Transcript Tuberculosis

Tuberculosis
January 28th, 2008
M. tuberculosis
Jasemine Yang and Tamara Bodnar
A Brief History of Tuberculosis (TB)
- Tuberculosis (phthisis) described since the
time of Hippocrates (460 BC - 370 BC)
- 1689: Doctor Richard Morton used the
term “consumption” to denote TB.
- Second half of the 17th century: high
death rates from TB in Europe.
- 1722: Doctor Benjamin Marten proposed
that TB could be transmitted in the air and
described TB as being caused by
“wonderfully minute living creatures”
- End of 19th century to the start of 20th
century: Principal cause of death in
Europe was TB.
- The romantic Era of TB
“Queen Guinevere” painted by William Morris
A Brief History of Tuberculosis (TB)
- 1865 Jean-Antoine Villemin: confirmed that
TB is contagious.
- Robert Koch:
- 1882: Isolated and cultured M.
tuberculosis.
- 1890: Announced the discovery of
tuberculin.
- Developed staining methods used to
identify the bacteria.
- 1905: Received the Nobel Prize
- Bacteriologist Paul Ehrlich developed ZiehlNeelsen staining.
- Late 1800’s: Edward Livingston Trudeau
established “Adirondack Cottage
Sanatorium”, first TB sanatorium in the US.
Visualization of M. tuberculosis
using the Ziehl-Neelsen stain
A Brief History of Tuberculosis (TB)
- 1896 Theobald Smith demonstrated that
bovine TB is caused by M. bovis.
- 1908 Albert Calmette and Camille Guérin
isolated M. bovis and grew it in ox bile.
- Identified a morphological variant of M.
bovis found to be avirulent, conferred
immunity against M. tuberculosis.
– Lead to the BCG vaccine (bacilli
Calmette-Guérin).
- Development of antibiotics to combat
infection:
– 1947: streptomycin, 1952: isoniazid
– The majority of drugs used to combat
infection were identified between 1945
and 1967.
– No new drugs developed since the 1980’s
- Reoccurrence of TB for two main reasons:
1)HIV/AIDS pandemic
2)Development of drug resistance
M. bovis
Tuberculosis in Humans
- Reservoir: Humans
- Transmission: Airborne disease (aerosol transmission)
- Symptoms:
Latent TB infection:
No symptoms
*Cannot spread TB
Active TB infection:
Bad cough
Coughing up blood/sputum
Chest pain
Loss of appetite
Weight loss
Fever
Chills
Night sweats
Swollen glands
*Contagious
Extra-pulmonary TB: Symptoms depend on location of infection
General symptoms: fatigue, fever, loss of appetite, weight loss.
TB of lymph nodes: swelling of lymph nodes
TB meningitis: neurological symptoms including headache
Spinal TB: Mobility impairments, pain
Mycobacterium Tuberculosis
General Characteristics
SEM of M. tuberculosis
Family – Myobacteria
Gram-positive aerobic rod-shaped bacilli
“Acid fast” bacteria
Lack of spore formation and toxin production
No capsule, flagellum (non-motile)
Generation time of 18- 24 hours but requires 3-4
weeks for visual colonies
Pathological Features
M. Tuberculosis
(stained in purple)
Principle cause of Human Tuberculosis
Intracellular pathogen (alveolar macrophages)
Waxy, thick, complex cellular envelope
Cell envelope components ex) sulfolipids
Produces tubercles, localized lesions of M.
tuberculosis
Mycobacterial Cellular Envelope
General Features
- Thick, waxy and complex
- Higher fluidity in more external
regions than internal regions
- Relatively impermeable to
hydrophilic solutes
- Contain porins (selective cationic
channels)
Main Components
- Peptidoglycan
 contains N-glycolylmuramic
acid instead of N-acetylmuramic
acid
- Arabinogalactan
- Mycolic Acids (60% of cellular
envelope)
- Lipoarabinomannan (LAM)
Mycobacterial Cellular Envelope
Contribution of Mycobacterial Cellular
Envelope to Pathogenesis
Resistance to Drying and Other Environmental Factors
- Thick, waxy nature of cellular envelope protects M. tuberculosis
from drying, alkali conditions, and chemical disinfectants
- Hinders entrance of antimicrobial agents
Entry into Host Cells
- Lipoarabinomannan (LAM) binds to mannose
receptors on alveolar macropages leading to
entry into the cell
Interference of Host Immune Response
- Glycolipids and sulfolipids decrease the effects of oxidative
cytotoxic mechanism
- Inhibition of phagosome and lysosome fusion inside macrophage
- Waxy cellular envelope prevents acidification of the bacteria inside
the phagosome
Factors Affecting Pathogenicity
Active Infection
- Only individuals with an active infection
can transmit the disease
Transmission
- Aerosolized droplets need to be <10μm in
order to evade the ciliated epithelium of
the lung to establish infection in the
terminal alveoli
Growth & Structure
- Only require a very few number of
bacteria to establish an infection (1-10
bacteria)
- Slow generation time
M. Tuberculosis in sputum
(stained in red)
Variability of Infection Rates
Exposure Time
- Most infected individuals expel relatively few bacilli,
transmission of TB usually occurs only after prolonged
exposure to someone with active TB.
- On average, 50% of people are likely to become infected
with TB if they spend 8hrs/day for six months or 24hrs/day
for two months working or living with someone with active
TB.
Health of Individuals
- Active TB typically occur in individuals whose immune
systems have been weakened by age, disease, improper
nutrition or use of immunosuppresive drugs.
Tuberculosis – Disease Progression
Primary Infection
In healthy individuals…
- M. tuberculosis phagocytosed by alveolar macrophages
leading to intracellular proliferation and tubercle formation
- Cell-mediated response develops and eliminates most of the
bacilli in 2-6 weeks
- Commonly asymptomatic
OR
- M. tuberculosis can remain dormant intracellularly
Tuberculosis – Disease Progression
Primary Infection
Immunocomprimised Individuals…
- Infection leads usually leads to
progressive primary tuberculosis,
where the pathogen breaks out of
the tubercles in the alveoli and
cause active disease
- Active disease leads to chronic
inflammation
- Death of pathogen and pulmonary
cells can lead to Gohn complex
and granuloma formation
- May lead to extrapulmonary
tuberculosis (TB infection outside
the lung in the CNS and lymph
nodes)
Latent Tuberculosis Infections
- Following exposure to TB: Inhaled bacilli usually
destroyed by host’s immune system (90-95% of the
time).
- Healthy person: Recruitment of T-cells and
macrophages which results in controlling the infection.
- Some bacilli can establish infection in macrophages
(phagosomes) leading to host immune response
- Bacilli forced into an inactive (latent), non-replicating
state.
- Survive intracellularly: prevent phagosome-lysosome fusion.
- Infection contained but not eradicated.
- The dormant bacteria are still viable, can be reactivated: Approximately 10% of latent infections will
develop into active TB if left untreated.
- Factors that lead to re-activation of the bacteria: HIV
co-infection, aging, cancer, diabetes etc
M. Tuberculosis colonies
Tuberculosis – Disease Progression
Note…
- Infection does not mean disease!
- Infection can lead to active disease or dormant state of
pathogen
- Active disease develops differently (Healthy individuals
VS. Immunocomprimised individuals)
Summary of TB Infection in Alverolar Macrophages
http://www.nature.com/nrmicro/animation/imp_ani
mation/index.html
Treatment
Antibacterial chemotherapy:
- Combination of first and second line drugs for
the first 2 months which could include:
-
Isoniazid
Rifampicin
Pyrazinamide
Streptomycin or Ethambutol
- Next 4 months, combination of:
- Isoniazid
- Rifampicin
- Early resistance to isoniazid: other first-line drugs
such as ethambutol, streptomycin, pyrazinamide and
fluoroquinolones can be added to drug arsenal
(treatment period also extended).
- These drugs are relatively effective in killing the bacteria,
however, they also produce a wide variety of side effects.
Treatment
First line drugs:
- Bactericidal agents: kill active bacteria, important in the
early stages of infection.
Second line drugs:
- Bacteriostatic: hinder bacterial growth.
- Strengthen treatment in the case of resistant bacteria.
- Less efficient and generally more toxic than first line
drugs.
Inappropriate chemotherapy:
- Monotherapy (single drug treatment)
- Decreased treatment period
- Low absorption of drugs
Treatment
Drug
Bactericidal or
Bacteriostatic
Mechanism of Action
Mutation
Rate
Side Effects
Isoniazid
Bactericidal to
rapidly dividing
bacteria and
bacteriostatic
to slowly
dividing
bacteria
Pro-drug: activated by a
bacterial catalase.
Inhibits enoyl-ACP reductase
(key enzyme in fatty acid
synthesis, different than
equivalent mammalian
enzymes)
1 in 105 - 106
Rash, abnormal liver function,
anemia, peripheral
neuropathy, mild CNS effects
Rifampicin
Bactericidal
Inhibits transcription by RNA
polymerase
1 in 108
Fever, immune reactions, GI
irritation, liver damage, can
cause tears and urine to turn
red/orange
Streptomycin
Bactericidal
Inhibits initiation of protein
synthesis
1 in 108 - 109
Damage to the ears, nausea,
rash, vomiting, vertigo
Ethambutol
Bacteriostatic
Prevents formation of the
cell wall
1 in 107
Decrease in visual acuity,
colourblindness and other
visual defects, joint pain,
nausea, vomiting, fever,
malaise, headache, dizziness
Fluoroquinolones
Bactericidal
Act manly on DNA gyrase
(DNA gyrase: introduces
negative supercoils into
DNA)
Tendon damage, heart
problems, swelling of face and
throat, shortness of breath,
rash, loss of consciouness
Pyrazinamide
Bacteriostatic,
Bactericidal
Accumuates causing
cellular damage
Joint pain, nauseau, vomiting,
rash, malaise, fever,
photosentivity
Drug Resistance and Tuberculosis
- M. tuberculosis: naturally resistant to
certain antibiotics due to presence of:
- Drug-modifying enzymes
- Drug-efflux systems
- Hydrophobic cell wall
- Mycobacteria undergo natural
mutations which can lead to
development of drug resistance.
- TB is treated by administration of
combination chemotherapy:
decreases probability of
development of drug resistance.
- Development of increasingly resistant
strains mainly due to: Patient noncompliance
MDR and XDR Tuberculosis
MDR: Multidrug-resistant strains:
-
Strains of tuberculosis resistant at least to rifampicin and isoniazid.
Mortality rate: 40-60%
Estimated that 50 million people are infected with MDR-TB.
MDR-TB is approximately 125 times more expensive to treat than
drug susceptible TB.
XDR: Extensively-drug resistant strains:
- Strains of tuberculosis resistant to rifampicin,
isoniazid and at least three of the following
classes of second-line drugs: aminoglycosides,
polypetides, fluoroquinolones, thioamides,
cycloserine and para-aminosalicylic acid.
MDR and XDR Tuberculosis
- Emergence due to lack of patient compliance during TB
treatment and inappropriate administration of TB drugs.
- Results in more aggressive forms of TB.
- Drug resistance does not increase infectiousness.
- MDR and XDR-TB: uncommon in developing nations lacking TB
drugs (high drug-susceptible TB rates)
- MDR and XDR-TB rates are higher in developed nations with
access to anti-TB drugs.
Tuberculosis and HIV/AIDS
- HIV pandemic has reversed much of the progress made in the past
few decades in combating TB.
- People with latent TB have a 10-20% of developing active TB in
their lifetime. People with HIV and latent TB are 100 times more
likely to develop active TB.
T cell
- HIV/AIDS leads to a compromised immune system:
- HIV infects CD4+ T cells, macrophages, dendritic cells.
- Result: decreased CD4+ T cells due to apoptosis of infected cells, CD8+
T cell mediated killing of infected cells
- The numbers of CD4+ T cells progressively decline (loss of cellmediated immunity) and the body is much more susceptible to
infection
Tuberculosis and HIV/AIDS
- A person with HIV/AIDS will have a
harder time fighting off the M.
tuberculosis infection due to a
compromised immune system.
- HIV infection can cause latent M.
tuberculosis infection to become
reactivated.
- TB is the leading cause of death for
people with HIV/AIDS: mean survival
rate is 430 days.
- MDR and XDR-TB and HIV/AIDS:
- Additional symptoms: excessive weight
loss, respiratory problems (including the
formation of lesions in the lungs).
- Mean survival rate: 45 days.
Discussion: The Challenges of TB Control
The WHO has developed a “Stop TB Strategy” outlining some the issues that
need to be addressed in order to stop the spread of disease:
-Expansion and enhancement:
-Legistlation/planning/human
resources/management/training
-Drug Resistance Surveillance (DRS)
-TB treatment and program management
guidelines
-An effective drug supply and
management system
-Address TB/HIV, MDR/XDR-TB and other challenges:
-TB challenges
-MDR-TB
-XDR-TB
-TB/HIV
-TB and air travel
-TB and poverty
-Global Drug Facility
-TB and gender
-Revised TB recording and reporting forms
-TB and prisons
-Electronic recording and reporting systems
-Enable and promote research:
-Global TB Control Report
-Drug research
-TB epidemiology and surveillance online
workshop
-Vaccine research
-Contribute to health system strengthening
-Engage all care providers
-Empower people with TB
-Community and patient involvement in TB care
-M. tuberculosis research
-Development of new diagnostic tools for
detecting latent, pulmonary and extrapulmonary TB.
Discussion: The Challenges of TB Control
From this list…
• What do you consider the top 5 most important issues?
• Are there any you feel are unimportant or relatively unimportant?
• Which do you feel would be the hardest to implement or attain?
Discussion: The Challenges of TB Control
The WHO has multiple goals concerning the control of TB including:
-
“By 2005: detect at least 70% of new sputum smear-positive TB
cases and cure at least 85% of these cases”.
“By 2015: reduce prevalence of and death due to TB by 50%
relative to 1990”.
“By 2050: eliminate TB as a public health problem (<1 case per
million population)”.
• What key issues need to be resolved and what developments
need to occur in order to reach these goals?
 Start by examining the “Stop TB strategy” list.
Discussion: The Challenges of TB Control
The WHO has multiple goals concerning the control of TB including:
-
“By 2005: detect at least 70% of new sputum smear-positive TB
cases and cure at least 85% of these cases”.
“By 2015: reduce prevalence of and death due to TB by 50%
relative to 1990”.
“By 2050: eliminate TB as a public health problem (<1 case per
million population)”.
• What key issues need to be resolved and what developments
need to occur in order to reach these goals?
 Start by examining the “Stop TB strategy” list.
Discussion: The Challenges of TB Control
• Based on these graphs from
the WHO, what do you think
the correlation is between
gender and rates of
tuberculosis infection?
• How should this be taken
into consideration when
planning programs against
TB?
Discussion: The Challenges of TB Control
• Why do you think there are more TB-dedicated facilities at the
national or provincial level?
• Do you think this may have an effect on the prevalence of
tuberculosis in these high-burden countries?
Why Does TB Need Global Attention?
-
-
-
Deadliest infectious diseases affecting humans.
Approximately 1/3 of the world population is
infected with M. tuberculosis.
8-10 million new cases of TB per year.
Leading cause of death among people with
HIV/AIDS.
Greatest infectious killer of women of child-bearing
age.
Results in approximately 3 million deaths per year.
- 26% of preventable deaths are due to TB.
- 7% of all deaths are due to TB.
-
-
New anti-TB agents needed to combat TB due to
high prevalence of drug-resistant strains.
In 1993 the WHO declared TB a “global public health
emergency” (only disease thus far to be given this
designation).