Global Health and Emerging Infections 2Old Enemies: Tuberculosis and Leprosy

Professor Mark Pallen

Bio303

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 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.

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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

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. BadmanJohn Bunyan 1680

Tuberculosis: History

Jinnah, during 1940s, ill with TB, dies aged 71 Sept 1948,~ 1 yr after Pakistan gains independence. First randomized trial of streptomycin against TB in 1947 by MRC

Mandela, diagnosed with TB in 1988 at age 70, treated, leads S. Africa to multiracial democracy, serves as first post-Apartheid president, 1994-1999, retires from office, still alive at age 92

Mycobacterium tuberculosis is different complex lipid-rich cell walls acid-fast bacilli (AFBs) grows very slowly

causes chronic infections hazard to lab & hospital staff

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

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

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

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

Tuberculosis: Pathology

Caseating granuloma

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

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

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

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

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

Tuberculosis: Treatment Multi-drug regimens

used prevent the

emergence of resistance during therapy & more effective

Ethambutol EMB or E Isoniazid INH or H Pyrazinamide PZA or

Z Rifampicin RMP or R Streptomycin STM or

S

Initial Phase: 3 drugs for 2 months

Continuation Phase: 2 drugs for 4 months

WHO regimens 2HREZ/4HR3

2SHRZ/4HR3

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

The Stop TB Strategy Vision: a TB-free world Goal: to substantially reduce

the global burden of TB by 2015

Objectives Achieve universal access to

quality diagnosis and patient-centred treatment

Reduce human and socioeconomic burden associated with TB

Protect vulnerable populations from TB, TB and HIV, and MDR-TB

Support development of new methods and enable timely and effective use

Protect and promote human rights in TB prevention, care and control

Millennium Development Goal 6, target 8: halt and begin to reverse the incidence of tuberculosis by 2015

Targets linked to the MDGs and endorsed by Stop TB Partnership: 2015: reduce prevalence of

and deaths due to tuberculosis by 50% relative to 1990

2050: eliminate tuberculosis as a public health problem (less than one case per million population)

The Global Plan to Stop TB launched at the

World Economic Forum in Davos, Switzerland on 27 January 2006

Bill Gates pledged $600 million

$56 billion 2006-15 to treat 50m TB patients and save 14m lives

aims to provide: Improved treatment

access New drugs New vaccine New diagnostics

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

HIV and TB 15% of TB cases are

HIV-positive TB accounts for 23% of

global deaths from HIV-AIDS

80% of HIV-TB cases in Africa; 25% in South Africa

In Eastern Europe, HIV and MDR-TB have doubled TB incidence since 1990

In England and Wales, HIV rate in TB up from 3% in 1999 to >8% in 2003; but decrease in USA

Major individual benefit of ART on risk of TB and mortality But unclear whether

scale-up of ART improves TB control

Also risk of TB immune reconstitution disease (TB-IRD)

Improved diagnostic assays Fluorescent microscopes

with light-emitting diode (LED) cheaper and longer-lasting

MODS: microscopic 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

Nucleic acid amplification techniques (NAATs)

T-cell based tests Urinary antigen detection

Foundation for Innovative New Diagnostics/Cepheid

Xpert MTB/RIF

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

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

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!

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

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+ overexpresses listeriolysin

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

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

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.

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?

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

Leprosy chronic infectious disease of skin

and peripheral nerves caused by Mycobacterium leprae

M. leprae discovered 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

Leprosy is curable!

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

Leprosy Control: Diagnosis skin lesion consistent

with leprosy and with definite sensory loss, with or without thickened nerves

positive skin smears

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

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

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

Leprosy: progress towards elimination

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

Any questions?