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.

1. Global Health and Emerging Infections 2
Old Enemies: Tuberculosis and Leprosy
Professor Mark Pallen
Bio303

2. Global Health and Emerging Infections
1. 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 2011
4. Operation Eradication. In this lecture, I will celebrate the global eradication of smallpox,
from the campaign's 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.

3. http://www.facebook.com/pages/Bio303-
Module/159615697415445

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

6. 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

7. Tuberculosis: History
Mandela, diagnosed with TB in
Jinnah, during 1940s, ill with TB, dies aged 1988 at age 70, treated, leads S.
71 Sept 1948,~ 1 yr after Pakistan gains Africa to multiracial
independence. 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

8. Mycobacterium tuberculosis is different
 complex lipid-rich cell walls
 acid-fast bacilli (AFBs)
 grows very slowly
 causes chronic infections
 hazard to lab & hospital staff

9. 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

10. 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

11. 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

13. 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

14. Tuberculosis: Pathology
Caseatinggranuloma

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

25. Four obstacles to progress
 The HIV-associated TB epidemic
 Drug-resistant TB
 Need for better diagnostic assays
 Limited efficacy of BCG vaccination

26. 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%

27. 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

28. Foundation for Innovative New Diagnostics/Cepheid
Xpert MTB/RIF

29. 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

30. 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

31. 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!

32. 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

33. 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

34. 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

35. 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.

36. 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?

37. 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
(g.besra@bham.ac.uk) if you want to do a PhD in
tuberculosis research

38. 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

46. Leprosy is curable!

47. 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

48. Leprosy Control: Diagnosis
 skin lesion consistent
with leprosy and with
definite sensory loss,
with or without
thickened nerves
 positive skin smears

49. 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

50. 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

51. 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

52. Leprosy: progress towards elimination

53. 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

54. Any questions?