Is tuberculosis elimination a reality?
Authors: Giovanni Sotgiu, Giovanni Battista Migliori
Journal: The Lancet Infectious Diseases (2014)

Multidrug-resistant (MDR) tuberculosis is a public health emergency and a challenging scenario for both patients and clinicians.1Falzon D Gandhi N Migliori GB et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBResistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.Eur Respir J. 2013; 42: 156-168Crossref PubMed Scopus (314) Google Scholar, 2Migliori GB Sotgiu G Gandhi NR et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBDrug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.Eur Respir J. 2013; 42: 169-179Crossref PubMed Scopus (208) Google Scholar In 2012, there were more than 450 000 incident cases and 170 000 deaths worldwide.3WHOGlobal tuberculosis report 2013. World Health Organization, Geneva2013Google Scholar Treatment of MDR tuberculosis is complex and expensive (€100 000 or more for drugs for one patient), especially its most severe, extensively drug-resistant forms.1Falzon D Gandhi N Migliori GB et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBResistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.Eur Respir J. 2013; 42: 156-168Crossref PubMed Scopus (314) Google Scholar, 2Migliori GB Sotgiu G Gandhi NR et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBDrug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.Eur Respir J. 2013; 42: 169-179Crossref PubMed Scopus (208) Google Scholar, 4Diel R Vandeputte J de Vries G Stillo J Wanlin M Nienhaus A Costs of tuberculosis disease in the European Union: a systematic analysis and cost calculation.Eur Respir J. 2014; 43: 554-565Crossref PubMed Scopus (127) Google Scholar Treatment is long (at least 2 years), the drugs are toxic (specific expertise is needed to manage adverse reactions), and the outcomes are poor (with low success and high death rates).1Falzon D Gandhi N Migliori GB et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBResistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.Eur Respir J. 2013; 42: 156-168Crossref PubMed Scopus (314) Google Scholar, 2Migliori GB Sotgiu G Gandhi NR et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBDrug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.Eur Respir J. 2013; 42: 169-179Crossref PubMed Scopus (208) Google Scholar New drugs will soon be available that will probably shorten and simplify treatment for MDR tuberculosis and increase effectiveness, and public health strategies have been developed to prevent the occurrence of drug resistance.5Gler MT Skripconoka V Sanchez-Garavito E et al.Delamanid for multidrug-resistant pulmonary tuberculosis.N Engl J Med. 2012; 366: 2151-2160Crossref PubMed Scopus (572) Google Scholar, 6Skripconoka V Danilovits M Pehme L et al.Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis.Eur Respir J. 2013; 41: 1393-1400Crossref PubMed Scopus (271) Google Scholar, 7Diacon AH Pym A Grobusch M et al.The diarylquinoline TMC207 for multidrug-resistant tuberculosis.N Engl J Med. 2009; 360: 2397-2405Crossref PubMed Scopus (670) Google Scholar The traditional approach of national tuberculosis programmes, focused on tuberculosis control (ie, rapid diagnosis and early, effective treatment of newly detected infectious cases), which was advocated by the WHO Stop TB Strategy, will soon be replaced by the post-2015 strategy focused on the concept of tuberculosis elimination (ie, fewer than one new sputum smear-positive tuberculosis case per 1 million population).8Diel R Loddenkemper R Zellweger JP et al.for the European Forum for TB InnovationOld ideas to innovate tuberculosis control: preventive treatment to achieve elimination.Eur Respir J. 2013; 42: 785-801Crossref PubMed Scopus (148) Google Scholar, 9D'Ambrosio L Dara M Tadolini M et al.on behalf of the European national programme representativesTuberculosis elimination: theory and practice in Europe.Eur Respir J. 2014; (published online Jan 16.)https://doi.org/10.1183/09031936.00198813Crossref Scopus (130) Google Scholar Whereas traditional contact tracing (eg, looking for the contacts of individuals with tuberculosis and MDR tuberculosis in progressive circles10WHORecommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries. World Health Organisation, Geneva2012Google Scholar) recommends identification and treatment of latently infected individuals and additional tuberculosis cases, new approaches recommend genotypic identification of the causative strain, monitoring of the epidemic, and initiation of adequate measures to manage it. One such approach is mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) strain typing. In The Lancet Infectious Diseases, Laura F Anderson and colleagues11Anderson LF Tamne S Brown T et al.Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracing.Lancet Infect Dis. 2014; (published online March 4.)http://dx.doi.org/10.1016/S1473-3099(14)70022-2Google Scholar report an assessment of transmission of MDR tuberculosis in the UK between 2004 and 2007, using the 24-loci MIRU-VNTR method together with epidemiological data collected through the national surveillance system and an ad-hoc cluster investigation questionnaire. The scope was to identify the relative frequency of MDR tuberculosis cases transmitted nationwide. 204 patients were diagnosed with MDR tuberculosis in the study period of whom 189 (92·6%) had an MIRU-VNTR profile. 15% of these cases were clustered. Furthermore, Anderson and colleagues analysed the risk factors associated with MDR tuberculosis transmission: being born in the UK (odds ratio 4·81; 95% CI 2·03–11·36, p=0·0005) and having a history of illicit drug use (4·75; 1·19–18·96, p=0·026) significantly increased the probability of transmission. Most cases (21 of 22) were transmitted in the household. The occurrence of MDR tuberculosis transmission in the UK is lower than in other European and non-European settings, probably as a consequence of scarce transmission occurring between specific population groups. The study is an excellent example of nationwide implementation of one of the European Centre for Disease Prevention and Control (ECDC) recommendations to eliminate tuberculosis in the European Union.12European Centre for Disease Prevention and ControlProgressing towards TB elimination. ECDC, Stockholm2010Google Scholar, 13European Centre for Disease Prevention and ControlA framework action plan to fight tuberculosis in the European Union. EDCD, Stockholm2008Google Scholar, 14Broekmans JF Migliori GB Rieder HL et al.World Health OrganizationInternational Union Against Tuberculosis and Lung DiseaseRoyal Netherlands Tuberculosis Association Working GroupEuropean framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group.Eur Respir J. 2002; 19: 765-775Crossref PubMed Scopus (294) Google Scholar Moreover, the identification of risk factors allows the prioritisation of the public health investigations, reducing the probability of transmission related to health-care system delay. The core strength of the study is the high proportion of MDR tuberculosis cases assessed with the novel diagnostic approach (ie, 24-loci MIRU-VNTR) and the ability to increase sensitivity compared with the traditional epidemiological investigations. However, other more sensitive techniques such as whole genome sequencing analysis could also have increased the ability to identify additional epidemiological links, which means that a potential underestimation of MDR tuberculosis transmission should be considered. Low culture confirmation (about 60% in the UK) could also have underestimated the true prevalence of transmission. Molecular methods have several public health applications, including identification of outbreaks, population groups at highest risk of transmission, transmission across jurisdictions, transmission chains, reinfected and relapsing cases, and laboratory cross-contamination.12European Centre for Disease Prevention and ControlProgressing towards TB elimination. ECDC, Stockholm2010Google Scholar However, several technical problems currently hinder their integration into national tuberculosis programmes, including the absence of a gold standard to effectively assess their discriminatory power. The ECDC recommends12European Centre for Disease Prevention and ControlProgressing towards TB elimination. ECDC, Stockholm2010Google Scholar, 13European Centre for Disease Prevention and ControlA framework action plan to fight tuberculosis in the European Union. EDCD, Stockholm2008Google Scholar, 14Broekmans JF Migliori GB Rieder HL et al.World Health OrganizationInternational Union Against Tuberculosis and Lung DiseaseRoyal Netherlands Tuberculosis Association Working GroupEuropean framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group.Eur Respir J. 2002; 19: 765-775Crossref PubMed Scopus (294) Google Scholar monitoring and assessment of transmission of drug-susceptible and drug-resistant mycobacterial strains by adoption of sensitive and specific molecular methods. Molecular fingerprinting, alongside classic epidemiological studies, will be helpful to discriminate real clusters of tuberculosis cases (ie, individuals infected by the same genotypes) and to (indirectly) assess the efficacy of a tuberculosis control programme implemented at a national or regional level. If we are to make tuberculosis elimination a reality, this UK experience needs to be followed up in other European Union countries. The implementation of molecular methods with increased sensitivity allows the bypassing of low discriminatory power associated with traditional contact tracing procedures, scaling up part of the European Union's tuberculosis elimination package.9D'Ambrosio L Dara M Tadolini M et al.on behalf of the European national programme representativesTuberculosis elimination: theory and practice in Europe.Eur Respir J. 2014; (published online Jan 16.)https://doi.org/10.1183/09031936.00198813Crossref Scopus (130) Google Scholar, 12European Centre for Disease Prevention and ControlProgressing towards TB elimination. ECDC, Stockholm2010Google Scholar, 13European Centre for Disease Prevention and ControlA framework action plan to fight tuberculosis in the European Union. EDCD, Stockholm2008Google Scholar, 14Broekmans JF Migliori GB Rieder HL et al.World Health OrganizationInternational Union Against Tuberculosis and Lung DiseaseRoyal Netherlands Tuberculosis Association Working GroupEuropean framework for tuberculosis control and elimination in countries with a low incidence. Recommendations of the World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Royal Netherlands Tuberculosis Association (KNCV) Working Group.Eur Respir J. 2002; 19: 765-775Crossref PubMed Scopus (294) Google Scholar This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on April 21, 2014 This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on April 21, 2014 We declare that we have no competing interests. Transmission of multidrug-resistant tuberculosis in the UK: a cross-sectional molecular and epidemiological study of clustering and contact tracingTransmission of MDR tuberculosis in the UK is low and associated with being UK born or illicit drug use. MIRU-VNTR typing with cluster investigation was more successful at identifying transmission events than conventional contact tracing. Individuals with tuberculosis who have had contact with a known MDR tuberculosis source case from a country of high tuberculosis burden should have drug-sensitivity testing on isolates to ensure appropriate treatment is given. Full-Text PDF Open AccessCorrectionsSotgiu G, Migliori GB. Is tuberculosis elimination a reality? Lancet Infect Dis 2014; 14: 364–65—This Comment is open access published under a CC BY-NC-ND licence. The online version has been corrected as of April 21, 2014. The print version is correct. Full-Text PDF