PULMONARY TUBERCULOSIS
- According to the WHO, TB is estimated to
- One of the oldest diseases known to affect
humans and the top cause of infectious
death worldwide
- Most often affects the lungs, although other
organs are involved in up to 1/3 of cases
- If untreated, the disease may be fatal within
5 years in 50–65% of case
- Transmission usually takes place through the
airborne spread of droplet nuclei produced
by patients with infectious pulmonary TB.
ETIOLOGY
- TB is a serious chronic pulmonary and
systemic disease caused most often by
M. tuberculosis
- M.bovis = characteristically resistant to
pyrazinamide; transmitted by
unpasteurized milk
- M. pinnipedii = infecting seals and sea
lions
- M. mungi = (isolated from banded
mongooses in southern Africa)
- M. orygis = (described in oryxes and
other Bovidae in Africa and Asia)
- M. microti = (the “vole” bacillus, a less
virulent organism).
- M. canetti = is a rare isolate from East
Africa
Morphology of M. Tuberculosis:
 Rod-shaped, non-spore-forming, thin
aerobic bacterium measuring 0.5 μm by
3 μm
 Neutral on Gram’s staining; acid-fast
bacilli [due to high content of mycolic
acid]
 Acid-fast bacilli is also due to long-chain
cross-linked fatty acids, and other cell-
wall lipids
EPIDEMIOLOGY
affect more than a bi individuals worldwide,
with 8.7 mil new cases and 1.4 mil deaths
each year
- TB flourishes wherever there is…
o Poverty; homelessness
o Crowding; immigrants from
high-burden countries
o Chronic debilitating illness
o Spread of the HIV epidemic
- Comorbidities that inc risk of TB:
o DM
o Hodgkin lymphoma
o Chronic lung disease
o Chronic renal failure
o Malnutrition; alcoholism
o Immunosuppression.
- Adults ≥65 y/o have the highest incidence
rate per capita; children <14 y/o the lowest
FROM EXPOSURE TO INFECTION
- MOT = droplet nuclei, which are aerosolized
by coughing, sneezing, or speaking
o Droplets may remain suspended in
the air for several hours
o As many as 3000 infectious nuclei
per cough
- Patients with sputum
smear–negative/culture-positive TB [and
extra PTB w/c is essentially noninfectious]
are less infectious
- The most infectious patients have cavitary
pulmonary disease or, much less commonly,
laryngeal TB
- In high-prevalence settings, up to 20
contacts (or 3–10 people per year) may be
infected by each AFB-positive case before
the index case is diagnosed
 FROM INFECTION TO DISEASE
- Primary TB:
o Clinical illness directly following infection
o Common among children in the first few
years of life and among
immunocompromised persons
o Not assoc with high-level transmissibility.
- Secondary (postprimary TB)
o Because of frequent cavitation
o More often infectious than is
primary disease
- Age as a factor:
o Incidence of TB is highest during late
adolescence and early adulthood
o Women: peaks at 25–34 years of age
o Risk inc in the elderly, possibly because
of waning immunity and comorbidity

PATHOGENESIS AND IMMUNITY

Infection and Macrophage Invasion [steps]
- MOT: Propelled infected droplet nuclei inhaled
by a close bystander
- A fraction (usually <10%) reach the alveoli; the
remainder are trapped in the upper airways and
expelled by ciliated mucosal cells
NATURAL HISTORY OF DISEASE
- Inactive macrophages phagocytose the bacilli
- 1/ 3 of pt died within 1 year after
- Adhesion of mycobacteria to macrophage is due
diagnosis
to binding of the bacterial cell wall to a variety
- >50% died within 5 years
of macrophage cell-surface molecules:
- 5-year mortality rate among sputum
o Complement receptors
smear–positive cases was 65%
 Activation enhances phagocytosis
- Survivors at 5 years, ~60% had
leading to opsonization of bacilli with
undergone spontaneous remission
C3 activation products such as C3b
and C3b
 - If bacilli are successful in arresting phagosome Host response, Granuloma Formation, Latency
maturation: - Initial stage: Replication of mycobacteria
o Replication begins within naïve unactivated macrophages
o Macrophage eventually ruptures and - Recruitment off additional macrophages for
releases its bacillary contents early granuloma
o Infects other phagocytic cells if they - In as study, M. TB-derived cAMP is secreted
ingest dying macrophages and their from the phagosome into host macrophages,
bacillary contents leading to…
NOTE: o Subversion of cell’s signal transduction
 ESX-1 secretion system pathways
o Mediates replication of bacteria o Stimulation in inc secretion of TNF-a and
o A mutation in this system impairs the recruitment of proinflammatory cell
capacity of apoptotic macrophages to o Chemoattractants and bacterial products
recruit uninfected cells >>> less released during the repeated rounds of
replication and fewer new granulomas. cell lysis and infection
 Earliest stage of primary tuberculosis (<3 o Dendritic cells access bacilli and migrates
wks) in the nonsensitized individual, bacteria to the draining lymph nodes
proliferate in the pulmonary alveolar o Presentation of mycobacterial antigens
macrophages and air spaces, >> bacteremia to T lymphocytes
and seeding of multiple sites. o Development of cell-mediated and
humoral immunity begins.
Virulence of Tubercle Bacilli NOTE: These initial stages of infection are usually
- Mycobacterial protein CarD controls rRNA asymptomatic.
transcription - (2-4wks after infection): Development of 2
o Its req for replication and persistence in host responses to M. TB
the host cell A. Macrophage-activating response
o Its loss exposes mycobacteria to oxidative  T cell–mediated phenomenon:
stress, starvation, DNA damage activation of macrophage that kills
and digests the bacilli
Host response, Granuloma response
Formation, Latency
B. Tissue-damaging
- Initial stage: Replication of mycobacteria
 a DTH rxn to bacillary antigens
within naïve unactivated macrophages
It destroys unactivated macrophages
- Recruitment off additional macrophages
that contain multiplying bacilli
for early granuloma
Causes necrosis of surrounding tissue
- In as study, M. TB-derived cAMP is
- Granulomatous lesions form due to…
o secreted from the phagosome into host
Development of specific immunity
macrophages, leading to…
o Accumulation of activated macro-
o Subversion of cell’s signal
phages at the site of the primary lesion
transduction pathways
NOTE: These lesions consist of accumulations of
o Stimulation in inc secretion of
lymphocytes and activated macrophages. Initially,
TNF-a and recruitment of
the tissue-damaging response can limit
proinflammatory cell
- M. TB growth is inhibited within this necrotic
environment by low O2 tension and low pH.
- LTBI:
o A result of a dynamic balance between
the mycobacteria and the host
o Formation of biofilms in necrotic areas
w/c they temporarily hide
o Not a binary state; a continuum along
w/c infection will eventually move in
the direction of full containment or
disease.
Macrophage-Activating Response:
- Cell-mediated immunity is critical at this early
stage
- Activated when bacillary antigens processed
by macrophages stimulate T lymphocytes to
release a variety of lymphokines
- Activated macrophage aggregate around
lesion’s center
- Leads to neutralization of tubercle bacilli
w/out further tissue destruction
- “Healed” lesions in the lung parenchyma and
hilar lymph nodes may later undergo
calcification.
Delayed-Type Hypersensitivity
- When macrophage-activating response is
weak, mycobacterial growth can be inhibited
only by intensified DTH rxn
- Causes…
o Lesion tends to enlarge further
o Progressive tissue damage
o Caseous material in lesion center
liquefies
 Drained thru bronchi
o Formation of cavities in the bronchial
wall and blood vessels
 This is where tubercle bacilli
multiply
 Then spill into the airways and
- In the early stages of infection…
o Bacilli are transported by macrophages
to regional lymph nodes
o Gained access to central venous return
o Reseed the lungs
o Disseminate beyond the pulmonary
vasculature throughout the body via
the systemic circulation >>
extraplumonary lesions
Role of macrophages and monocytes
- Macrophages:
o directly phagocytose tubercle bacilli
o secrete various cytokines causing…
 Formation of granulomas
 Systemic effects (e.g., fever and
weight loss)
o Primary mechanism is probably r/t
prod. of oxidants (ie reactive oxygen
intermediates or NO)
 Has antimycobacterial activity
 Inc synthesis of cytokines such as
TNF-α and IL-1 that regulates
release of oxidants
o Undergo apoptosis
 Defensive mechanism to prevent the
release of cytokines and bacilli
 Via sequestration in the apoptotic cell
- T cells (mainly CD4+ T lymphocytes
o Induces protection thru prod of cytokines
such as IFN-y
 IFN-γ mobilizes antimicrobial
peptides (defensins) against the
bacteria
 Stimulates autophagy