European Respiratory Monograph 58, December 2012 ERS Tuberculosis Publl,htd by European Respiratory Society 2012 December 2012 Print I BN: 978-1-84984-027-9 Online ISBN: 978-1-84984-028-6 Edited by Print ISS : 1025 448x Christoph Lange and Giovanni Battista Migliori Online I N: 2075-6674 Printed by Page Bros Ltd, orwich, UK Managing Editor: Rachel White European Respiratory Society 442 Glossop Road, Sheffield, SI02PX, UK Tel: 44 114 2672860 E-mail: Monogmph@ersj.org.uk Editor in Chief All material is copyright to European Tobias Welte Respiratory, ociety. It may not be reproduced in any way including electronic means without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editor, or publisherrs. This book is one in a series of European Respiratory Monographs. Each individual is ue provide a comprehensive overview ofo ne pecific clini cal area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides fa ctualand u eful scientific detail, drawing on pecific ca e MIX studies and looking into the diagnosisa nd management of individual FSC patients. Previously published titles in this series are listed at the back of FSC*C023114 lhi Monograph. Contents Number 58 December 2012 Preface Guest Editors vi Introduction viii 1. Microbiology of Mycobacterium tuberculosis and a new diagnostic test for TB Vera Katalinic-Jankovic, Lucinda Furci and Da11iela Maria Cirillo 2. Epidemiology of TB 14 Lia D'Ambrosio, Antonio Spanevello and Rosella Centis 3. Pulmonary diseases caused by non-tuberculous mycobacteria 25 Jakko van lngen, David E. Griffith, Timothy R. Aksamit and Dirk Wagner 4. Human genetic variability and susceptibility to pulmonary TB 38 Thorsten 1l1ye and Christian G. Meyer 5. State of the art in vaccine development against TB 59 Tom H.M. Ottenhoff and Stefan H.E. Kaufmann 6. Prevention of TB in areas of low incidence 72 Roland Diel and Albert ienhaus 1. Prevention of TB in areas of high incidence 84 Ben }. Marais, H. Simon Schaaf and Dick Menzies 8. TB drug resistance in high-incidence countries 95 Keertan Dheda, Grant Theron, Jonathan G. Peter, Greg Symons, Rodney Dawson and Paul Willcox 9. TB drug resistance in low-incidence countries I 11 Kai Kliiman, Gunar Gii11t/1er a11d Alan Altraja 10. Diagnosis of TB: state of the art 124 Jonathan G. Peter, Richard N. van Zyl-Smit, Claudia M. Denkinger and Madhukar Pai 11. Omics and single molecule detection: the future of TB diagnostics 144 Graham H. Bothamley, Morten Rulnvald and Delia Goletti 12. reat en of B Jo . Caminero lb rto Matt /Ji and fu i toph Lang 13. Management of adverse drug events in TB therapy 167 hi hiu L unKi Chari - I. D I y, Han L. Ri der and ing \. ai Yt l 14. TB in migrants 1 1 ma w l ont Ii an io anni ot iu 15. Bin chi dren b'/; b h hi taker, hristin Jones nd B ate ampm nn 16. 8 as an occupational disease 21 lbert ienhaus nj h blon Fi li. . Ring hausen fos' Torr osta, miniqu Trip di nd Ian i I 17. TB in the immu ocompromised host 0 artin est r, r os Bumba ea Raqu I Duar e and hris oph ang 18. he WHO s ra egy for B con rol and elimina ion 2 M rina T dolini and Giovann; B ftista igUori CM credit application form 2 5 LICUIOR E HI This JOU al is a member of and subscribes to L e pr1ne1pLE!s or th Comm1lle on Pubtic:c1tion EI ics. Preface W ith the introduction of tuberculostatic antibiotics and the improve ment of living conditions in developed countries, it was generally felt thal the problem of Luberculosis (TB) had been overcome. However, the persistent problems caused by the di ease that were seen in developing countries were not really noticed beyond expert circles. With the spread of AID in the 1980s, TB returned to the forefront of attention as one of the major opportunistic infections in AIDS patients. In the years that followed, the first reports of difficult-to-treat multidrug-resistant (MDR)-TB were published. ln the beginning, reports were limited to countries with a high AIDS prevalence; however, after the collapse of the Soviet Union and the opening of the former Communist countries to the West, the full extent of MOR-TB became clear. The number of presentations that focussed on TB at the 2012 European Respiratory Society (ERS) Congress in Vienna was truly amazing. Many of the contributions reported increasing MOR in different parts of the world. A recently published sludy from eight countries, including Estonia, Latvia and Russia, demonstrated a dramatic increase in extensively drug-resistant (XDR)-TB I l]. Previous treatment with second-Line anti-TB drugs was shown to be the main risk factor. The development of new drugs has been significantly slower than the increase in resistance; 10 years on, there have been no adva11ces specifically for this area. Only antibiotics approved for other indications, such as fluoroquinoloncs and linezolid, have provided new treatment options. It is thanks to the commitment of the World Health Organization (WHO) and the support of private foundations (primarily the Bill and Melinda Gates Foundation) that there has been research into new tuberculostatic substances. Some of these are currently being tested in early clinical trials, giving hope of improved treatment options in the future. It is clear, then, that TB is once again a subject of intense interest. This edition of the European Respiratory Monograph (ERM) is therefore particularly topical, as it presents current scientific discussion in the practice of TB diagnosis and treatment. I would like to congratulate the Guest Editors of this issue of the ERM, who have brought together contributions from the best experts in the field. Thi book provides an excellent overview of the topic, and should be of intere t to general practitioners and chest physician , as well as those in industry and in public health who are faced with the problem of TB everyday. References I. Dalton T, CigielskiP , Akksilp , et al. Prevalence of and risk factors. for resistance to second- line drugs in people with multidrog-resistant tuberculosis in eight countries: a pro pectivecohort study. Lancet2 012; [Epub ahead of print I. J::ur Respir tonogr 2012; 58: v. Copyright ER. DOI: I0.1183/1025448)(.)0040012. Print I B : 978-1-84984-027-9. Online I BN: 978-1-84984-028-6. Print I • : 1025·448x. Online ISSN: 2075-6674. Guest Editors Chris1oph Lange i a physician and biologist. He was appointed as Professor of Medicine .it the University of Liibeck (Liibeck, Germany) in 2009 and is currently the Leading Allending Phy ician at the Medical Clinic/Head of the Division of Clinical Infectious Dbcascs al the Rest.1rch Center Bo~tel (Borstel, Germany). Since 2005, he ha been Co-Chair of the Center of Infectious Diseases (DGI) at the Rt< earch Center Bor tel and the Univer icy of Lubeck. and he is Vice-Chair of the Center of Infection and Inflammation at the University of Uibeck (ZIEL). Following clinical training in Cape Town ( outh Africa), Cleveland, OH (USA), and hospitals in Germany, he is board certified in internal medicine, pulmonary and critical care medicine, infectious diseases, alkrgology Jnd sleep medicine. His res<.'arch focus is on 1ubcrculosis (TB), in Christoph Lange which he has been principle investigator of national and international muhicentrc tudies, and a coordinator of consensu documents. C. Lange is Head of the Respiratory Infection Assembly (Assembly 10} of the European Re piratory Society (ERS) (2011-2014) and was previously (2008-2011) chair of the Tuberculosis Group (Group 10.2) of this A!.M>mbly. He is the Founding Chair of the Tuberculosis Network European Trials Group (TBNET), which he headed from 2006 to 2012. ince 2011, he has bc<.'n a member of the steering committee of the Mycobacteriology Study Group (F.SGMYC) of 1he European Society for Clinical Microbiology and Infectious Diseases, and from 2009 to 2012, he was the chair of the Mycobacteriology tudy Group of the DGI. C. Lange b an As ociate Editor of the T11tematio11nl Journal of Tr,berrnlosis nud L1111g Disenses, an As~ociate Editor of l11fectio11 and Section Editor for Respiratory Infections of the Cliuical Respiratory Joumal. He has been a Guest Editor for TB ~eric in Lht· Europcfl11 Respiratory Jouma/ (ERn and Rcspirology. C. Lange"~ appointed a Visiting Professor at the University of Medicine and Pharmacy of the Republic of Moldova in Chisinau (Moldova) in 2011 and a Fellow of the Infectious Diseases Society of America. Giovanni Battista Migliori, MD, FRCP (Lond) is Director of the World Health Organization (WI 10) Collaborating Centre for TB and Lung Diseases (Fondazione . Maugeri, Tradate, Italy), a Profes~or in the Applied Health Sciences Department of the University of Pavia (Pavia. Italy) and a Visiting Professor Jt the Mayo Clinic (Rochester, M , U A). He originally specialised in respiratory medicine in Pavia and then in medical statistics and epidemiology. He has developed global experience in TB, TB/HIV and HIV/AIDS care and control in Africa (Benin, Burkina, Democratic Republic of Congo, Egypt, Ethiopia, Mozambique and Tanzania), A~ia (India and Thailand), Europe (Croatia. Esto11ia, Kosovo, Latvia, Moldova, Romania, Russia, Giovanni Battista Turkey and Ukr-Jine) and Latin America (Mexico). G.B. Migliori ha served as Migliori ER Tuberculo is Group Chair (Group 10.2). as Head of the Respiratory Infections Assembly (Ass<.'mbly 10) (2008-2010), Long Range Planning Committee Chair (2011-2013), and is presently the F.R WHO and European Centre for Di~ase Control Liaison Officer and Secretary General Elect. Since 2007, he ha been an Associate Editor of the ERJ and ince 2011 of the /11tCT"n"tio1wl )01m1al of T11bCT"cr,losis !>:-1: I 02~~ IHx Oulu>< tSSt,,: 2075·"674 2011) and the Respirolo!,'Y TB Seri~ (20 IO), and has collaborated in the Lancet TB Series (2011). Within the International Union against Tuberculosis and Lung Disease (IUALffi), he was Secretary General and President (2008--2009) of the Europe Region. He currently serves WHO as a member of STAG (Scientific Technical Advisory Group, 2010-2012), \'\IJ 10 EURO as a member of TAG (Technical Advisory Board) as well as the GFATM (Global Fund Against AIDS, Tuberculosis and Malaria) as Rotating Member, TRP (Technical Review Panel and Consultant), the GDF {Global Drug Facilit)•) and the European Commission (TAC!S programme, Expert Group and the Scientific Committee of EDCTP (European and Developing Countries Clinical TriJls Partnership)). G.B. Migliori is former Secretary ofTBNET (2006-2011). Introduction Christoph Lange"'#," and Giovanni Battista Miglior,+ • Div,sio11 of Climrnl iufmiaus D,S<'asO, • Mrd,col Cli11ic, ResMrch (',,.,,rrr Horstrl, Horsrr/, 'Cr11ur for I11fmio11 m,d 1,rj1amma1Jot1, Unil'rrsJJy ofU J/xck, llihtd:. Gtr11iauy. 'WHO C<,llnhorati11g C,,,,t,>t for TB a11d l1111g Di!U'a>i';, fo111/11Zio11r S. Mnugt"ri, Ctirr am/ Rts<-nrrl, /ruri1u1t, Trndatt, ltnly Cormponi/r,,«; C lnngr, Cliuirnl foftttious DistaSN, RrSMrcl, Cmttr Bor,rrl, Pnrknllf't' JS, 2J//45 &mtrl, Gmnnny. F-mail: rla11gt"@fz lxmrrl.dr A lthough the global incidence of tuberculosis (TB) is slowly declining, the disease stiU remains one of the leading causes of morbidity and mortality worldwide. In many regions of the world, including parts of Europe, the high incidence of TB is an indicator of poverty and healthcare inequalities. In countries with a low incidence of TB, the disease is mainly related to risk group; for example, recent dose contacts of infected index patients, migrants from high-incidence countries, HIV-infected individuals, and those with other immunodeficiencies and co-morbidities. Targeting these groups in order to prevent TB is particularly impo1tant if the ultimate goal of eliminating the disease is to be achieved. The emergence of antimicrobial drug resistance in Mycobacterium tuberculosis strains with multidrug- (MOR) and extensively drug-resistant (XDR) profiles has become a major obstacle to achievement of the Millennium Development Goal of TB, which aims for the elimination of the disease by 2050. However, for the first time in many centuries, new drugs for the treatment of TB will soon become available. These new weapons must be used wisely. There may be a further barrier to disease elimination: medical students and even residents of internal medicine from indusnialised countries may complete their education without seeing a single patient with TB. This lack of experience is reflected in the diagnostic delay een in these countrie . However, important advances have been achieved in the prevention, diagnosis and treatment of TB in recent years. This has been due to the hard work and dedication of leaders in the field, many of whom have kindly agreed to contribute to this issue of the European Respiratory Monograph (ERM). We arc very grateful for their commitment to the field and for their support in the compilation of this publication. This issue of the ERM includes up-to-date information on TB epidemiology, as well as control and elimination strategies. TB prevention, including the late t developments in novel vaccine research, and recent advance in the diagnosis and treatment of latent infection with M. tuberculosis, are al o pre ented. The issue also covers state-of-the-art diagnosis of TB and the treatment of active TB in patients from different risk groups, including cases of M. tuberculosis drug resistance and complications of therapy. We hope that this issue of the ERM will prove a u eful and valuable reference source to our coUeagucs, and will inspire young clinicians and scientists to enter this fascinating field. Eur Respir Monogr 2012; 58: viii. Printed in UK-all rights reserved, Copyright ERS 2012. European Respiratory Monograph; DOI: 10.1183/1025<148x.10039512. Print ISBN: 978-1-84984-027-9. Online ISB : 978-1-84984--028-6. Print ISS : 1025-448x. Online I N:2 075-6674. Chapter 1 Microbiology of • Mycobacterium tuberculosis and a new diagnostic test for TB Vera Katalinic-Jankovic*, Lucinda Furci" and Daniela Maria Cirillo" SUMMARY: Tuberculo i (TB) has been one of the mo t 'CrOJti.ln Nation.ii ln.iitut~ or Public Health, 11! NRL and ~NRL, ugn,b, important human di eases for centuries now. It is mainly caused Cro;alia. •Emerging Bacterial P.11hogcn_-. Unit by Mycobacterium tuberculosis, a highly elusive bacillus. This 1 San lbffJd< Sciion or Immunology. which enable urvival for a long as decade . The fight with such 1 ran,pl.rntauon .1nd lnf«nous a smart rival gives rise to the necessity for early diagnosis Di~~ San Raffatlt <;ci~11ific lnsttlut<, Via Oli;cttin;i ~ MilJn, and appropriate treatment. The ability to rapidly detect M. Italy. Email: ci rillo.d.a.nida hsr.it tuberculosis in clinical specimens, a well a drug resi tance, i essential for the appropriate treatment of TB patients and the prevention of spread of drug-resi tant train . New molecular tools are now u ed in many countries as part of a standard Laboratory diagnosis. It is clear that important advances in TB diagno i have recently been made and potentially useful new tools are emerging. Nevcrtheles , there is still a lot to be done, especially in high-burden countries where fast identification and early treatment are needed. lur RII. 1-1.l. Copyrlllf,1 I R5 1012. KEYWORDS: Diagnostic tools, drug resistance, immunity, 001: tO.tt~.lllO?s+IQ<.10012}11 Print l~BN ~711-l-l!-1:11\4-027·~ latency, Mycobacterium tuberculosis, pathogenesis Onlin< 1~81': ~11<·1·114•1>4·0211-6 !'Tint bS'I 1025-H~• Onlmc l!-1,),1: ?07~7~ I n 1882, Robert Koch discovered Mycobaderi11111 tuberrnlosis., the bacillus responsible for tuberculosis (TB), thus identifying TB as an infectious disease [ l]. This discovery led hortly thereafter to the identification of methods to stain bacilli in cliniral specimens, making the organisms identifiable with the use of light microscopy. uch was the birth of TB diagnostic and of microbial diagnostics in general. The name Mycobacteri11m, which means "fungus bacterium", was introduced in 1896 (2]. It describes the way that the tubercle bacillus grows on the surface of liquid media as rnould Like pellicles [2]. These aerobic, asporogenous rods have been referred to as the "ducks of the microbial world" due to their thick, wax-y outer coating. The genus Mycobacterium comprises a number of aerobic bacteria and is the only member of the family Mycobacteriaceae, haring an unusually high genomic D A G+C content (62-70%) and the production of mycolic acids with the closely related genera Nocardia and Corynebncterium within the order Aclinomycctales. The most important member of the genus, M. tuberculosis, is an intracellular pathogen that does not possess the classic bacterial virulence factors such as toxins, capsules or fimbriae. Several structural and physiological properties of the bacterium are recognised for their contribution to virulence and pathology of the disease. M. tuberculosis is an aerobic, non-spore forming, non-motile bacillus with a high cell wall content of high molecular weight lipids, which comprise approximately 60% of the cell wall structure. Due to this cell wall composition, mycobacteria stain poorly with Gram stain but are described as acid-fast, as once stained with hot carbol-fuchsin it resists decolourisation with acidified organic solvents (Ziehl-Neelsen stain) [3]. The high lipid concentration in the cell wall accounts for its impermeability and resistance to antimicrobial agents, and resistance to killing by acidic and alkaline compounds in both the intra and extracellular environment. !vi. tuberculosis has the ability to form serpentine structures ( cords). The cord factor is primarily associated with virulent M. tuberculosis strains. Although its exact role in M. tuberculosis virulence is unclear, it is known to be toxic to mammalian cells and to be an inhibitor of polymorphonuclear leucocyte migration. M. tuberculosis grows successfully under aerobic conditions but it is also able to survive in oxygen-deprived environments. In vivo, M. tuberculosis grows better in tissues with a high oxygen content, such as the lungs. The bacillus divides every 20-22 hours, and this slow replication rate and the ability to persist in a latent state means that individuals infected with M. tuberculosis require long periods of drug and preventive therapies. TB is caused by M. tuberculosis and TB complex members (Mycobacterium bovis, M. bovis bacille Calmette-Guerin (BCG), Mycobacterium africanum, Mycobacterium canettii, Mycobacterium pinnipedii and Mycobacterium microti) and is one of the most intensively studied human diseases. It can target practically any organ of the body and clinical microbiological studies have been performed for decades. Humans are the only reservoir for the M. tuberculosis species, although many animals are also susceptible to infection [4 ]. M. bovis was responsible for about 6% of all human deaths in Europe before the introduction of milk pasteurisation and attenuation of a laboratory strain of M. bovis led to the development of the BCG vaccine in 1921. In the 1950s, it became clear that other Mycobacterium spp. in addition to those causing TB and leprosy were also human pathogens. In 1959, RUNYON [SJ proposed a classification of these non-tuberculous mycobacteria (NTM) into four major groups, based on growth rates and colony pigmentation. NTMs are generally free-living organisms that are ubiquitous in the environment around the world, and can be found in deserts, under rocks and among dried roots of vegetation [6 ]. Their optimal habitat in the environment is close to fresh water, both flowing and static. Currently, more than 150 NTM species have been identified. Phylogenetic trees are available that depict genetic relatedness based on homology of the 16S ribosomal RNA (rRNA) gene sequence. Mycobacteria that have highly homologous rRNA sequences are closely related and are on neighbouring branches of the tree [7]. The mycobacterial phylogenetic tree can be further subdivided into fast- and slow-growing bacteria. The fast growers form colonies on selective media in less than 7 days, whereas the slow growers take more than 7 days. In addition, within the genus Mycobacterium a number of species are grouped into complexes (e.g. Mycobacterium avium and M. tuberculosis complexes) that include bacterial species that have a high degree of genetic similarity and cause similar disease syndromes. The M. tuberculosis complex species share 99.9% sequence identity and probably evolved from a single clonal ancestor. Advances in mycobacterial genomics are providing evidence that the amount of sequence variation in the M. tuberculosis genome might have been underestimated and that some genetic diversity does have important phenotypic consequences. Studies of the phylogeny and biogeography of M. tuberculosis have revealed six main strain lineages that are associated with particular geographical regions [8 ]. Pathogenesis and immunity Early steps of infection !vi. tuberculosis is a highly successful bacterial pathogen that mainly targets host macrophages, key mediators of both innate and adaptive immune response. In lung infections, M. tuberculosis is typycallyi nhaled into the body, passes through the airways and reaches the alveolar space. Here, it interacts with dendritic cells [9, 10], alveolar macrophages and pulmonary epithelial cells, but its optimal hosts are alveolar macrophages and other mononuclear phagocytes [ 11 ]. M. tuberculosis gains entry into alveolar macrophages through receptor-mediated phagocytosis, a normal feature of the innate immune system. Two main routes are exploited: bacterial cell surface molecules activate complement proteins present in the alveolar space, which are then recognised by complement receptors on macrophages; or alveolar macrophages recognise bacterial mannose residues (particularly mannose-capped lipoarabinomannan), directly through binding with macrophage mannose receptors (fig. 1) [ 12). Alveolar macrophages are attractive targets for M. tuberculosis because they are adapted to the task of removing small airborne particles through phagocytosis, and Inhaled M. tuberculosis ', Alveolar space Scavenger receptors 3 M. tuberculosis uptake receptors M. tuberculosis recognition receptors TLR4 DC-SIGN Phagocyte Figure 1. Early steps of phagocyte infection. 1) Mycobacterium tuberculosis Is inhaled through the airways and travels all the way to the alveoli of the lower portion of the lungs where it establishes stage I infection. 2) In the alveolar space, mycobacteria are actively phagocytosed by resident macrophages and dendritic cells. 3) Complement receptors (CR) are primarily responsible for uptake of opsonised M. tuberculosis and mannose receptors, and scavenger receptors for the uptake of nonopsonlsed M. tuberculosis. 4) Recognition receptors and Toll-like receptors (TLRs) are expressed not only at the cell surface but also In phagosomes; therefore, immune activation may occur with or without phagocytosis. NOD: nucleotide-binding oligomerisation domain protein; NLRP3: NOD, LAA and pyrin domain containing 3; DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3 grabbing nonlntegrin.

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