 49%. In the multivariable regression model, unsuccessful treatment was significantly associated with increasing age (odds ratio (OR) = 1.02 per a one-year increase, 95% confidence interval (CI): 1.02-1.02), MDR-TB (OR = 8.7, 95% CI: 5.09-14.97), male sex (OR = 1.40, 95% CI: 1.28-1.52), and foreign origin (OR = 1.32, 95% CI: 1.03-1.70). The data highlight that special efforts are required for patients with MDR-TB and the elderly aged ≥65 years, who have particularly low TSR. To allow for valid monitoring at EU level all countries should aim to report TO for all TB cases.

Review of the national tuberculosis programme in Romania

Romania has the highest incidence of TB in the European Union (EU)/European Economic Area (EEA),representing one quarter of the EU/EEA TB burden. A review of the national TB programme in Romaniawas jointly organized by the WHO Regional Office for Europe and the European Centre for DiseasePrevention and Control, with WHO leading all operations, from 10 to 21 March 2014. The reviewacknowledged the high rates of detection and treatment success achieved among patients with drugsusceptibleforms of TB; it also pointed to the large proportion of patients with multidrug-resistant TB whoare not detected or are poorly treated. The review identified major challenges to be addressed atprogramme level as well as at health system level and gave the Ministry of Health and the national TBprogramme 14 main recommendations for improvement.

Long-term follow-up after thoracoscopic resection of solitary pulmonary tuberculoma.

BACKGROUND: Pulmonary tuberculosis continues to be a significant health problem, especially due to increasing incidence of multi-resistant mycobacteria and patients with immunodeficiency. Pulmonary tuberculoma, like other solitary lung nodules, can often be a diagnostic challenge; moreover no consensus exists on the management strategy. AIM: To analyze the results of tuberculoma treatment with thoracoscopic lung resection, followed by anti-tuberculosis treatment (ATT). METHODS: All patients who underwent thoracoscopic resection of tuberculoma between 1996 and 2008 were retrospectively analyzed. The diagnosis was confirmed morphologically and/or microbiologically. Data were collected from case reports, outpatient medical records, Estonian Tuberculosis Registry and National Population Registry. RESULTS: Forty-three patients (25 men, 18 women) with mean age of 43.3 (range 15-68) years were included. Thoracoscopic approach was converted to thoracotomy in three cases. Median postoperative stay in surgical department was four days. No intra-hospital mortality occurred. Eleven patients received pre-operative ATT for 8 to 288 (median 115) days and 42 patients were treated post-operatively for 40 to 672 (median 185) days. One patient defaulted in ATT. First-line drugs were prescribed in 37 and second-line in five patients. During the median follow-up of 9.0 (range 3.2 to 16.1) years, none of the patients developed relapse. CONCLUSIONS: Thoracoscopic pulmonary resection provides a minimally invasive opportunity for morphological and microbiological diagnosis of tuberculoma; and results in an excellent cure rate in combination with ATT.

Is tuberculosis crossing borders at the Eastern boundary of the European Union?

BACKGROUND: The Eastern border of the European Union (EU) consists of 10 countries after the expansion of the EU in 2004 and 2007. These 10 countries border to the East to countries with high tuberculosis (TB) notification rates. We analyzed the notification data of Europe to quantify the impact of cross-border TB at the Eastern border of the EU. METHODS: We used TB surveillance data of 2010 submitted by 53 European Region countries to the European Centre for Disease Prevention and Control and the World Health Organization Regional Office for Europe. Notified TB cases were stratified by origin of the case (national/foreign). We calculated the contribution of foreign to overall TB notification. RESULTS: In the 10 EU countries located at the EU Eastern border, 618 notified TB cases (1.7% of all notified TB cases) were of foreign origin. Of those 618 TB cases, 173 (28.0%) were from countries bordering the EU to the East. More specifically, 90 (52.0%) were from Russia, 33 (19.1%) from Belarus, 33 (19.1%) from Ukraine, 13 (7.5%) from Moldova and 4 (2.3%) from Turkey. CONCLUSIONS: Currently, migrants contribute little to TB notifications in the 10 EU countries at the Eastern border of the EU, but changes in migration patterns may result in an increasing contribution. Therefore, EU countries at the Eastern border of the EU should strive to provide prompt diagnostic services and adequate treatment of migrants.

Multidrug-resistant tuberculosis management in resource-limited settings.

Evidence of successful management of multidrug-resistant tuberculosis (MDRTB) is mainly generated from referral hospitals in high-income countries. We evaluate the management of MDRTB in 5 resource-limited countries: Estonia, Latvia, Peru, the Philippines, and the Russian Federation. All projects were approved by the Green Light Committee for access to quality-assured second-line drugs provided at reduced price for MDRTB management. Of 1047 MDRTB patients evaluated, 119 (11%) were new, and 928 (89%) had received treatment previously. More than 50% of previously treated patients had received both first- and second-line drugs, and 65% of all patients had infections that were resistant to both first- and second-line drugs. Treatment was successful in 70% of all patients, but success rate was higher among new (77%) than among previously treated patients (69%). In resource-limited settings, treatment of MDRTB provided through, or in collaboration with, national TB programs can yield results similar to those from wealthier settings.

Tuberculosis during fundamental societal changes in Estonia with special reference to extrapulmonary manifestations.

STUDY OBJECTIVES: To characterize the incidence of extrapulmonary tuberculosis (EPTB) in Estonia, by site and age, in conditions of marked pulmonary tuberculosis (TB) increase, ie, during the period of fundamental societal changes, but where TB incidence has not been influenced by HIV infection. DESIGN AND SETTING: A retrospective study. PATIENTS: All new cases of EPTB (n = 622) detected in Estonia from 1991 to 2000. RESULTS: The incidence of pulmonary TB in Estonia increased from 21.5 in 1991 to 44.6/100,000 in 2000. In contrast, the incidence of EPTB did not increase at the same pace, changing only from 3.6 in 1991 to 4.7/100,000 in 2000. The increase in the incidence of EPTB was significantly lower than that of pulmonary TB (p < 0.05), and the relative frequency of EPTB among overall TB steadily decreased from 17.0% in 1991 to 10.1% in 2000. The incidence of EPTB forms with a long latency period (eg, osteoarticular and urogenital TB) remained unchanged, while that of EPTB forms with a short latency period (eg, intrathoracic lymph node TB) increased (p < 0.05). The number of cases of urogenital, pleural, and osteoarticular TB increased with age; the number of cases of intrathoracic lymph node TB decreased with age. The bacteriologic confirmation rate was lower in EPTB than in pulmonary TB and varied according to site. CONCLUSION: There was no increase in the incidence of EPTB during 10 years despite the dramatic increase in overall TB. The proportion of EPTB among all TB tended to decrease with increasing age, and different EPTB sites prevailed in different age groups.