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Bio303 Lecture 2 Two Old Enemies, TB and Leprosy


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In this lecture I will focusing on another of the most serious infectious threats to humanity, tuberculosis, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection. I will also discuss a related mycobacterial infection, leprosy and recent progress in its control.

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Bio303 Lecture 2 Two Old Enemies, TB and Leprosy

  1. 1. Global Health and Emerging Infections 2 Old Enemies: Tuberculosis and Leprosy Professor Mark Pallen Bio303
  2. 2. Global Health and Emerging Infections1. The Global Burden of Infection and an Old Enemy, Malaria. In this lecture I will survey the global burden of infection, including its human and economic costs, and examine the problem of neglected tropical diseases before focusing on one of the most serious infectious threats to humanity: malaria, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection.2. Two Old Enemies, TB and Leprosy. In this lecture I will focusing on another of the most serious infectious threats to humanity, tuberculosis, outlining its evolutionary origins, impact on human health and wealth and the steps taken to control and treat this infection. I will also discuss a related mycobacterial infection, leprosy and recent progress in its control.3. New foes. In this lecture I will describe emerging infections, their epidemiology and ecology and the threats that they pose. I will focus on three case studies: SARS, pandemic flu and the German STEC outbreak of May-June 20114. Operation Eradication. In this lecture, I will celebrate the global eradication of smallpox, from the campaigns beginnings in Gloucestershire to the last tragic cases here in Birmingham. I will discuss what is required for an infectious disease to be eradicated and summarise progress on disease eradication, focusing on poliomyelitis and guinea worm.5. Lab Diagnosis of Infectious Disease. Here I will provide an overview of how infections are diagnosed in the clinical microbiology lab, focusing not just on technologies, old and new, but on practical issues and workflows crucial to optimal use of the lab.
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  4. 4. Tuberculosis: Background Infection, usually of the lungs (but can affect other organs), caused by Mycobacterium tuberculosis Most infections asymptomatic or latent ~10% lead to active disease (cough with haemoptysis, plus quartet of fever, malaise, night sweats, weight loss): if untreated, often fatal In 2007, ~13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths Half million cases of multidrug-resistant TB
  5. 5. Tuberculosis in History devastating effect on society  100 years ago one in five of the population was destined to die of tuberculosis...  Chopin, Keates, the Brontes, Kafka, DH Lawrence, Orwell all died from the disease… “Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave.” The Life and Death of Mr. Badman John Bunyan 1680
  6. 6. Tuberculosis: History Mandela, diagnosed with TB inJinnah, during 1940s, ill with TB, dies aged 1988 at age 70, treated, leads S.71 Sept 1948,~ 1 yr after Pakistan gains Africa to multiracialindependence. First randomized trial of democracy, serves as first post-streptomycin against TB in 1947 by MRC Apartheid president, 1994- 1999, retires from office, still alive at age 92
  7. 7. Mycobacterium tuberculosis is different complex lipid-rich cell walls acid-fast bacilli (AFBs) grows very slowly  causes chronic infections hazard to lab & hospital staff
  8. 8. Mycobacterium tuberculosis is different resistant to common antibiotics  need months of multi-drug treatment with special agents intra-cellular pathogen  thrives inside macrophages, forming granulomas  antibodies have no effect  cell-mediated immune response needed for protection
  9. 9. Tuberculosis: Natural History Primary infection  asymptomatic or non-specific symptoms: fever, malaise, weight loss, night sweats  Inhalation of tubercle bacilli  leads to lung infection  Ingestion of tubercle bacilli  tonsils & cervical nodes  small bowel with mesenteric nodes  Implantation into skin
  10. 10. Tuberculosis: Natural History Progressive Primary Infection  Local erosion, dissemination, metastatic infection (e.g. TB meningitis) Latent infection Reactivation  latent period between primary infection and reactivation can be several decades
  11. 11. Tuberculosis: Features Clinical features  Constitutional  Fever, Malaise, Weight loss, Night sweats  Focal  Cough, Haemoptysis, Chest pain Radiological features  Patchy opacities mainly in the upper zone  cavitation, calcification, hilar shadowing  diffuse nodular shadowing in miliary TB
  12. 12. Tuberculosis: PathologyCaseatinggranuloma
  13. 13. Tuberculosis Control Eliminate poverty  Improved hygiene, housing diet etc Bovine TB  Pasteurisation, control animal reservoirs, badger culls?? Vaccination  Immunisation with BCG traditionally in UK at 11-13 years  at birth in at risk infants
  14. 14. Tuberculosis Control Case Management and Follow-up  Infection Control: side-room isolation of open “smear- positive” cases in hospital  Diagnosis: Microscopy, Culture, Sensitivities  Treatment: rapidly renders cases non-infectious  Follow up of contacts: NOTIFIABLE DISEASE
  15. 15. Bacille Calmette-Guérin (BCG) Tuberculosis vaccine strain  derived from a virulent isolate of the bovine tubercle bacillus Attenuation achieved between 1908 and 1921  230 serial passages on glycerinated potato medium containing beef bile By 1921, shown to  be safe in animals  provide protection against challenge with virulent M. tuberculosis Given to > 3 billion people BUT trials show variable efficacy against pulmonary tuberculosis 0-80% effectiveness!  and BCGosis in HIV-infected infants
  16. 16. Diagnosis: Microscopy and Culture stain poorly with the Gram-stain rely on the Acid-fast staining  Ziehl-Neelsen  Auramine fluorescence staining Lowenstein-Jensen slopes  M. tuberculosis grows after 4-6 weeks, rough buff an tough, breadcrumb-like colonies Problems:  Cases passively ascertained  Delays between visit to clinic and diagnosis lead to delays in treatment
  17. 17. Diagnosis: Tuberculin Testing Mantoux test, Heaf test  Purified protein derivative (PPD)  delayed type (Type IV) hypersensitivity Positive  Induration not erythema  past or present infection  or previous BCG vaccination Negative  no previous infection or vaccination
  18. 18. Tuberculosis: Treatment Multi-drug regimens  Initial Phase: 3 drugs for used 2 months  prevent the emergence  Continuation Phase: 2 of resistance during drugs for 4 months therapy & more effective  WHO regimens  Ethambutol EMB or E  2HREZ/4HR3  Isoniazid INH or H  2SHRZ/4HR3  Pyrazinamide PZA or Z  Rifampicin RMP or R  Streptomycin STM or S
  19. 19. Directly observed short-course therapy DOTS: WHO-recommended strategy with five components:  Government commitment  Case detection by sputum smear microscopy  Standardized treatment regimen directly observed for at least the first two months  Regular drug supply  Standardized recording and reporting system that allows assessment of treatment results Lasts 6 months; prone to dropout; concerns over ethics Currently implemented in 184 countries DOTS-plus for MDR-TB
  20. 20. The Stop TB Strategy Vision: a TB-free world  Millennium Development Goal 6, Goal: to substantially reduce the target 8: halt and begin to reverse global burden of TB by 2015 the incidence of tuberculosis by 2015 Objectives  Targets linked to the MDGs and  Achieve universal access to endorsed by Stop TB Partnership: quality diagnosis and patient- centred treatment  2015: reduce prevalence of and deaths due to tuberculosis by  Reduce human and 50% relative to 1990 socioeconomic burden associated with TB  2050: eliminate tuberculosis as a public health problem (less  Protect vulnerable populations than one case per million from TB, TB and HIV, and MDR- population) TB  Support development of new methods and enable timely and effective use  Protect and promote human rights in TB prevention, care and
  21. 21. The Global Plan to Stop TB launched at the World  $56 billion 2006-15 to Economic Forum in treat 50m TB patients Davos, Switzerland on and save 14m lives 27 January 2006  aims to provide: Bill Gates pledged $600  Improved treatment million access  New drugs  New vaccine  New diagnostics
  22. 22. Four obstacles to progress The HIV-associated TB epidemic Drug-resistant TB Need for better diagnostic assays Limited efficacy of BCG vaccination
  23. 23. HIV and TB 15% of TB cases are HIV-  Major individual benefit of positive ART on risk of TB and TB accounts for 23% of mortality global deaths from HIV-  But unclear whether scale- AIDS up of ART improves TB control 80% of HIV-TB cases in  Also risk of TB immune Africa; 25% in South reconstitution disease (TB- Africa IRD) In Eastern Europe, HIV and MDR-TB have doubled TB incidence since 1990 In England and Wales, HIV rate in TB up from 3%
  24. 24. Improved diagnostic assays Fluorescent microscopes with  Nucleic acid amplification light-emitting diode (LED) techniques (NAATs) cheaper and longer-lasting  T-cell based tests MODS: microscopic  Urinary antigen detection observation drug-susceptibility assay  Sputum cultured in tissue culture plate ± drugs  Wells examined daily for growth, using inverted microscope  M. tuberculosis shows typical corded appearance  Time to detection of culture ~8 days
  25. 25. Foundation for Innovative New Diagnostics/Cepheid Xpert MTB/RIF
  26. 26. Novel immunodiagnostics: T-spot ELISPOT assay: counts T cells that produce gamma interferon in response to TB antigens Detects clinical and subclinical infection Detects antigens found only in virulent TB, so does not detect response to BCG vaccine Sensitive and specific BUT high-tech, first-world test
  27. 27. MDR- and XDR-TB MDR-TB = resistance to rifampicin and isoniazid XDR-TB = resistance to rifampicin, isoniazid, any fluoroquinolone and one second-line injectable agent, i.e. amikacin, kanamycin or capreomycin near-doubling of MDR cases since 2000 ~5% or ~0.5M of TB cases worldwide=MDR-TB ~6% or ~40 000 cases of MDR=XDR ~60% of reported MDR-TB in former Soviet Union, India and China, but underestimated in Africa
  28. 28. MDR- and XDR-TB MDR-TB/XDR-TB treatment regimens devised as part of national tuberculosis programme  use additional drugs and for longer  ethical and medico-legal dilemmas with XDR-TB Treatment outcomes of XDR-TB remain poor, especially in HIV-positives  XDR-TB hospital outbreak in Tugela Ferry, South Africa in 2006, 52 of 53 patients died; ~fortnight from diagnosis to death!  overall mortality in South African cohort was 42%, with one year mortality 36%  comparable to an aggressive cancer!
  29. 29. New therapeutic options: new hope! Moxifloxacin  fluoroquinolone with long half-life and sterilizing activity against M. tuberculosis; now in phase III REMox trial of 4 mth regimen TMC207  diarylquinoline with activity on ATP synthase; once-weekly TMC207-rifapentine-pyrazinamide cures mice in two months! In Phase II trials  OPC-67683 a nitroimidazole and PA-824 a nitroimidazopyran In Phase I trials  pyrrole derivative LL3858 and diamine compound SQ109
  30. 30. New anti-TB vaccination strategies Improving BCG by adding immunogenic TB antigens, to enhance and broaden immune responses Attenuating strains through deletion of genes for specific metabolic pathways required for survival or full virulence  rBCG30 overexpresses Ag85B  rBCGΔureC:Hly+ overexpresseslisteriolysin Prime-boost strategies that amplify initial “protective” immune response through subsequent inoculation with viral vectors encoding TB antigens  MVA85A modified vaccinia expressing Ag85A in Phase IIb trial
  31. 31. Are we winning? Global target of treatment success rate of ≥ 85% for new smear-positive cases reached in 2007, but not in nine high-burden countries In 2008, DOTS implemented in 180 countries (91% of those reporting) including all 22 high-burden countries  36 million patients cured between 1995 and 2008  Case fatality rate from 8% to 4%  6m deaths averted through scaling up DOTS, compared to pre-995 scenario
  32. 32. Are we winning? Global case detection rate increased 6X 1995-2008, but stabilised ~ 60%  Target of 70%, originally set for 2000, then postponed to 2005, reached in only six high-burden countries, not yet reached globally 360K HIV-TB patients identified in 2008, ~25% of estimated 1.4 m total  Only 114000 were enrolled on antiretroviral treatment (ART)  Screening for TB in HIV-positive individuals went from 0.6m to 1.4m 2007-8, but only 4% of people with HIV infection worldwide.
  33. 33. Are we winning? The Millennium Development Goal target to halt and begin to reverse tuberculosis incidence by 2015 is estimated to have been reached in 2004 globally  BUT the decline is less than 1% per year. With present efforts, the targets to halve prevalence and death rates by 2015, compared with 1990 rates, will probably be met in most regions  BUT might not be met worldwide Threat of XDR-TB looms  Back to sanatoria and surgery?
  34. 34. Will we win against tuberculosis? The long-term elimination target, to reduce incidence to less than one case per million by 2050, will not be reached with existing technologies and approaches Tuberculosis will not be eliminated in my lifetime  But maybe will in your lifetimes or in your children’s lifetimes?  Do you want to help? Contact Del Besra ( if you want to do a PhD in tuberculosis research
  35. 35. Leprosy chronic infectious disease of skin and peripheral nerves caused by Mycobacterium leprae M. lepraediscovered by Armauer Hansen in 1873  first bacterium identified as causing a disease in humans  Leprosy sometimes called Hansen’s disease Peripheral anaesthesia leads to chronic course of incurable disfigurement and physical disabilities, often culminating in rejection and exclusion from society
  36. 36. Leprosy is curable!
  37. 37. Leprosy Humans only reservoir  apart from armadillos in USA Spectrum of disease spanning  multibacillary (MB) or lepromatous leprosy  paucibacillary (PB) or tuberculoid leprosy MB leprosy is infectious  7 billion organisms/gram of tissue  nose blow most likely source  route of entry to body unknown
  38. 38. Leprosy Control: Diagnosis skin lesion consistent with leprosy and with definite sensory loss, with or without thickened nerves positive skin smears
  39. 39. Leprosy Control: Multi-Drug Therapy single drugs lead to resistance  long MDT needed to prevent relapse but patients no longer infectious after first monthly dose  since 1995, thanks to WHO/Nippon Foundation/Novartis MDT free in all endemic countries WHO recommendations:  MB leprosy treat for12 months (24 months until 1997)  Rifampicin: 600mg once a month  Dapsone: 100mg daily  Clofazimine: 300mg once a month and 50 mg daily  PB leprosy treat for 6 months  Rifampicin: 600mg once a month  Dapsone: 100mg daily
  40. 40. Leprosy: progress towards elimination Over past 20 years, >14 million leprosy patients have been cured!  Global prevalence dropped by 90%  from 21.1 per 10,000 inhabitants to <1 per 10,000 inhabitants Dramatic decrease in the global disease burden   5,200,000 in 1985  805,000 in 1995  753,000 in1999  213,000 in 2008
  41. 41. Leprosy: progress towards elimination Leprosy eliminated (prevalence <1 in 10000) from 119 of 122 countries of where considered public health problem in 1985. Leprosy in the world of 2007  DR Congo and Mozambique achieved elimination (<1 in 10000).  pockets of high endemicity in Angola, Brazil, Central African Republic, DR Congo, India, Madagascar, Mozambique, Timor, Nepal and Tanzania  new case detections remain high in India and Indonesia
  42. 42. Leprosy: progress towards elimination
  43. 43. Will we win against leprosy? Stunning progress in my lifetime  But remains questionable whether leprosy can be eliminated with current approaches  But I live in hope that my grandchildren will one day be born into a world without leprosy
  44. 44. Any questions?