Advertisement

Drug-Resistant Tuberculosis

  • Faiz Ahmad KhanEmail author
  • Greg FoxEmail author
  • Dick Menzies
Reference work entry

Abstract

Tuberculosis, an airborne infectious disease caused by the organism Mycobacterium tuberculosis, has been a leading cause of death for centuries and remains a major cause of morbidity and mortality in many parts of the world. In 2012, 8.6 million people became sick with tuberculosis, and 1.3 million died from this curable disease (World Health Organization 2013a). While the majority of cases are caused by strains susceptible to all antituberculosis antibiotics, drug resistance is a major concern that carries the potential to reverse decades of progress in tuberculosis control. This chapter examines the global epidemiology of drug-resistant tuberculosis and the drivers for development of drug resistance and its spread within populations. We explore the reasons for the complex nexus between drug resistance and access to health care, including case studies of countries whose epidemics have taken different trajectories. We examine the important implications of drug-resistant tuberculosis for health systems in both the developed world and low- and middle-income countries. Finally, we discuss the elements needed to control the spread of drug-resistant tuberculosis.

Keywords

Tuberculosis MDR-TB XDR-TB nosocomial tuberculosis health systems 

References

  1. Addington WW, Agarwal MK, Banner AS (1977) Toward shorter-course antituberculosis chemotherapy. Chest 71(5):565CrossRefPubMedGoogle Scholar
  2. Ahuja SD, Ashkin D, Avendano M et al (2012) Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med 9(8):e1001300CrossRefPubMedPubMedCentralGoogle Scholar
  3. Almeida Da Silva PE, Palomino JC (2011) Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J Antimicrob Chemother 66(7):1417–1430CrossRefPubMedGoogle Scholar
  4. Andrews JR, Shah NS, Gandhi N et al (2007) Multidrug-resistant and extensively drug-resistant tuberculosis: implications for the HIV epidemic and antiretroviral therapy rollout in South Africa. J Infect Dis 196(Suppl 3):S482–S490CrossRefPubMedGoogle Scholar
  5. Armstrong GL, Conn LA, Pinner RW (1999) Trends in infectious disease mortality in the United States during the 20th century. JAMA 281(1):61–66CrossRefPubMedGoogle Scholar
  6. Babalik A, Babalik A, Mannix S, Francis D, Menzies D (2011) Therapeutic drug monitoring in the treatment of active tuberculosis. Can Respir J 18(4):225–229CrossRefPubMedPubMedCentralGoogle Scholar
  7. Basu S, Stuckler D, McKee M (2011) Addressing institutional amplifiers in the dynamics and control of tuberculosis epidemics. Am J Trop Med Hyg 84(1):30CrossRefPubMedPubMedCentralGoogle Scholar
  8. Becerra M, Appleton S, Franke M et al (2011) Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet 377:147–152CrossRefPubMedGoogle Scholar
  9. Bell WJ, Brown PP (1960) Bacterial resistance to streptomycin, pas and isoniazid in untreated patients with symptomatic pulmonary tuberculosis in Ashanti. Tubercle 41:247–252CrossRefPubMedGoogle Scholar
  10. Bhaumik S (2013) India’s human rights commission seeks answers over shortage of TB drugs. Br Med J 347:f4301CrossRefGoogle Scholar
  11. Bloom BR, Murray CJ (1992) Tuberculosis: commentary on a reemergent killer. Science 257(5073):1055–1064CrossRefPubMedGoogle Scholar
  12. Boehme CC, Nabeta P, Hillemann D et al (2010) Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 363(11):1005–1015CrossRefPubMedPubMedCentralGoogle Scholar
  13. Borrell S, Gagneux S (2011) Strain diversity, epistasis and the evolution of drug resistance in Mycobacterium tuberculosis. Clin Microbiol Infect 17(6):815–820CrossRefPubMedPubMedCentralGoogle Scholar
  14. Bradford WZ, Martin JN, Reingold AL, Schecter GF, Hopewell PC, Small PM (1996) The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 348(9032):928–931CrossRefPubMedGoogle Scholar
  15. Brigden G, Nyang’wa BT, du Cros P et al (2014) Principles for designing future regimens for multidrug-resistant tuberculosis. Bull World Health Organ 92(1):68–74CrossRefPubMedGoogle Scholar
  16. Brudney K, Dobkin J (1991) Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 144(4):745–749CrossRefPubMedGoogle Scholar
  17. Centers for Disease Control and Prevention (1999) Primary multidrug-resistant tuberculosis–Ivanovo Oblast, Russia, 1999. MMWR Morb Mortal Wkly Rep 48(30):661–664Google Scholar
  18. Cohen J (2013) Infectious disease. Approval of novel TB drug celebrated--with restraint. Science 339(6116):130CrossRefPubMedGoogle Scholar
  19. Coker R (1998) Lessons from New York’s tuberculosis epidemic. Tuberculosis is a political as much as a medical problem-and so are the solutions. Br Med J 317(7159):616CrossRefGoogle Scholar
  20. Coninx R, Mathieu C, Debacker M et al (1999) First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Lancet 353(9157):969–973CrossRefPubMedGoogle Scholar
  21. Cox HS, Niemann S, Ismailov G et al (2007) Risk of acquired drug resistance during short-course directly observed treatment of tuberculosis in an area with high levels of drug resistance. Clin Infect Dis 44(11):1421–1427CrossRefPubMedGoogle Scholar
  22. Crofton J (1959) Chemotherapy of pulmonary tuberculosis. Br Med J 1(5138):1610–1614CrossRefPubMedPubMedCentralGoogle Scholar
  23. Crofton J (1960) Tuberculosis undefeated. Br Med J 2(5200):679–687CrossRefPubMedPubMedCentralGoogle Scholar
  24. Crofton J, Mitchison DA (1948) Streptomycin resistance in pulmonary tuberculosis. Br Med J 2(4588):1009–1015CrossRefPubMedPubMedCentralGoogle Scholar
  25. Dalton T, Cegielski P, Akksilp S et al (2012) Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 380(9851):1406–1417CrossRefPubMedGoogle Scholar
  26. Daniels M, Hill AB (1952) Chemotherapy of pulmonary tuberculosis in young adults; an analysis of the combined results of three medical research council trials. Br Med J 1(4769):1162–1168CrossRefPubMedPubMedCentralGoogle Scholar
  27. David HL (1970) Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol 20(5):810–814PubMedPubMedCentralGoogle Scholar
  28. Dowdy DW, Chaisson RE, Maartens G, Corbett EL, Dorman SE (2008) Impact of enhanced tuberculosis diagnosis in South Africa: a mathematical model of expanded culture and drug susceptibility testing. Proc Natl Acad Sci U S A 105(32):11293–11298CrossRefPubMedPubMedCentralGoogle Scholar
  29. Drobniewski F, Tayler E, Ignatenko N et al (1996a) Tuberculosis in Siberia: 2. Diagnosis, chemoprophylaxis and treatment. Tuberc Lung Dis 77(4):297–301CrossRefGoogle Scholar
  30. Drobniewski F, Tayler E, Ignatenko N et al (1996b) Tuberculosis in Siberia: 1. An epidemiological and microbiological assessment. Tuberc Lung Dis 77(3):199–206CrossRefGoogle Scholar
  31. Dye C (2009) Doomsday postponed? Preventing and reversing epidemics of drug-resistant tuberculosis. Nat Rev Microbiol 7(1):81–87CrossRefPubMedGoogle Scholar
  32. East African/British Medical Research Council (1973a) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis: second report. The Lancet 301(7816):1331–1339Google Scholar
  33. East African/British Medical Research Council (1973b) Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis: third report. The Lancet 304(7875):237–240Google Scholar
  34. Escombe AR, Oeser CC, Gilman RH et al (2007) Natural ventilation for the prevention of airborne contagion. PLoS Med 4(2):e68CrossRefPubMedPubMedCentralGoogle Scholar
  35. Falzon D, Jaramillo E, Schunemann HJ et al (2011) WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 38(3):516–528CrossRefPubMedGoogle Scholar
  36. Falzon D, Gandhi N, Migliori G et al (2013) Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. Eur Respir J 42(1):156–168CrossRefPubMedGoogle Scholar
  37. Farmer P, Bayona J, Becerra M et al (1998) The dilemma of MDR-TB in the global era. Int J Tuberc Lung Dis 2(11):869PubMedGoogle Scholar
  38. Fitzpatrick C, Floyd K (2012) A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis. Pharmacoeconomics 30(1):63–80CrossRefPubMedGoogle Scholar
  39. Ford CB, Shah RR, Maeda MK et al (2013) Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nat Genet 45(7):784–790CrossRefPubMedPubMedCentralGoogle Scholar
  40. Fox W, Ellard GA, Mitchison DA (1999) Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis 3(10 Suppl 2):S231–S279PubMedGoogle Scholar
  41. Fox GJ, Barry SE, Britton WJ, Marks GB (2013) Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J 41(1):140–156CrossRefPubMedGoogle Scholar
  42. Frick M, Jiminez-Levi E (2013) Report on tuberculosis research funding trends, 2005–2012. In: Harrington M (ed) New York: Treatment Action Group http://www.treatmentactiongroup.org/sites/tagone.drupalgardens.com/files/201310/TAG_TB_2013_8.5.pdf
  43. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW (1993) The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 328(8):521–526CrossRefPubMedGoogle Scholar
  44. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA (1995) Tuberculosis in New York City–turning the tide. N Engl J Med 333(4):229–233CrossRefPubMedGoogle Scholar
  45. Gandhi NR, Moll A, Sturm AW et al (2006) Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368(9547):1575–1580CrossRefPubMedGoogle Scholar
  46. Gelmanova IY, Keshavjee S, Golubchikova VT et al (2007) Barriers to successful tuberculosis treatment in Tomsk, Russian federation: non-adherence, default and the acquisition of multidrug resistance. Bull World Health Organ 85(9):703–711CrossRefPubMedPubMedCentralGoogle Scholar
  47. Global Drug Facility Stop TB Partnership GDF impact on SLD dynamics. Available at: http://www.stoptb.org/assets/documents/gdf/whatis/SecondLineDrugs.pdf. Accessed Jan 2014
  48. Hazbon MH, Brimacombe M, Bobadilla del Valle M et al (2006) Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 50(8):2640–2649CrossRefPubMedPubMedCentralGoogle Scholar
  49. Jenkins HE, Zignol M, Cohen T (2011) Quantifying the burden and trends of isoniazid resistant tuberculosis, 1994–2009. PLoS One 6(7):e22927CrossRefPubMedPubMedCentralGoogle Scholar
  50. Jensen PA, Lambert LA, Iademarco MF, Ridzon R (2005) Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. MMWR Morb Mortal Wkly Rep 54:1–141Google Scholar
  51. Kenyon TA, Valway SE, Walter WI, Onorato IM, Castro KG (1996) Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N Engl J Med 334(15):933–938CrossRefPubMedGoogle Scholar
  52. Kim S, Bai G, Hong Y (1997) Drug-resistant tuberculosis in Korea, 1994. Int J Tuberc Lung Dis 1(4):302–308PubMedGoogle Scholar
  53. Kim JY, Mukherjee JS, Rich ML, Mate K, Bayona J, Becerra MC (2003) From multidrug-resistant tuberculosis to dots expansion and beyond: making the most of a paradigm shift. Tuberculosis 83(1–3):59–65CrossRefPubMedGoogle Scholar
  54. Kimerling ME, Kluge H, Vezhnina N et al (1999a) Inadequacy of the current WHO re-treatment regimen in a Central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 3(5):451–453PubMedGoogle Scholar
  55. Kimerling ME, Kluge H, Vezhnina N et al (1999b) Inadequacy of the current WHO re-treatment regimen in a Central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 3(5):451–453PubMedGoogle Scholar
  56. Knox R, MacLean KS, Robson JM (1952) New results with isonicotinic acid hydrazide. Br Med J 1(4767):1081CrossRefPubMedCentralGoogle Scholar
  57. Kochi A (1999) Directly observed treatment for tuberculosis. Lancet 353(9147):147–148CrossRefPubMedGoogle Scholar
  58. Landesman SH (1993) Commentary: tuberculosis in New York City–the consequences and lessons of failure. Am J Public Health 83(5):766–768CrossRefPubMedPubMedCentralGoogle Scholar
  59. Laserson KF, Kenyon AS, Kenyon TA, Layloff T, Binkin NJ (2001) Substandard tuberculosis drugs on the global market and their simple detection. Int J Tuberc Lung Dis 5(5):448–454PubMedGoogle Scholar
  60. Lienhardt C, Sillah J, Fielding K et al (2003) Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in the Gambia, West Africa. Pediatrics 111(5 Pt 1):e608–e614CrossRefPubMedGoogle Scholar
  61. Medical Research Council Streptomycin in Tuberculosis Trials Committee (1948) Streptomycin treatment of pulmonary tuberculosis. Br Med J 2(4582):769–782CrossRefGoogle Scholar
  62. Menzies D, Benedetti A, Paydar A et al (2009) Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med 6(9):e1000150CrossRefPubMedPubMedCentralGoogle Scholar
  63. Mitnick C, Bayona J, Palacios E et al (2003) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 348(2):119–128CrossRefPubMedGoogle Scholar
  64. Moodley P, Shah NS, Tayob N et al (2011) Spread of extensively drug-resistant tuberculosis in Kwazulu-Natal Province, South Africa. PLoS One 6(5):e17513CrossRefPubMedPubMedCentralGoogle Scholar
  65. Murray JF (2004) A century of tuberculosis. Am J Respir Crit Care Med 169(11):1181–1186CrossRefPubMedGoogle Scholar
  66. Nardell E, Dharmadhikari A (2010) Turning off the spigot: reducing drug-resistant tuberculosis transmission in resource-limited settings. Int J Tuberc Lung Dis 14(10):1233–1243PubMedPubMedCentralGoogle Scholar
  67. Nodieva A, Jansone I, Broka L, Pole I, Skenders G, Baumanis V (2010) Recent nosocomial transmission and genotypes of multidrug-resistant Mycobacterium tuberculosis. Int J Tuberc Lung Dis 14(4):427–433PubMedGoogle Scholar
  68. O’Brien RJ, Nunn PP (2001) The need for new drugs against tuberculosis. Obstacles, opportunities, and next steps. Am J Respir Crit Care Med 163(5):1055–1058CrossRefPubMedGoogle Scholar
  69. Oxlade O, Falzon D, Menzies D (2012) The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis. Eur Respir J 39(3):626–634. doi:10.1183/09031936.0065311. Epub 2011 Aug 4CrossRefPubMedGoogle Scholar
  70. Pablos-Mendez A, Knirsch CA, Barr RG, Lerner BH, Frieden TR (1997) Nonadherence in tuberculosis treatment: predictors and consequences in New York City. Am J Med 102(2):164–170CrossRefPubMedGoogle Scholar
  71. Pablos-Mendez A, Raviglione MC, Laszlo A et al (1998) Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 338(23):1641–1649CrossRefPubMedGoogle Scholar
  72. Pantoja A, Fitzpatrick C, Vassall A, Weyer K, Floyd K (2013) Xpert Mtb/Rif for diagnosis of tuberculosis and drug-resistant tuberculosis: a cost and affordability analysis. Eur Respir J 42(3):708–720CrossRefPubMedGoogle Scholar
  73. Parwati I, van Crevel R, van Soolingen D (2010) Possible underlying mechanisms for successful emergence of the Mycobacterium tuberculosis beijing genotype strains. Lancet Infect Dis 10(2):103–111CrossRefPubMedGoogle Scholar
  74. Pooran A, Pieterson E, Davids M, Theron G, Dheda K (2013) What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa? PLoS One 8(1):e54587CrossRefPubMedPubMedCentralGoogle Scholar
  75. Prasad R (2010) Multidrug and extensively drug-resistant TB (M/XDR-TB): problems and solutions. Indian J Tuberc 57(4):180–191PubMedGoogle Scholar
  76. Rieder HL, International Union Against Tuberculosis and Lung Disease (1999) Epidemiologic basis of tuberculosis control. International Union Against Tuberculosis and Lung Disease, ParisGoogle Scholar
  77. Shilova MV, Dye C (2001) The resurgence of tuberculosis in Russia. Philos Trans R Soc Lond B Biol Sci 356(1411):1069–1075CrossRefPubMedPubMedCentralGoogle Scholar
  78. Simpson JM (1959) Drug resistance in out-patients treated with sodium pas and isoniazid cachets. Tubercle 40:453–456CrossRefPubMedGoogle Scholar
  79. Snider DE Jr, La Montagne JR (1994) The neglected global tuberculosis problem: a report of the 1992 world congress on tuberculosis. J Infect Dis 169(6):1189–1196CrossRefPubMedGoogle Scholar
  80. Steingart KR, Sohn H, Schiller I et al (2013) Xpert(R) Mtb/Rif assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 1, CD009593Google Scholar
  81. Sterling TR (2006) Drug-resistant tuberculosis in New York City: lessons to remember. Clin Infect Dis 42(12):1711–1712CrossRefPubMedGoogle Scholar
  82. Streicher EM, Muller B, Chihota V et al (2012) Emergence and treatment of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in South Africa. Infect Genet Evol 12(4):686–694CrossRefPubMedGoogle Scholar
  83. Sun G, Luo T, Yang C et al (2012) Dynamic population changes in Mycobacterium tuberculosis during acquisition and fixation of drug resistance in patients. J Infect Dis 206(11):1724–1733CrossRefPubMedPubMedCentralGoogle Scholar
  84. Udwadia ZF, Pinto LM, Uplekar MW (2010) Tuberculosis management by private practitioners in Mumbai, India: has anything changed in two decades? PLoS One 5(8):e12023CrossRefPubMedPubMedCentralGoogle Scholar
  85. van der Werf MJ, Langendam MW, Huitric E, Manissero D (2012) Multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis. Eur Respir J 39(6):1511–1519CrossRefPubMedGoogle Scholar
  86. Van Deun A, Maug AK, Salim MA et al (2010) Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 182(5):684–692CrossRefPubMedGoogle Scholar
  87. Weyer K, Mirzayev F, Migliori GB et al (2013) Rapid molecular TB diagnosis: evidence, policy making and global implementation of Xpert Mtb/Rif. Eur Respir J 42(1):252–271CrossRefPubMedGoogle Scholar
  88. World Health Organization (2009) WHO policy on TB infection control in health-care facilities, congregate settings and households. World Health Organization, GenevaGoogle Scholar
  89. World Health Organization (2010a) Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. World Health Organization, GenevaGoogle Scholar
  90. World Health Organization (2010b) Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response. WHO, GenevaGoogle Scholar
  91. World Health Organization (2011a) Guidelines for the programmatic management of drug-resistant tuberculosis – 2011 update. WHO, GenevaGoogle Scholar
  92. World Health Organization (2011b) Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015: WHO progress report 2011. World Health Organization, GenevaGoogle Scholar
  93. World Health Organization (2012) Global tuberculosis report 2012. WHO, GenevaGoogle Scholar
  94. World Health Organization (2013a) Global tuberculosis report 2013. WHO, GenevaGoogle Scholar
  95. World Health Organization (2013b) Definitions and reporting framework for tuberculosis – 2013 revision. World Health Organization, GenevaGoogle Scholar
  96. World Health Organization, Regional Office for Europe (2011) Roadmap to prevent and combat drug-resistant tuberculosis : the consolidated action plan to prevent and combat multidrug- and extensively drug-resistant tuberculosis in the WHO European Region 2011–2015. WHO/Regional Office for Europe, CopenhagenGoogle Scholar
  97. World Health Organization, Stop TB Department (2008) Guidelines for the programmatic management of drug-resistant tuberculosis. World Health Organization, GenevaGoogle Scholar
  98. World Health Organization, Stop TB Department (2010) Treatment of tuberculosis: guidelines, 4th edn. World Health Organization, GenevaGoogle Scholar
  99. World Health Organization, Stop TB Partnership (2010) The Global Plan to Stop TB 2011–2015: transforming the fight towards elimination of tuberculosis. World Health Organization, GenevaGoogle Scholar
  100. Zhao M, Li X, Xu P et al (2009) Transmission of MDR and XDR tuberculosis in Shanghai, China. PLoS One 4(2):e4370CrossRefPubMedPubMedCentralGoogle Scholar
  101. Zhao Y, Xu S, Wang L et al (2012) National survey of drug-resistant tuberculosis in China. N Engl J Med 366(23):2161–2170CrossRefPubMedGoogle Scholar
  102. Zignol M, Gemert WV, Falzon D et al (2012a) Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ 90(2):111–119CrossRefPubMedGoogle Scholar
  103. Zignol M, van Gemert W, Falzon D et al (2012b) Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ 90(2):111–119DCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Montreal Chest InstituteMontrealCanada
  2. 2.Woolcock Institute of Medical ResearchThe University of SydneySydneyAustralia
  3. 3.Respiratory DivisionMcGill UniversityMontrealCanada

Personalised recommendations