Tuberculosis

Tuberculosis is a prototype example of granulomatius

inflammation

Present since antiquity , fragments of spinal column from

Egyptian mummies from 2400BC show pathologic changes of TB
In Greece it was called phthisis ,consumption.
 Hippocrates described it as the most widespread disease which
is always fatal
Exact pathological and anatomic descriptions appeared in the
17th century
In 1720 English physician Benjamin Marten , TB could be caused
by "wonderfully minute living creatures“
In 1882, Robert Koch discovered a staining technique that
enabled him to see Mycobacterium tuberculosis

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Epidemiology
- Infects about 1/3 of the world population
- Kills about 3 million patients each year
- Single most important cause of death on earth
- With improvements in social conditions and
introduction of effective antibiotics there has been a
decrease in incidence in western countries
- Since mid 1980s increase again due to HIV

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According to 2007 WHO report
Incidence of all forms of TB – 341 per 100,000
Smear positive TB-152 per 100,000
Prevalence of all forms of TB-546 per 100,000
Mortality -73 per 100,000
TB is the third cause of hospital admission after
deliveries and malaria
Second cause of death after malaria

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Etiology and pathogenesis
- Caused by mycobacteria species:
 Are aerobic non spore forming, non-motile bacilli
 Have waxy coat (causes them to retain the red dye in
acid fast stain)
 Grows slowly in culture with a doubling time of 24
hours and 3-6 weeks are required to produce visible
growth in culture

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cont..

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Two species of mycobacterium cause TB
 M. tuberculosis and M. bovis
 M. tuberculosis is transmitted by inhalation of infective
droplets coughed or sneezed to the air by a patient with TB
 M. bovis is transmitted by milk from diseased cows and first
produce intestinal or tonsillar lesions
 Rarely, it transmits via breached skin surfaces and conjunctiva
 M. avium and M. intracellulare two closely related
mycobacterium that have no virulence in normal hosts but
cause disseminated infections in 15-24% of patients with
AIDS

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 M. TB pathogenicity is related to its ability to escape killing by macrophages
and induced delayed type hypersensitivity which has been attributed to
several components of M. TB cell wall including:
- Cord factor(which is a cell wall glycolipid component aviable on virulent
strains)
- LAM (lipoarabinomannan):It inhibits macrophage activation by interferonδ
 LAM induce macrophages to secrete TNF - α which causes fever, weight loss,
and tissue damage and LAM also induce IL-10 which suppresses
mycobacteria induced T-cell proliferation
- Complement activated on surface of the mycobacteria may opsinize the
organism and faclitate its uptake by macrophages complement receptor CR3
(mac-1 integrin) without triggering the respiratory burst necessary to kill the
organisms.
- M. TB heat-shock protein which is similar to human heat shock protein and
may have a role in autoimmune reactions induced by M. tuberculosis.
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Who are those more susceptible to develop tuberculosis?
Race: North American Indians, black Africans and Asians
are much more susceptible than others
Age: Extremes of ages due to imperfect immune responses
Immunologic and other host factors
immunocompromized patients are more liable to develop
tuberculosis.
These include patients with steroid therapy or
immunosuppressive drugs, HIV infection, diabetes
mellitus, cirrhosis, malnutrition and damage of lung for
example with silicosis etc.
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M. TB resides in phagosomes which are not acidified
into lysosomes, inhibition of acidification is has been
associated with urease secreted by mycobacteria
- Cell mediated or hypersensitivity type IV reaction to
the tubercle bacillus probably explains organisms
destructiveness in tissues and the emergence of
resistance to the organism
- On initial exposure to the organism inflammatory
response is nonspecific resembling the reaction to any
form of bacterial invasion

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- Within 2-3 weeks coincident with the appearance of
positive skin reactions the reaction becomes
granulomatous and the center of granulomas become
caseous forming typical “soft tubercles”
-Pattern of host response depends on whether the
infection represent a primary first exposure to the
organism or secondary reaction

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Primary infection
- Is an infection of a person who have not had prior
contact with
- Begins with inhalation of the mycobacteria and ends
with T cell-mediated immune response that induces
hypersensitivity to the organisms and controls 95% of
the infections
- Most often in the periphery of one lung inhaled M. TB
is first phagocytosed by alveolar macrophages, and
transported by these cells to hilar lymph nodes

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Naïve macrophages are unable to kill mycobacteria
and the mycobacteria multiply and lyze these host
cells and infect other macrophages and sometimes
disseminate through the blood to other parts of the
lung and elsewhere in the body

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After few weeks T-cell mediated immunity demonstrated
by a positive PPD test reaction develops
-Mycobacteria activated T-cells with macrophages in three
ways
1.secrete interferon which activates macrophages to kill
intercellular mycobacteria through reactive nitrogen
intermediates including NO, NO2 and HNO3 ,this is
associated with formation of epithelioid granulomas
and clearance of mycobacteria
2.CD8+ suppressor T cells lyse macrophages infected with
mycobacteria
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3.CD4-CD8- (double negative) T-cells lyze macrophages
without killing mycobacteria
lysis of macrophages result in caseating granuloma
-Mycobacteria cannot grow in this acidic extracellular
environment lacking in oxygen and so the
mycrobacterial infection is controlled.
- The lung lesion of primary tuberculous infection is
known as the Ghon focus.
- It is located in the sub pleural area of the upper
segments of the lower lobes or in the lower segments of
the upper lobes
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The lesion in the lung together with the lesion of the
hilar lymphnode is referred to as the Ghon complex
Microscopically, the classic lesion of TB is a caseous
granuloma which has a soft semisolid core surround
by epithelioid macrophages, Langhans giant cells
lymphocytes and peripheral fibrous tissue

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Primary pulmonary tuberculosis,
Ghon complex.
The gray-white parenchymal
focus is under the pleura in the
lower part of the upper lobe.
Hilar lymph nodes with
caseation are seen on the left

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 The morphologic spectrum of
tuberculosis. A characteristic tubercle at
low magnification (A) and in detail (B)
illustrates central granular caseation
(right) that is surrounded by epithelioid
and multinucleated giant cells (left).
This is the usual response seen in
individuals who have developed cell-
mediated immunity to the organism. C,
Occasionally, even in
immunocompetent individuals,
tubercular granulomas may not show
central caseation; hence, irrespective of
the presence or absence of caseous
necrosis, special stains for acid-fast
organisms must be performed when
granulomas are present in histologic
sections. D, In immunosuppressed
individuals, tuberculosis may not elicit a
granulomatous response ("nonreactive
tuberculosis"); instead, sheets of foamy
histiocytes are seen, packed with
mycobacteria that are demonstrable
with acid-fast stains

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Fate of primary complex include
i). T-cell mediated immune response induces hypersensitivity
to the organisms and controls 95% of primary infection.
-This is associated with progressive fibrosis and calcification of
persistent caseous debris.
-Moreover, most bacilli die but few remain viable for years
until the person’s immune response fails.
ii. Progressive primary tuberculous pneumonia: commonly
seen in children less than five years of age but it can occur in
adults as well in those with suppressed or defective immunity.

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Cont..
iii. Subpleural focus may discharge bacilli or antigen into the
pleural cavity resulting in the development of pleural effusion.
-It is common in adolescent infected with M. tuberculosis for the
first time.
Hilar or mediastinal groups of lymph nodes enlargement
with caseous necrosis that may result in:
a. Obstruction of the bronchus by the enlarged lymph nodes
leading to lobar collapse.
b. The caseous hilar lymph node may penetrate the bronchial
wall and resulting in rupture of the wall with pouring of caseous
materials into the bronchus hence, tuberculosis broncho-
pneumonia ensues.
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Cont..
iv. The caseous materials may be disseminated to other
parts of the body via blood streams.
v. Seeding of the bacilli in lungs, bones, kidneys,
fallopian tubes, bladder, epididimis etc, that may persist
in and their subsequent reactivation produces
destructive, necrotizing granulmatious disease,
sometimes known as end organ tuberculosis.

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Others sites of primary tuberculosis infection
i. Intestinal primary infection
 The primary complex is similar to that of the lungs the initial site may be
in the gum with lymphatic spread of bacilli to the cervical lymph nodes
 The commonest location for the primary lesion is the illocaecal region
with local mesenteric node involvement.
ii. Lymph nodes
 Tuberculous lymph adenitis is the most common type of extra
pulmonary tuberculosis
 It frequently involves the cervical groups of lymph nodes with
enlargement, and subsequent periadenitis followed by matting and
eventual ulcerations if left untreated.
iii. Skin is also involved in various forms of tuberculosis

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- if the infected person lacks an appropriate
immunological response the granulomas are less
organized and may consist of only an aggregate of
macrophages lacking the architecture and Langhans
giant cells.

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Progressive primary tuberculosis
Generally develops in children and is a continuation of
the primary infection
The infection spreads widely with the involvement of
regional lymph node ,pleura. .
Tuberculosis in young children is almost invariably
accompanied by hilar or mediastinal lymphadenopathy
Enlarged lymph nodes may compress bronchi, causing
obstruction and subsequent segmental or lobar collapse

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Bacilli reach the bloodstream from the pulmonary
lesion or the lymph nodes and disseminate into
various organs, where they may produce
granulomatous lesions
Although healing frequently takes place,
immunocompromised persons (e.g., patients with HIV
infection) may develop miliary tuberculosis and/or
tuberculous meningitis.

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Usually apical lesions which enlarge with caseation
Erosion of blood vessels results in hemoptysis

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Post primary TB (secondary TB)
- reinfection
- reactivation of dormant disease

Reasons for Reinfection

- Strains of the mycobacterium may particularly be

virulent
- Or host is particularly susceptible
e.g. if the infected person is immunologically immature as
in young child or immunosuppressed as in patients with
AIDS
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Granulomas of secondary tuberculosis most often occur
in the apex of the lungs but may be widely
disseminated in the lungs, kidneys ,meninges, marrow
and other organs.
- Two special features of secondary tuberculosis are
caseous necrosis and cavities
-Cavities are typically 2-4cm in diameter but can reach
as big as 10cm

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Secondary
pulmonary
tuberculosis.
The upper parts of
both lungs are
riddled with gray-
white areas of
caseation and
multiple areas of
softening and
cavitation.

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Cont..
Miliary tuberculosis
- Hematogenous dissemination of tuberculous lesions
throughout the body
- The term military is descriptive of the small yellow
white lesions that resemble millet seeds
-Certain tissues are relatively resistant to tuberculosis
infection so it is rare to find tuberculosis in heart,
striated ,muscle, thyroid and pancreas

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Cont..
Miliary tuberculosis
of the spleen.
The cut surface
shows numerous
gray-white
granulomas.

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Cont..

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In certain instances hematogenously spread organism are
destroyed in all tissues but persist in only one organs
[isolated end organ disease] eg
-lungs
-cervical lymph nodes (scrofula)
-produce mass of firm lymph nodes,there can be chronic
fstulous tract
-CNS
Most often in young children but also develops in adults,
especially those infected with HIV
Meninges (tuberculous meningitis) or
Mass lesion in the brain-tuberculoma
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-Lumbar puncture is the cornerstone of diagnosis
-Cerebrospinal fluid (CSF) reveals a high leukocyte
count (up to 1000/L), usually with a predominance of
lymphocytes
-A protein content of 1–8 g/L (100–800 mg/dL); and a
low glucose concentration
Urinary tract (Kidneys)
sterile pyuria- WBCs in urine but culture negative

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Cont..
Adrenals
-spread is usually bilateral
-cortical destruction may lead to Addisons disease
bones (TB ostemyelitis)
-In vertebra tuberculosis ,thoracic and lumbar (Pott’s
disease) ,may cause kyphosis
-Long fistulas may form along the psoas muscle to
open and drain into the groin region
-Other joints like hip and knee can be involved
Genital tb
-fallopian tube and endometrium
-epididymis
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TB in the upper airways
A complication of advanced cavitary pulmonary
tuberculosis
May involve the larynx, pharynx, and epiglottis
Symptoms include hoarseness, dysphonia, and
dysphagia in addition to chronic productive cough
Acid-fast smear of the sputum is often positive

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TB and HIV
The HIV epidemic worsened the TB situation by
Accelerating the progression from primary infection to
disease
Increasing the reactivation rate of TB
Increasing the reinfection rate

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Cont..
M. TB and M. avium–intracellulare lesion in AIDS can
take three forms, depending on degree of
immunosuppression

1. In M.TB prevalent areas

-Usually well formed granulomas composed of epithelioid
cells, Langhans giant cells and lymphocytes in these
lesion, AFB are few

2.When HIV positive patients develop AIDS and are

moderately immunosuppressed (CD4.C200/uc)
-M.TB infection is frequently caused by reactivation or
exposure to new mycobacteria
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On histology granulomas are less well formed, more
frequently necrotic and contain more abundant AFB
Sputum is positive for AFB in 31%-82% of patients
with AIDS, only 33% of the patients are reactive to PPD
Extra plumonary tuberculosis occurs in 70% of such
patients

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Cont..
3. opportunistic infections with M. avium
intercellulare complex
- In severely immunocompromise patients (CD4 <60/ul)
- Most infections originate in GIT
- Usually widely disseminated throughout the RES
causing enlargement of involved Lymph nodes, liver
and spleen.
- Granulomas, lymphocytes and tissue destruction are
rare.

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Diagnosis of TB
AFB Microscopy
From sputum or of tissue (e.g., a lymph node biopsy)
Has relatively low sensitivity (40–60%) in confirmed
cases of pulmonary tuberculosis
Mycobacterial Culture
egg- or agar-based medium (e.g., Löwenstein-Jensen
or Middlebrook 7H10)

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 grow slowly, 4–8 weeks
Nucleic Acid Amplification
Radiographic Procedures
Serologic Tests
Based on detection of antibodies to a variety of
mycobacterial antigens
Tuberculin Skin Testing

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IFN- Release Assays (IGRAs)
measure T cell release of IFN- in response to
stimulation with the highly tuberculosis-specific
antigens

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