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TB Flashcards

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1
Q

History of TB

A
  • an ancient disease
  • Genus Mycobacterium: >150 mya
  • progenitor may have infected early hominids in East Africa
  • first CAs of modern M.tb: ~15-20,000 ya
  • egyptian mummies (~2400 BC) + art: evidence of TB
  • Dr. Granville ancient DNA typing of spines; had a TB hunch
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2
Q

Phthisis

A
  • Ancient Greece
  • Hippocrates: fatal disease, esp. for young adults
  • accurately defined symptoms, characteristic lung lesions
  • Isocrates: infectious origin
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3
Q

King’s Evil/Scrofula

A
  • Middle Ages England
  • ‘King’s touch’: cure (Queen Anne was the last to do it)
  • 16C, Fracastoro: clearly defined as contagious
  • 1671, de La Boe: pulmonary tubercles = scrofula; enlarged lymph nodes
  • 18C: ‘Great White Plague’, ‘White Death’; anaemia causes white pallour
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4
Q

Koch

A
  • ‘Die Aetiologie der Tuberculose’
  • identified, isolated and cultivated tubercule bacillus
  • 1882: presented
  • 1905: Nobel Prize
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5
Q

Koch’s Postulates - the basics

A
  • 1884
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6
Q

Koch’s Postulates - the specifics

A
  1. suspected CA absent from all healthy organisms; present in all diseased organisms
  2. isolated from diseased organism grown in pure culture
  3. cause the same disease when inoculated into a healthy, susceptible organism
  4. reisolated from inoculated, diseased organism
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7
Q

Isocrates

A

infectious origin

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8
Q

Koch

A

physician and microbiologist

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9
Q

CA

A

causative agent

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10
Q

TB epidemic - the basics

A
  • one of the most infectious mortal pathogens globally
  • 1/4 population latently infected
  • SSA: conc.
  • LICs
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11
Q

TB epidemic - 2022:

A
  • 10.6 million symptomatic
  • 1.3 million fatal (167,000 HIV-coinfected)
  • 8 countries: 68% global causes
  • 30 countries: 87% global causes
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12
Q

> 100,000 causes in

A
  • Nigeria
  • Democratic Republic of Congo
  • Pakistan
  • India
  • Indonesia
  • China
  • Bangladesh
  • Philippines
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13
Q

HIV hotspot

A
  • Pakistan
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14
Q

HIV secondary hotspots

A
  • India
  • China
  • Phillipines
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15
Q

GDP/capita

A
  • +ve correlation with undernutrition
  • -ve correlation with incidence
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16
Q

Aetiology - the basics

A
  • when you grow it in agar it looks a bit fungal
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17
Q

Aetiology - the specifics

A
  • straight/slightly curved rods (2-4micrometres)
  • aerobic
  • non-motile
  • slow growing (3 week generation time)
  • Gram +ve
  • human obligate pathogen
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18
Q

milliary TB

A

bloodstream

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19
Q

Pathogenesis - the basics

A
  • can go anywhere, dissemination
  • milliary TB
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20
Q

Pathogenesis - the specifics

A

i) exposure and infection; aerosol - lungs
ii) TCR overwhelmed
iii) latent as granuloma
iv) elimination; lifelong containment; reactivation

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21
Q

no symptoms

A
  • innate clearance
  • immune memory; adaptive clearance
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22
Q

latent TB (LBTI)

A
  • initial control
  • no symptoms
  • no transmission
  • 10% lifetime risk of activation
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23
Q

active TB

A
  • unable to control
  • symptomatic
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24
Q

active TB symptoms

A
  • coughing up blood + sputum
  • losing weight
  • fatigue
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25
reinfection is correlation with
reactivation; complex
26
TB is common in
infants; increased mortality rate
27
Granuloma - the basics
- macroscopic - formed by immunity - prevents dissemination: alive but contained; not actively replicating
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Granuloma - the specifics
- T cell - B cell - neutrophil - NK - macrophage - DC
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Subclinical
- asymptomatic/unusual - sputum testing - 55% - >30,000 @ high risk
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30,000 @ high risk
- HIV+ - TB in last 2 years
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Incipient TB - the basics
- allows for bidirectionality + fluctuation
32
Incipient TB - the specifics
i) subclinical stages from which transmission may occur without recognisable symptoms ii) regression/resolution to milder disease iii) diagnosis + treatment before recognisable symptoms develop
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Uninfected <->
latent <-> incipient <-> no symptoms <-> symptoms not recognised (subclinical) <-> recognisable symptoms -...-> mortality
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treatment occurs at the
subclinical and clinical phases
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Immunity
i) lung infection ii) macrophages iii) DCs iv) neutrophils
36
TB as a lung infection
- alveolar macrophages - DCs sample tissue - phagocytosis, lymph nodes trafficking, TC presentation - CD4+, 8+ activation; effector functions - immune memory - B cells produce Abs
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Macrophages in TB
- first line of defence - main reservoir for bacterial survival + replication (immuno-privileged) - array of receptors; TLR, complement
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DCs in TB
- receptor-mediated uptake - low-level replication (not a major niche) - primary APCs; bridge innate and adaptive
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Neutrophils in TB
- controversial role - contribute to blood control - neutrophilia at time of diagnosis: associated with delayed clearance of sputum bacteria - may attract TCs + direct maturation - may haver suppressive functions (detrimental)
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CD4+ in TB
- HIV synergy - necessary - KO: lethal - Th1
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Th1 in TB
IFNgamma; TNFalpha; IL-2
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IFNgamma in TB
- central - KO is highly susceptible
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CD8+ in TB
- controversial; CD4+ redundancy - cytotoxic/cytokine-producing
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B cells in Ab in TB
- suggested
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Tuberculin
- when you culture in liquid in medium, secreted - 1809, Koch: "substances that halted the growth of tuberculosis bacilli in vitro and vivo" - evidence only reproduced by his son-in-law
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in vitro experiment
auto-experimentation
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in vivo experiment
- naive guinea pigs - protective
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Recapitulated attempts to isolate tuberculin
- violent fever - necrosis, sloughing + healing of skin lesions: caused by Lupus vulgaris - deep lesions in lung/spine: necrosis; highly deleterious
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Tuberculin as a treatment for pulmonary TB
- n = 1061 - 1.1% cured - 34% improvement - 55% no improvement - 4% died
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Tuberculin as a treatment for bone TB
- n = 708 - 2% cured - 54% improvement - 42% no improvement - 1.1% died
51
Delayed-type hypersensitivity (DTH)
- aka: "Koch phenomenon" - severe/exaggerated immunity - type IV - against secreted tubercule proteins - can cause tissue damage/illness - mediated by cellular response - induration, swelling, monocytic infection; immunopathology
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DTH use
i) "sensitised" T cells have been previously infected/vaccinated ii) intradermally inject soluble molecules to activate sensitised cells iii) symptoms can be used to identify previous exposure
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induration
hard swelling
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Florence Seibert, 1897-1991:
- identified active agent of tuberculin as a protein - isolated pure from purified protein derivative (PPD) - used as a skin test for diagnosis; (inter)national standard
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Tuberculin skin test (TST)
- aka. Mantoux, Mendel-Mantoux, PPD, Heaf test - screening for LTBI - heterogeneous Ag mixture - standard dose infected ID - previous exposure: DTH; measure diameter of induration
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ID
intradermally
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>= 5mm +ve in
- HIV-infected - recent contact - fibrotic changes on chest radiograph consistent with prior TB - organ transplants - immunosuppressed; >=15mg/day prednisone for >= 1mo
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>= 10mm +ve in
- immigrants <= 5 years from highly prevalent countries - injection drug users - residents and employees of high risk congregate settings - mycobacteriology laboratory personnel - high risk individuals - <4yos - infants, children and adolescents exposed to adults of high risk
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>=15mm +ve
in persons w/ no known risk factors
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False +ves
- BCG vaccinated - NTMa - incorrect TST antigens - incorrectly administered - incorrectly interpreted
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NTMa
- non-tuberculous mycobacteria
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False -ves
- recent infection (8-10wks) - very old infection (many years) - <6mo's - certain viral illnesses/live-virus vaccines - incorrectly administered - incorrectly interpreted - immunocompromised (HIV) - delayed
63
Interferon-gamma release assays (IGRA)
- tests for infection not disease: we need a test to differentiate between the two - by sp. T cells
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Advantages of IGRAs
- > specificity - single patient - results within 24hrs - prior BCG doesn't cause false +ves - in most endemic countries, BCG is given @ birth - 99.8% similarity
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TB treatment 1900-50
- sanitaria - sunlight, horizontal bed rest
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Treatment - 1900-50 - the specifics
- artificial pneumothorax - artificial pneumopentoneum - thoracoplasty - plombage - phrenic nerve crush - lung resection
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Treatment - 1900-50 - the basics
- various degrees of success - not controlling the pandemic
68
Antibiotics - the basics
- since TB is bacterial, this is the mainstay of treatment
69
Standard (short-course) treatment in UK:
- Isoniazid and rifampicin for 6 months - + Pyrazinamide and ethambutol for first 2 months - latent TB: isoniazid and rifampicin for 3 months/isoniazid alone for 6 months
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Treatment gaps persist
only 27% of eligible children under 5 years started on treatment
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Limitations of TB treatment
- Prolonged and complex - Lots of side-effects - Poor adherence - Do not ensure complete cure - Expensive - Drug resistant strains
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side-effects
- hepatitis - sickness - fatigue - loss of vision/hearing
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drug resistant strains
2/5 people with R-TB access treatment
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Therapeutic vaccines - the basics
after disease/infection
75
Therapeutic vaccines - the specifics
I) activate, reinforce, direct, broaden and curb immunity ii) useful iii) used in conjunction with drug therapies; combinational
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Why are therapeutic vaccines useful
- drugs not available/effective - adverse side-effects/toxicity - R/persistence
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M. vaccae
- natural protection - non-pathogenic environmental (soil, water) - shortens treatment - converts existing necrotising tissue -> protective - Th1 up regulation - Th2 downregulation; polarising - increased sputum conversion rate/X-ray appearances of TB patients - clinical trial pipeline: conflicting, population-dependent outcomes - approved in China - developed as prophylactic
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RUT1
- targets "persistent" bacteria
80
"persistent" bacteria
- non-replicative, dormant - under stress conditions (e.g. immunity; drugs) - administered after a short period of chemotherapy to kill actively replicated bacteria; combinatorial - reduced bacillary load, local DTH - Phase IIb, SA
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Phase IIb results from SA of RUT1
- safe, immunogenic in LTBI subjects - 1 month post-isoniazid
82
prophylactic vaccination
- Edward Jenner
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History of BCG vaccine
- late 19C - Bacillus Calmette-Guerin - given to most people in the history of the world ever - the only currently available prophylactic vaccine against TB - cowpox prevented smallpox - first clinical trials of M. books in Italy - 1908: potato grown in France - 1921: given to humans - public acceptance: slow! - Liubeck disaster - post-WWII: public health drive - saved millions of lives
84
Describe the 1908 potato-grown M. bovis
- decreased virulence factors - tested in guinea pig - no disease in animals - attenuated w/o target modification - subcultured >200 times over 13 years
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Liubeck disaster
- 240 infants - 70 died
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Describe the post-WWII public health drive
- safety principle established - best safety principle of any vaccine
87
Pros of BCG vaccine
- reliable protection against disseminated disease during childhood - some efficacy against leprosy - effective at preventing pulmonary TB in some countries
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disseminated disease
- TB meningitis - milliary TB
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leprosy
M. leprae
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BCG effectiveness at preventing pulmonary TB in the UK
80%
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Non-specific effects of BCG vaccine - the basics
- observational/epidemiological studies in LMICs - easy to run: characteristic big scar - lower neonate mortality
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Non-specific effects of BCG vaccine - the specifics
- decreased sepsis, fever and respiratory infections
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BCG mechanism
- monocyte epigenetic modification - metabolic reprogramming
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post-BCG secondary infections
- monocytes produce more pro-inflammatory cytokines
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pro-inflammatory cytokines
- IL-Ibeta - TNF - IL-6
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BCG as a treatment for bladder cancer
- standard treatment with good efficacy - direct delivery via catheter as solution through urethra - for non-invasive tumours
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Cons of the BCG vaccine
- extremely variable efficacy against pulmonary TB (particularly low in tropics) - 0% efficacy in some endemic regions - even when efficacy is high, wanes after c. 15years - contraindicated in HIV+ neonates/mothers since it is a live, replicating vaccine
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Describe the hypothesis for 0% BCG vaccine efficacy in some endemic regions
nontuberculosis mycobacteria exposure masking/blocking
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Why is it so hard to make a new TB vaccine?
- antigens unknown (complex) - no immune correlates of protection - poor animal models; no LTBI/granulomas - no human challenge model; unethical, lasting effects
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Correlates of protection
- needs clinical efficacy trials - high candidate testing - low trial length - allow early prediction of vaccine failure - bridging studies - across pop.s and age groups
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vaccine pipeline in 2000
none
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vaccine pipeline in 2024
- Phase I: 4 - Phase IIa: 3 - Phase IIb: 2 - Phase III: 6
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BCG improvements
- revaccination - route compartmental targeting - recombinant strains
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Describe revaccination
- 45.4% efficacy - homologous prime-boost
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Describe route compartmental targeting
- IV/aerosol transmission
106
Describe aerosol BCG vaccine
- effective in mice and NHPs - superior to intradermal vaccination - measured: colony forming units
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Describe the mucosal BCG vaccine
- pulmonary dissemination still occurs - extrathoracic - in arbitrary/cf units
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Describe the intravenous BCG vaccine
- extremely effective in NHPs (Macaca mulatta) - CT lung scans - difficult in children - increased CD4+, CD8+ induction - "high frequency of antigen-responsive T cells across all lung parenchymal tissues" - 6mo delay - 9/10 highly protected - 6 asymptomatic: PET; "sterile protection" - model for defining immune correlates - vaccine-elicited protection mechanism
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Macaca mulatta
- highly susceptible - prevents susceptibility/limits
110
Increased CD4+/8+ induction in M. mulatta intravenous BCG vaccines
- blood - spleen - bronchoalveolar lavage - lung lymph nodes
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What did they measure in intravenous BCG vaccine study?
- computed tomography imaging - mycobacterial growth - pathology - granuloma formation
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viral vectored vaccines
i) pathogenic antigen identified ii) gene encoding pathogen antigen isolated iii) recombining with viral genome iv) administer to vaccine recipient
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viral vectored vaccine administration
- vector cell entry - expression/possible secretion of Ag in human cell - MHCI loading - stimulates immunity
114
ChAdOx1 85A prime-MVA85A boost - the basics
- Phase I - previously effective in animal studies
115
ChAdOx1 85A prime-MVA85A boost - Phase I
- safety and immunogenicity in healthy adults - adverse events (AEs) - measured Ag-sp. ex vivo IFNgamma, EliSpot, IgG Elisa, Ag-sp. IC IFNgamma, TNFalpha, IL2, IL17
116
ChAdOx1 85A prime-MVA85A boost - the specifics
- 42 healthy, vaccinated adults - low prime dose - high primes dose - prime boost - prime-prime boost
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Results of ChAdOx1 85A prime-MV85A boost:
- mild/moderate AEs - no Serious Adverse Events - prime prime boost = non-significant - prime boost - well-tolerated and immunogenic
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Results of ChAdOx1 85A prime-MV85A prime boost result:
- Ag85A-sp. EliSpot - IC cytokine CD4+, 8+ - polyfunctional CD4+ - CD8+; IFNgamma+, TNF-alpha - serum IgG
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polyfunctional CD4+
- IFNgamma - TNF-alpha - IL-2
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correlates of protection
use as a surrogate of infection
121
Controlled Human Infection Models (CHIM) - the basics
intentionally infecting vaccinated individuals w/ a pathogen
122
Controlled Human Infection Models (CHIM) - the specifics
- malaria - typhoid - influenza - cholera - RSV
123
A CHIM for TB using BCG
- healthy adults - BCG-naïve and BCG-vaccinated receive MVA85A - challenges w/ intradermal BCG post-4 wks - skin biopsies take 2wks post-challenge - BCG load quantified by culture (cfu) and PCR
124
Ex vivo and in vivo assays
correlate
125
When testing BCG CHIM's, measure
- growth ratio - copy number
126
Bovine TB transmission
- 1971: BTB first identified in badgers - badgers can transmit M. bovis to cattle - strains of M. bovis in cattle typically match local strains in badger population - Bayesian phylogenetic/ machine-learning approaches to bacterial genome data quantify the roles of badgers and cattle in M. bovis infection dynamics (the majority of which are intra-specific)
127
Culling
- UK: range of strategies introduced since 1975 - changes behaviour/disease patterns; perturbation effect - 1996: increased incidence, uncertainty; stopped - 1998-2005: Randomised Badger Culling Trial (RBCT)
128
Describe the RBCT
- 30x randomly selected 1000km^2 areas - 10x triplets - 3x treatments - no culling (monitor control); proactive; reactive culling - proactive culling: local decrease; increase over 2 years; neighbouring increase - reactive culling 27% increase - stopped - 4 years post-cull: -23% inside (modest, time-consuming); +25% in 2km buffer - 5 years post-cull: -28% inside; no effect in 2km buffer -
129
RBCT out-takes
- larger areas - hard borders - "the perturbation effect"
130
Badgers pre-cull
- territorial social groups - low movement
131
Badgers post-cull: "the perturbation effect"
- less badgers - decreased territoriality - increased movement - increased infection; disease spread
132
Culling - the conclusions
can reduce the no. of infected badgers in an area, but will also likely lead to an increase in disease spread in the remaining populations
133
Badger treatment - the current position - the specifics
- badger pop. survey -> new TB surveillance programmes - accelerated work on cattle vaccine - Badger Vaccinator Fiel Force
134
Badger treatment - the current position - the basics
- scientists, farmers, vets, conservationists
135
Bovine TB in humans - the basics
- prevent w/ BCG - underestimated - 10% of all cases in some countries
136
Badger Vaccinator Field Force
- vaccination sited
137
Bovine TB in humans - the specifics
I) unpasteurised milk ii) unvaccinated individuals - not always pneumal; complex diagnostic
138
M. bovis - the basics
- naturally R to some Mtb ABs - poor cattle health and welfare - decreased economic productivity
139
M. bovis - the situation
- 140,000 new cases - 12,000 deaths
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M. bovis in white-tailed deer
- USA - PPE for Hunters
141
M. bovis in wildlife
- Asian Elephant - Chacma baboons - Panthers - American Mink - Jaguar - Sea lions - pet cats
142
Mb in Asian Elephant
- Nepal - Thailand - India
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Mb in Chacma baboons
- SA - African lions, buffalo
144
Mb in panthers
Argentina
145
Mb in Jaguar
- Venezuela - USA -> White Rhinoceros
146
Mb in American mink
Argentina
147
Mb in sea lions
Netherlands
148
Mb in pet cats
- commercial raw food diet - cutaneous granuloma - outdoor lifestyle dogma; hunting behaviour
149
Mb management approaches
- test + cull - pasteurisation - infected/contact animal removal - post mortem meat inspection - intensive surveillance (on farm visits) - adequate local legislation - effective movement controls - individual animal identifications - AMs - vaccination
150
Hendra virus, Australia
- a One Health success - Paramyxoviridae - Brisbane, 1994 - horse racing stables
151
Describe the horse racing stables; Brisbane, 1994
- acute equine respiratory disease - 13/20 infected horses dyeing in 2 weeks - trainer, stable-hand infected - died; Hendra-isolated from kidney
152
Hendra virus natural reservoir, 1996
fruit bat
153
HeV horse vaccine
2012
154
Rabies, Namibia
- hotspot - Northern - dogs, humans - financial burden - travel cost for PeP - control: dog vaccination - 2015: 25 deaths - 2022: 7 deaths
155
Challenges to One Health
- lack of funding for animal health - vet education + careers limited - environmental sector under-representation - LMIC + HIC power imbalance - demonstrating economic benefit to policymakers
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