Pulmonary Tuberculosis

PULMONARY TUBERCULOSISPULMONARY TUBERCULOSIS
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HISTORY OF TBHISTORY OF TB
AN OLD DISEASEAN OLD DISEASE
• May have evolved fromMay have evolved from M bovisM bovis; acquired; acquired
by humans from domesticated animalsby humans from domesticated animals
~15,000 years ago~15,000 years ago
• Endemic in humans when stable networksEndemic in humans when stable networks
of 200-440 people established (villages) ~of 200-440 people established (villages) ~
10,000 years ago; Epidemic in Europe after10,000 years ago; Epidemic in Europe after
1600 (cities)1600 (cities)
• 354-322 BC - Aristotle – “When one comes354-322 BC - Aristotle – “When one comes
near consumptives… one does contract theirnear consumptives… one does contract their
disease… The reason is that the breath isdisease… The reason is that the breath is
bad and heavy…In approaching thebad and heavy…In approaching the
consumptive, one breathes this perniciousconsumptive, one breathes this pernicious
air. One takes the disease because in thisair. One takes the disease because in this
air there is something disease producing.”air there is something disease producing.”

TB is an ancient disease. Signs of skeletal TB (Pott disease) have beenTB is an ancient disease. Signs of skeletal TB (Pott disease) have been
found in remains from Europe from Neolithic times (8000 BCE), ancientfound in remains from Europe from Neolithic times (8000 BCE), ancient
Egypt (1000 BCE), and the pre-Columbian New World.Egypt (1000 BCE), and the pre-Columbian New World.
TB was recognized as a contagious disease by the time of HippocratesTB was recognized as a contagious disease by the time of Hippocrates
(400 BCE), when it was termed "phthisis" (Greek from phthinein, to(400 BCE), when it was termed "phthisis" (Greek from phthinein, to
waste away).waste away).
In English, pulmonary TB was long known by the term “consumption.”In English, pulmonary TB was long known by the term “consumption.”
German physician Robert Koch discovered and isolated M tuberculosisGerman physician Robert Koch discovered and isolated M tuberculosis
in 1882.in 1882.

PHTHISISPHTHISISPHTHISISPHTHISIS
In 46o B.C.,the Greek physician Hippocrates described tuberculosisIn 46o B.C.,the Greek physician Hippocrates described tuberculosis
as an "almost always fatal disease of the lungs."The Greeks calledas an "almost always fatal disease of the lungs."The Greeks called
the disease phthisis(pronounced "TEE-sis"),which means wasting orthe disease phthisis(pronounced "TEE-sis"),which means wasting or
decay.decay.
In 46o B.C.,the Greek physician Hippocrates described tuberculosisIn 46o B.C.,the Greek physician Hippocrates described tuberculosis
as an "almost always fatal disease of the lungs."The Greeks calledas an "almost always fatal disease of the lungs."The Greeks called
the disease phthisis(pronounced "TEE-sis"),which means wasting orthe disease phthisis(pronounced "TEE-sis"),which means wasting or
decay.decay.
Hamdi TurkeyHamdi Turkey

CDC Tuberculosis CaseCDC Tuberculosis Case
Definition for Public HealthDefinition for Public Health
SurveillanceSurveillance
CDC Tuberculosis CaseCDC Tuberculosis Case
Definition for Public HealthDefinition for Public Health
SurveillanceSurveillance

M TUBERCULOSIS AS CAUSATIVEM TUBERCULOSIS AS CAUSATIVE
AGENT FOR TUBERCULOSISAGENT FOR TUBERCULOSIS
M TUBERCULOSIS AS CAUSATIVEM TUBERCULOSIS AS CAUSATIVE
AGENT FOR TUBERCULOSISAGENT FOR TUBERCULOSIS
1882 –1882 – Robert KochRobert Koch – “one– “one
seventh of all human beingsseventh of all human beings
die of tuberculosis and… if onedie of tuberculosis and… if one
considers only the productiveconsiders only the productive
middle-age groups,middle-age groups,
tuberculosis carries away one-tuberculosis carries away one-
third and often more ofthird and often more of
these…”these…”

OBJECTIVESOBJECTIVESOBJECTIVESOBJECTIVES
The TB ScenarioThe TB Scenario
Defining TB: Cause, Transmission, andDefining TB: Cause, Transmission, and
ManifestationsManifestations
Risk of TB infectionRisk of TB infection
Diagnosing Pulmonary TuberculosisDiagnosing Pulmonary Tuberculosis
TB Treatment and CureTB Treatment and Cure
Preventing transmissionPreventing transmission
Proper Management of TB casesProper Management of TB cases

THE BURDEN OF TBTHE BURDEN OF TBTHE BURDEN OF TBTHE BURDEN OF TB
TB remains the leading cause of death worldwide from aTB remains the leading cause of death worldwide from a
single infectious agentsingle infectious agent
It is estimated that between 2000-2020, nearlyIt is estimated that between 2000-2020, nearly one billionone billion
peoplepeople will be newly infected,will be newly infected, 200 million people200 million people will getwill get
sick, andsick, and 35 million35 million will die from TB- if control is notwill die from TB- if control is not
further strengthenedfurther strengthened
With the increased incidence of AIDS, TB has become more aWith the increased incidence of AIDS, TB has become more a
problem in the US and the worldproblem in the US and the world
It is currently estimated that 1/2 of the world populationIt is currently estimated that 1/2 of the world population (3.1(3.1
billion) is infected with TBbillion) is infected with TB

EPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGY
Tuberculosis (TB), which is caused by a complex of organisms, MycobacteriumTuberculosis (TB), which is caused by a complex of organisms, Mycobacterium
tuberculosis, Mycobacterium bovis, and Mycobacterium africanum, is antuberculosis, Mycobacterium bovis, and Mycobacterium africanum, is an
ancient human disease.ancient human disease.
Evidence of TB can be found in human remains dating back to Neolithic times.Evidence of TB can be found in human remains dating back to Neolithic times.
The most recent World Health Organization data estimate that 1.86 billionThe most recent World Health Organization data estimate that 1.86 billion
persons are currently infected with TB.persons are currently infected with TB.
At any time, an estimated 16 million persons worldwide demonstrate activeAt any time, an estimated 16 million persons worldwide demonstrate active
disease, and 8 million new active cases develop each year, of which 3.5 milliondisease, and 8 million new active cases develop each year, of which 3.5 million
manifest as the infectious pulmonary form of the disease.manifest as the infectious pulmonary form of the disease.
This remarkable prevalence of disease is estimated to be responsible for at leastThis remarkable prevalence of disease is estimated to be responsible for at least
2 million deaths each year, making TB the most frequent infectious cause of2 million deaths each year, making TB the most frequent infectious cause of
death in the world and the seventh most frequent cause of morbidity among alldeath in the world and the seventh most frequent cause of morbidity among all
diseases.diseases.

The World Health Organization declared TB a worldThe World Health Organization declared TB a world
global emergency in 1993; however, economic andglobal emergency in 1993; however, economic and
political commitment to TB control programs is lackingpolitical commitment to TB control programs is lacking
in many countries, and it is estimated that 95% of newin many countries, and it is estimated that 95% of new
cases of TB occur in countries with limited resources.cases of TB occur in countries with limited resources.
This situation facilitates inappropriate or unsustainedThis situation facilitates inappropriate or unsustained
TB therapy, which in turn has promoted a rise in theTB therapy, which in turn has promoted a rise in the
rates of multidrug-resistant TB (MDR-TB)rates of multidrug-resistant TB (MDR-TB)
EPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGY

ETIOLOGYETIOLOGYETIOLOGYETIOLOGY
Mycobacterium tuberculosis is theMycobacterium tuberculosis is the
causative organism of pulmonarycausative organism of pulmonary
tuberculosistuberculosis
Non-spore forming, non motile,Non-spore forming, non motile,
pleiomorphic, weakly gram-positive,pleiomorphic, weakly gram-positive,
curved rod about 2-4 um longcurved rod about 2-4 um long
Appear beaded or clumped in stainedAppear beaded or clumped in stained
clinical specimens or culture mediaclinical specimens or culture media
Grow best at 37-41 cGrow best at 37-41 c
Grow slowly, their generation time beingGrow slowly, their generation time being
12-24 hour12-24 hour

MODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSION
Airway droplets: the main modeAirway droplets: the main mode
of transmission from personof transmission from person
infected with pulmonary TB toinfected with pulmonary TB to
others by respiratory droplets.others by respiratory droplets.
Ingestion: Less frequentlyIngestion: Less frequently
transmitted by ingestion oftransmitted by ingestion of
mycobacterium bovis found inmycobacterium bovis found in
unpasteurized milk productsunpasteurized milk products
Direct inoculationDirect inoculation

Pulmonary TB is a disease of respiratory transmission,Pulmonary TB is a disease of respiratory transmission,
patients with active disease expel bacilli into the air by:patients with active disease expel bacilli into the air by:
CoughingCoughing
SneezingSneezing
ShoutingShouting
Or any other way that will expel bacilli into the airOr any other way that will expel bacilli into the air

Millions of tubercle bacilli in lungsMillions of tubercle bacilli in lungs
( mainly in cavities)( mainly in cavities)
Coughing projects droplets nucleiCoughing projects droplets nuclei
into the air that contain tubercleinto the air that contain tubercle
bacillibacilli
One cough can release 3,000One cough can release 3,000
droplet nucleidroplet nuclei
One sneeze can release tens ofOne sneeze can release tens of
thousands of droplet nucleithousands of droplet nuclei
As few as five M. tuberculosisAs few as five M. tuberculosis
(MTB) bacilli are necessary for(MTB) bacilli are necessary for
human infectionhuman infection

Optimal conditions for transmission include:Optimal conditions for transmission include:
OvercrowdingOvercrowding
Poor personal hygienePoor personal hygiene
Poor public hygienePoor public hygiene

FATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLS
Large droplets settle to the ground quicklyLarge droplets settle to the ground quickly
Smaller droplets form " droplet nuclei" of 1-5 µm inSmaller droplets form " droplet nuclei" of 1-5 µm in
diameter, only TB-containing particles small enough to reachdiameter, only TB-containing particles small enough to reach
the vulnerable environment of the alveolar space (typicallythe vulnerable environment of the alveolar space (typically
<5–10 µm) are considered infectious. After inhalation, these<5–10 µm) are considered infectious. After inhalation, these
infectious particles deposit preferentially in the dependentinfectious particles deposit preferentially in the dependent
lower half of the lung, where they subsequently initiate alower half of the lung, where they subsequently initiate a
primary focus of infection.primary focus of infection.
Droplet nuclei can remain airborneDroplet nuclei can remain airborne

NOT EVERYONE WHO IS EXPOSED TONOT EVERYONE WHO IS EXPOSED TO
TB WILL BECOME INFECTEDTB WILL BECOME INFECTED
NOT EVERYONE WHO IS EXPOSED TONOT EVERYONE WHO IS EXPOSED TO
TB WILL BECOME INFECTEDTB WILL BECOME INFECTED
ExposureExposureExposureExposure
Infection (30%)Infection (30%)Infection (30%)Infection (30%)
No infection (70%)No infection (70%)No infection (70%)No infection (70%)
Non specificNon specific
immunityimmunity
AdequateAdequate
InadequateInadequate
Early progression (5%)Early progression (5%)Early progression (5%)Early progression (5%)
Containment (95%)Containment (95%)
Latent TBLatent TB
Containment (95%)Containment (95%)
Latent TBLatent TB
immunologicalimmunological
defensesdefenses
immunologicalimmunological
defensesdefenses
AdequateAdequate
InadequateInadequate

HIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSION
Persons more likely to progress from LTBI to TB disease includesPersons more likely to progress from LTBI to TB disease includes::
HIV infected personsHIV infected persons
Persons with a history of prior, untreated TB or fibrotic lesions on CXRPersons with a history of prior, untreated TB or fibrotic lesions on CXR
Recent TB infection (within the past 2 years)Recent TB infection (within the past 2 years)
Injection drug usersInjection drug users
Age ( very young or very old)Age ( very young or very old)
Patients with certain medical conditions ( DM, chronic renal failure,Patients with certain medical conditions ( DM, chronic renal failure,
hemodialysis, solid organ transplantation, cancer, malnourished patient,hemodialysis, solid organ transplantation, cancer, malnourished patient,
silicosis)silicosis)

LTBI VS TB DISEASELTBI VS TB DISEASELTBI VS TB DISEASELTBI VS TB DISEASE
LTBILTBI TB diseaseTB disease
Tubercle bacilli in the bodyTubercle bacilli in the body
TST or QFT-Gold results usually positiveTST or QFT-Gold results usually positive
CXR usually normalCXR usually normal CXR usually abnormalCXR usually abnormal
Sputum smear and culturesSputum smear and cultures
negativenegative
Sputum smear and culturesSputum smear and cultures
positivepositive
No symptomsNo symptoms
Symptoms such as cough,fever,Symptoms such as cough,fever,
weight lossweight loss
Not infectiousNot infectious Often infectious before treatmentOften infectious before treatment
Not a case of TBNot a case of TB A case of TBA case of TB

SPREAD OF TB TO OTHERSPREAD OF TB TO OTHER
PARTS OF THE BODYPARTS OF THE BODY
SPREAD OF TB TO OTHERSPREAD OF TB TO OTHER
PARTS OF THE BODYPARTS OF THE BODY
Lungs (85% of all cases)Lungs (85% of all cases)
PleuraPleura
CNSCNS
Lymph nodesLymph nodes
Genitourinary systemGenitourinary system
Bones and jointsBones and joints
Disseminated ( eg miliary)Disseminated ( eg miliary)

TB CAN AFFECT ANY PART OFTB CAN AFFECT ANY PART OF
THE BODYTHE BODY
TB CAN AFFECT ANY PART OFTB CAN AFFECT ANY PART OF
THE BODYTHE BODY

PATHOGENESISPATHOGENESIS
The bacilli implant in areas of high partial pressure of oxygen:The bacilli implant in areas of high partial pressure of oxygen:
•LungLung
•Renal cortexRenal cortex
•Reticule endothelial systemReticule endothelial system
The principal cause of tissue destruction from M tuberculosisThe principal cause of tissue destruction from M tuberculosis
infection is related to the organism's ability to incite intenseinfection is related to the organism's ability to incite intense
host immune reactions to antigenic cell wall proteinshost immune reactions to antigenic cell wall proteins

This is known as the primary infection, the patient will healThis is known as the primary infection, the patient will heal
and a scar will appear in the affected loci.and a scar will appear in the affected loci.
There will also be a few viable bacilli/spores may remain inThere will also be a few viable bacilli/spores may remain in
these areas( particularly in the lung), the bacteria at this timethese areas( particularly in the lung), the bacteria at this time
goes into a dormant state, as long as the person's immunegoes into a dormant state, as long as the person's immune
system remains active and functions normallysystem remains active and functions normally
When a person immune system is depressed, a secondaryWhen a person immune system is depressed, a secondary
reactivation occurs. 85-90% this reactivation occurs in thereactivation occurs. 85-90% this reactivation occurs in the
lungslungs

About 90% of those infected with mycobacterium tuberculosis areAbout 90% of those infected with mycobacterium tuberculosis are
asymptomatic (latent TB infection), with only a 10% lifetime chance thatasymptomatic (latent TB infection), with only a 10% lifetime chance that
latent infection will progress to TB disease.latent infection will progress to TB disease.
Tuberculosis is classified into:Tuberculosis is classified into:
A.A. Primary pulmonary TBPrimary pulmonary TB
B.B. Secondary pulmonary TBSecondary pulmonary TB
C.C. Miliary TBMiliary TB
D.D. Extra pulmonary TB ( CNS, Bones, joints, adrenal, renal etc...)Extra pulmonary TB ( CNS, Bones, joints, adrenal, renal etc...)

When inhaled, droplet nuclei are deposited within the terminalWhen inhaled, droplet nuclei are deposited within the terminal
airspaces of the lung. The organisms grow for 2-12 weeks, untilairspaces of the lung. The organisms grow for 2-12 weeks, until
they reach 1000-10,000 in number, which is sufficient to elicitthey reach 1000-10,000 in number, which is sufficient to elicit
a cellular immune response that can be detected by a reactiona cellular immune response that can be detected by a reaction
to the tuberculin skin test.to the tuberculin skin test.
Mycobacteria are highly antigenic, and they promote aMycobacteria are highly antigenic, and they promote a
vigorous, nonspecific immune response. Their antigenicity isvigorous, nonspecific immune response. Their antigenicity is
due to multiple cell wall constituents, including glycoproteins,due to multiple cell wall constituents, including glycoproteins,
phospholipids, and wax D, which activate Langerhans cells,phospholipids, and wax D, which activate Langerhans cells,
lymphocytes, and polymorphonuclear leukocyteslymphocytes, and polymorphonuclear leukocytes

MICROSCOPIC PICTUREMICROSCOPIC PICTURE
The Ghon focus consistsThe Ghon focus consists
of a central area of pinkof a central area of pink
caseous necrosiscaseous necrosis
surrounded bysurrounded by
inflammatory infiltrateinflammatory infiltrate
and walled of by an areaand walled of by an area
of granulation tissueof granulation tissue
containing multinucleatedcontaining multinucleated
Langhans giant cellsLanghans giant cells

FATE OF PRIMARY TBFATE OF PRIMARY TB
This depends on:This depends on:
Virulence of the organismVirulence of the organism
Dose of infectionDose of infection
Degree of resistance of the hostDegree of resistance of the host
A.A.If the patient resistance is good and the organism is of low virulence, GhonIf the patient resistance is good and the organism is of low virulence, Ghon
complex undergo healing and over time usually evolve to fibrocalcific nodulescomplex undergo healing and over time usually evolve to fibrocalcific nodules
B.B.If the patient resistance is poor and/or the organism of high virulence,If the patient resistance is poor and/or the organism of high virulence,
progressive pulmonary tuberculosis will develop, the primary Ghon focus in theprogressive pulmonary tuberculosis will develop, the primary Ghon focus in the
lung enlarges rapidly, erodes the bronchial tree, and spreadlung enlarges rapidly, erodes the bronchial tree, and spread

HOST'S IMMUNE SYSTEMHOST'S IMMUNE SYSTEM
AND TB DISEASEAND TB DISEASE
More important than the virulence of the infecting strain, however, mayMore important than the virulence of the infecting strain, however, may
be genetic differences in the host’s immune system.be genetic differences in the host’s immune system.
IL-12 is important for the development of cell-mediated immunity, andIL-12 is important for the development of cell-mediated immunity, and
defects in the IL-12 receptor have been associated with disseminateddefects in the IL-12 receptor have been associated with disseminated
mycobacterial infection following bacille Calmette-Guérin (BCG)mycobacterial infection following bacille Calmette-Guérin (BCG)
vaccination.vaccination.
Tumor necrosis factor-α (TNF-α) is responsible for granuloma formationTumor necrosis factor-α (TNF-α) is responsible for granuloma formation
and also for the production of reactive nitrogen intermediates needed toand also for the production of reactive nitrogen intermediates needed to
kill intracellular bacilli, and high rates of active TB have been describedkill intracellular bacilli, and high rates of active TB have been described
following the administration of anti–TNF-α antibodies.following the administration of anti–TNF-α antibodies.

IFN-α is necessary for the production of TNF-α by macrophages, andIFN-α is necessary for the production of TNF-α by macrophages, and
genetic absence of the IFN-γ receptor has been associated withgenetic absence of the IFN-γ receptor has been associated with
disseminated nontuberculous mycobacterial infections in humans. Somedisseminated nontuberculous mycobacterial infections in humans. Some
have hypothesized that subtle alterations in the IFN-γ receptor may behave hypothesized that subtle alterations in the IFN-γ receptor may be
responsible forresponsible for
variations in susceptibility to the development of TB: variability in thevariations in susceptibility to the development of TB: variability in the
HLA-D gene locus, possibly related to a reduced affinity of the class IIHLA-D gene locus, possibly related to a reduced affinity of the class II
major histocompatibility complex for mycobacterial antigens, inmajor histocompatibility complex for mycobacterial antigens, in
addition to genetic polymorphisms in the natural resistance–associatedaddition to genetic polymorphisms in the natural resistance–associated
macrophage protein-1 (NRAMP-1) , have been associated with anmacrophage protein-1 (NRAMP-1) , have been associated with an
increased likelihood for the development of clinically apparent disease.increased likelihood for the development of clinically apparent disease.
HOST'S IMMUNE SYSTEMHOST'S IMMUNE SYSTEM
AND TB DISEASEAND TB DISEASE

PATHOGENESISPATHOGENESISPATHOGENESISPATHOGENESIS
TB diseaseTB diseaseTB diseaseTB disease
ImmunityImmunityImmunityImmunityHypersensitivityHypersensitivityHypersensitivityHypersensitivity
HealingHealingDiseaseDisease

Type IV hypersensitivity reaction:Type IV hypersensitivity reaction:
T cells ----->macrophages----> granulomaT cells ----->macrophages----> granuloma
Activated macrophages -----> epithelioid cellsActivated macrophages -----> epithelioid cells
Self destruction by lysosomal enzymesSelf destruction by lysosomal enzymes

Infected macrophages secrete interleukin-12 (IL-12), whichInfected macrophages secrete interleukin-12 (IL-12), which
promotes a nonspecific immune response mediatedpromotes a nonspecific immune response mediated
primarily by natural killer cells and / T cells.γ δprimarily by natural killer cells and / T cells.γ δ
The nonspecific immune response may retard the localThe nonspecific immune response may retard the local
infection but is usually unable to control it, and bacilliinfection but is usually unable to control it, and bacilli
spread to local lymph nodes, where they may enter thespread to local lymph nodes, where they may enter the
blood (bacillemia). From this point, TB infection is ablood (bacillemia). From this point, TB infection is a
systemic process characterized by lymphatic andsystemic process characterized by lymphatic and
hematogenous spread and the deposition of bacilli inhematogenous spread and the deposition of bacilli in
multiple extrapulmonary sites (i.e., bones, meninges,multiple extrapulmonary sites (i.e., bones, meninges,
kidney, and the posterior apical segment of the lungs),kidney, and the posterior apical segment of the lungs),
creating the potential for disease in virtually any anatomiccreating the potential for disease in virtually any anatomic
location.location.

MTB antigens in association with the class II major histocompatibilityMTB antigens in association with the class II major histocompatibility
complex are presented to naive CD4+ T cells, heralding the onset ofcomplex are presented to naive CD4+ T cells, heralding the onset of
specific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cellspecific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cell
immunity).immunity).
Anti-TB CD4+ T cells coordinate the specific immune response by twoAnti-TB CD4+ T cells coordinate the specific immune response by two
routes:routes:
The onset of the cytotoxic T-lymphocyte response several weeks afterThe onset of the cytotoxic T-lymphocyte response several weeks after
infection coincides with the development of caseous necrosis at the site ofinfection coincides with the development of caseous necrosis at the site of
primary infection and the development of delayed-type hypersensitivityprimary infection and the development of delayed-type hypersensitivity
(a)(a) secretion of IL-2 supports cytotoxic T-lymphocyte function, allowingsecretion of IL-2 supports cytotoxic T-lymphocyte function, allowing
these cells to kill other cells already infected with MTB directlythese cells to kill other cells already infected with MTB directly
(b)(b) secretion of interferon-γ (IFN-γ) primes uninfected macrophages,secretion of interferon-γ (IFN-γ) primes uninfected macrophages,
allowing them to kill the intracellular pathogen efficiently.allowing them to kill the intracellular pathogen efficiently.
(a)(a) secretion of IL-2 supports cytotoxic T-lymphocyte function, allowingsecretion of IL-2 supports cytotoxic T-lymphocyte function, allowing
these cells to kill other cells already infected with MTB directlythese cells to kill other cells already infected with MTB directly
(b)(b) secretion of interferon-γ (IFN-γ) primes uninfected macrophages,secretion of interferon-γ (IFN-γ) primes uninfected macrophages,
allowing them to kill the intracellular pathogen efficiently.allowing them to kill the intracellular pathogen efficiently.

Primary pulmonary TB is an infection of persons who havePrimary pulmonary TB is an infection of persons who have
not had prior contact with the tubercle bacillusnot had prior contact with the tubercle bacillus
Inhaled bacilli are commonly deposited in alveoliInhaled bacilli are commonly deposited in alveoli
immediately beneath the pleura, usually in the lower partimmediately beneath the pleura, usually in the lower part
of the upper lobes or the upper part of the lower lobesof the upper lobes or the upper part of the lower lobes
When inhaled, droplet nuclei are deposited in terminalWhen inhaled, droplet nuclei are deposited in terminal
airspaces of the lungairspaces of the lung
Macrophages ingest the bacilli and transport them toMacrophages ingest the bacilli and transport them to
regional lymph nodesregional lymph nodes
PRIMARY PULMONARY TBPRIMARY PULMONARY TB

The primary infection characteristicallyThe primary infection characteristically
produces a " Ghon complex" formed of:produces a " Ghon complex" formed of:
1.1. Ghon focus: small area of pneumonicGhon focus: small area of pneumonic
consolidation about 1-3 cm in diameter, sub-consolidation about 1-3 cm in diameter, sub-
pleural in location present in the base of thepleural in location present in the base of the
upper lobe or apex of the lower lobeupper lobe or apex of the lower lobe
2.2. Tuberculous lymphangitis: of the drainingTuberculous lymphangitis: of the draining
lymphatic channelslymphatic channels
3.3. Tuberculous lymphadenitis: of theTuberculous lymphadenitis: of the
tracheobronchial nodes which are enlarged,tracheobronchial nodes which are enlarged,
matted together and their cut surface showmatted together and their cut surface show
areas of caseous necrosisareas of caseous necrosis

Spread if infection will take place by:Spread if infection will take place by:
A.A. Local spread: to the surrounding lung tissue and pleuraLocal spread: to the surrounding lung tissue and pleura
B.B. Lymphatic spread: along bronchi, leading toLymphatic spread: along bronchi, leading to
tuberculous bronchopneumoniatuberculous bronchopneumonia
C.C. Hematogenous spread: leading to miliary TB orHematogenous spread: leading to miliary TB or
isolated organ TB or miliary TB of the lungisolated organ TB or miliary TB of the lung

•• Most often a childhood infection in endemic settingsMost often a childhood infection in endemic settings
•Few clinical symptoms in immunocompetent hostsFew clinical symptoms in immunocompetent hosts
•Lymphangitic spread to hilar and paratracheal nodes resultLymphangitic spread to hilar and paratracheal nodes result
in enlargement of these structuresin enlargement of these structures
•Often the only residua of primary infection is a positive skinOften the only residua of primary infection is a positive skin
test and the Ranke complextest and the Ranke complex
•Primary progressive tuberculosis occurs in a minority ofPrimary progressive tuberculosis occurs in a minority of
casescases

The natural history of primary pulmonary tuberculosis in adultsThe natural history of primary pulmonary tuberculosis in adults
EventEvent TimeTime CommentComment
Alveolar depositionAlveolar deposition
of tubercle bacilliof tubercle bacilli
00 Bacilli engulfed byBacilli engulfed by
alveolar macrophagesalveolar macrophages
Bacilli proliferateBacilli proliferate
and disseminateand disseminate
3-8 weeks3-8 weeks
Tuberculin skin testTuberculin skin test
becomes reactive;becomes reactive;
CXR may becomeCXR may become
abnormalabnormal
Some patientsSome patients
develop pleurisy; adevelop pleurisy; a
minority developminority develop
miliary diseasemiliary disease
8-26 weeks8-26 weeks
High risk period forHigh risk period for
pulmonary and extrapulmonary and extra
pulmonary diseasepulmonary disease
26-156 weeks26-156 weeks
10% infected will10% infected will
develop TBdevelop TB

COMPLICATIONS OFCOMPLICATIONS OF
PRIMARY TUBERCULOSISPRIMARY TUBERCULOSIS
PRIMARY TUBERCULOSISPRIMARY TUBERCULOSIS
Collapse/ consolidationCollapse/ consolidation
BronchiectasisBronchiectasis
Obstructive emphysemaObstructive emphysema
BroncholithBroncholith
Erythema nodosumErythema nodosum
Phlyctenular conjunctivitisPhlyctenular conjunctivitis
Pleural effusionPleural effusion
Miliary TBMiliary TB
Progressive primary tuberculosisProgressive primary tuberculosis

Secondary(cavitary) TB usually results from reactivation of aSecondary(cavitary) TB usually results from reactivation of a
dormant, endogenous tubercle bacilli in a sensitized patientdormant, endogenous tubercle bacilli in a sensitized patient
who has had previous contact with the tubercle bacilluswho has had previous contact with the tubercle bacillus
In some cases the disease is caused by reinfection withIn some cases the disease is caused by reinfection with
exogenous bacilliexogenous bacilli
The lesion begins as a tubercle, the micro-organismsThe lesion begins as a tubercle, the micro-organisms
searching for a high oxygen tension, usually settle in thesearching for a high oxygen tension, usually settle in the
apical portion of one or both lungsapical portion of one or both lungs
SECONDARY PULMONARY TBSECONDARY PULMONARY TB

A tubercle is no larger than 3A tubercle is no larger than 3
cm and consists of a centralcm and consists of a central
area of caseous necrosisarea of caseous necrosis
surrounded by granulomatoussurrounded by granulomatous
tissue containing the typicaltissue containing the typical
Langhans giant cellsLanghans giant cells
The tubercle is separated fromThe tubercle is separated from
the surrounding tissue by athe surrounding tissue by a
layer of fibrous tissuelayer of fibrous tissue
infiltrated with lymphocytesinfiltrated with lymphocytes

FATE OF SECONDARYFATE OF SECONDARY
PULMONARY TBPULMONARY TB
Healing by fibrosis with dystrophic calcification occurs in mostHealing by fibrosis with dystrophic calcification occurs in most
cases when the dose of infection is small, virulence of thecases when the dose of infection is small, virulence of the
organism is low and the patient resistance is goodorganism is low and the patient resistance is good
Spread of infection occurs when the patient resistance is poorSpread of infection occurs when the patient resistance is poor
and the virulence of the organism is high, spread occursand the virulence of the organism is high, spread occurs
directly by lymphatic,natural passages and blood streamdirectly by lymphatic,natural passages and blood stream
Fibrocaseous tuberculosis with cavitation occurs withFibrocaseous tuberculosis with cavitation occurs with
moderate dose of the organism and moderate resistance of themoderate dose of the organism and moderate resistance of the
patientpatient

Primary pulmonary TBPrimary pulmonary TB Secondary pulmonary TBSecondary pulmonary TB
Mainly occurs in children but canMainly occurs in children but can
occasionally occurs in elderly andoccasionally occurs in elderly and
adultsadults
Mainly occurs in adultsMainly occurs in adults
Mainly Asymptomatic or withMainly Asymptomatic or with
minimal symptoms and may goesminimal symptoms and may goes
unrecognizedunrecognized
SymptomaticSymptomatic
Septum for AFB is rarely positiveSeptum for AFB is rarely positive Usually positiveUsually positive
Associated with hypersensitivityAssociated with hypersensitivity
phenomenon ( erythema noduom)phenomenon ( erythema noduom)
Not associated withNot associated with
hypersensitivityhypersensitivity
Site of involvement on is the lowerSite of involvement on is the lower
portion of the upper lobe and theportion of the upper lobe and the
upper portion of the lower lobeupper portion of the lower lobe
Apex of both lungs and the upperApex of both lungs and the upper
portion of the lower lobeportion of the lower lobe
On CXR : an area of consolidationOn CXR : an area of consolidation
or pleural effusionor pleural effusion
Typically cavitary lesion over theTypically cavitary lesion over the
apexapex
Non infectiousNon infectious
Highly infectious in sputumHighly infectious in sputum
positive casespositive cases

FIBROCASEOUS TB WITHFIBROCASEOUS TB WITH
CAVITATIONCAVITATION
FIBROCASEOUS TB WITHFIBROCASEOUS TB WITH
CAVITATIONCAVITATION
The cavity is chronic withThe cavity is chronic with
fibrotic walls, lined byfibrotic walls, lined by
caseous material and iscaseous material and is
traversed by blood vesselstraversed by blood vessels
and bronchiand bronchi
The surrounding lung tissueThe surrounding lung tissue
shows multiple focal areasshows multiple focal areas
of caseation and otherof caseation and other
cavitiescavities

FIBROCASEOUS TBFIBROCASEOUS TB
FIBROCASEOUS TBFIBROCASEOUS TB
Spread to the pleura causing----> pleural effusion, fibrinousSpread to the pleura causing----> pleural effusion, fibrinous
pleurisy, tuberculous empyema, pneumothorax,pleurisy, tuberculous empyema, pneumothorax,
pyopneumothoraxpyopneumothorax
Coughing of the content of the cavity leads to: tuberculousCoughing of the content of the cavity leads to: tuberculous
tracheobronchitis, tuberculous laryngitis, tuberculoustracheobronchitis, tuberculous laryngitis, tuberculous
glossitis and tuberculous enteritisglossitis and tuberculous enteritis
Erosion of the traversing blood vessels leads to: hemoptysis,Erosion of the traversing blood vessels leads to: hemoptysis,
hematogenous spreadhematogenous spread
Secondary amyloidosisSecondary amyloidosis

MILIARY TUBERCULOSISMILIARY TUBERCULOSIS
It is the disseminated form of tuberculosis and is caused byIt is the disseminated form of tuberculosis and is caused by
seeding of the bacilli through lymphatic a or blood vesselsseeding of the bacilli through lymphatic a or blood vessels
Sites : the lung, lymph nodes, kidneys, adrenals, bone marrow,Sites : the lung, lymph nodes, kidneys, adrenals, bone marrow,
spleen, liver, meninges, brain, eye grounds, and genitaliaspleen, liver, meninges, brain, eye grounds, and genitalia
Fate: all granulomas have similar features and follow the sameFate: all granulomas have similar features and follow the same
progression, namely focal collections of histocytes, followed byprogression, namely focal collections of histocytes, followed by
epithelioid cells, Langhans giant cells, central caseationepithelioid cells, Langhans giant cells, central caseation
necrosis and eventually fibrosis and mineralizationnecrosis and eventually fibrosis and mineralization

Gross picture:Gross picture:
Minute, yellow-white lesions resembling millet seeds ( hence miliary)Minute, yellow-white lesions resembling millet seeds ( hence miliary)
Gross picture:Gross picture:
Minute, yellow-white lesions resembling millet seeds ( hence miliary)Minute, yellow-white lesions resembling millet seeds ( hence miliary)
MILIARY TUBERCULOSISMILIARY TUBERCULOSISMILIARY TUBERCULOSISMILIARY TUBERCULOSIS

CLINICAL FEATURESCLINICAL FEATURES

Symptoms and signs of primary pulmonarySymptoms and signs of primary pulmonary
TuberclosisTuberclosis
AsymptomatAsymptomat
icic A great majority especially adultsA great majority especially adults
Brief febrileBrief febrile
illnessillness At the time of tuberculin conversionAt the time of tuberculin conversion
Anorexia,Anorexia,
failure to gainfailure to gain
weightweight
In few cases with more severe infection or lowIn few cases with more severe infection or low
host resistancehost resistance
CoughCough
If LN or granulation tissue impinge onIf LN or granulation tissue impinge on
bronchial wallbronchial wall
SputumSputum Rare in childrenRare in children
HypersensitiHypersensiti
vityvity
phenomenonphenomenon
Erythema nodosum, phlyctenularErythema nodosum, phlyctenular
conjunctivitis , dactalitisconjunctivitis , dactalitis

Symptoms and signs of secondary pulmonarySymptoms and signs of secondary pulmonary
CoughCough
Initially minimal and dry at early morning, thenInitially minimal and dry at early morning, then
productive of small amount of sputum and present all theproductive of small amount of sputum and present all the
dayday
FeverFever
Diurnal with early morning and late afternoon rise, LowDiurnal with early morning and late afternoon rise, Low
grade fever and in advanced cases associated withgrade fever and in advanced cases associated with
drenching night sweats and diaphoresisdrenching night sweats and diaphoresis
HemoptysisHemoptysis
Blood streak sputum and occasionally massiveBlood streak sputum and occasionally massive
hemoptysis in complicated caseshemoptysis in complicated cases
Loss ofLoss of
weightweight
Hence the name phthisis or wasting in advancedHence the name phthisis or wasting in advanced
untreated casesuntreated cases
AnorexiaAnorexia
and fatigueand fatigue Systemic manifestation of the diseaseSystemic manifestation of the disease
CracklesCrackles Characteristically post tussive over the involved areaCharacteristically post tussive over the involved area
AmorphicAmorphic
breath soundbreath sound
Or cavernous breath sound over a large cavityOr cavernous breath sound over a large cavity
communicating with a patent bronchuscommunicating with a patent bronchus

DIAGNOSISDIAGNOSISDIAGNOSISDIAGNOSIS

DIAGNOSISDIAGNOSIS
Any cough that persists more than 2 weeks should beAny cough that persists more than 2 weeks should be
evaluated for pulmonary TB in the appropriate clinicalevaluated for pulmonary TB in the appropriate clinical
context ( poor patient, overcrowded, bad hygiene etc)context ( poor patient, overcrowded, bad hygiene etc)
A full history and physical examination should beA full history and physical examination should be
undertakenundertaken
A minimum of 2 sputum samples, ( the first on spot and theA minimum of 2 sputum samples, ( the first on spot and the
second in the early morning preferably fasting ) should besecond in the early morning preferably fasting ) should be
examined, the sputum sample should be of a good qualityexamined, the sputum sample should be of a good quality
representative of lower respiratory tract.representative of lower respiratory tract.

RADIOLOGYRADIOLOGY
The following characteristics of chest radiograph favor theThe following characteristics of chest radiograph favor the
diagnosis of tuberculosisdiagnosis of tuberculosis
Shadows mainly in the upper zonesShadows mainly in the upper zones
Patchy or nodular shadowsPatchy or nodular shadows
The presence of a cavity or cavitiesThe presence of a cavity or cavities
The presence of calcificationThe presence of calcification
Bilateral shadows especially if theses are in the upper zonesBilateral shadows especially if theses are in the upper zones

PRIMARY PULMONARY TBPRIMARY PULMONARY TBPRIMARY PULMONARY TBPRIMARY PULMONARY TB
Lymphadenopathy is the hallmark of primaryLymphadenopathy is the hallmark of primary
disease in childhood, seen in up to 90% of casesdisease in childhood, seen in up to 90% of cases
Usually affects the hilum and right paratrachealUsually affects the hilum and right paratracheal
regionsregions
Bilateral adenopathy occurs in one third of casesBilateral adenopathy occurs in one third of cases
Adenopathy usually seen in association withAdenopathy usually seen in association with
parenchymal consolidation or atelectasisparenchymal consolidation or atelectasis
Lymphadenopathy can be the only manifestationLymphadenopathy can be the only manifestation
of TB in young childrenof TB in young children
Adenopathy resolves slowly, and nodalAdenopathy resolves slowly, and nodal
calcification may occur six months after the initialcalcification may occur six months after the initial
infectioninfection
Pleural effusion may occur in a minority of casesPleural effusion may occur in a minority of cases

RADIOGRAPHIC RESIDUAL OFRADIOGRAPHIC RESIDUAL OF

Ranke's ComplexRanke's ComplexRanke's ComplexRanke's Complex Simon fociSimon fociSimon fociSimon foci

POST PRIMARY PULMONARYPOST PRIMARY PULMONARY
TBTB
Post-primary TB represents 90 percent of adult cases in the non-HIV-infectedPost-primary TB represents 90 percent of adult cases in the non-HIV-infected
populationpopulation
Results from reactivation of a previously dormant focus seeded at the time ofResults from reactivation of a previously dormant focus seeded at the time of
primary infectionprimary infection
Apical-posterior segments of the upper lobes (80 to 90 percent of patients),Apical-posterior segments of the upper lobes (80 to 90 percent of patients),
followed in frequency by the superior segment of the lower lobes and thefollowed in frequency by the superior segment of the lower lobes and the
anterior segment of the upper lobesanterior segment of the upper lobes
The original site of spread is occasionally associated with Simon foci—residualThe original site of spread is occasionally associated with Simon foci—residual
uni- or bilateral apical fibronodular shadows from primary infectionuni- or bilateral apical fibronodular shadows from primary infection
Post-primary disease also known as reactivation TB, recrudescent TB, chronicPost-primary disease also known as reactivation TB, recrudescent TB, chronic
TB, endogenous reinfection, and adult type progressive TBTB, endogenous reinfection, and adult type progressive TB

THE RADIOGRAPHIC APPEARANCETHE RADIOGRAPHIC APPEARANCE
OF POST-PRIMARY DISEASEOF POST-PRIMARY DISEASE
Upper lobe infiltratesUpper lobe infiltrates
Cavitary lesionsCavitary lesions
TuberculomasTuberculomas
Absence of lymphadenopathyAbsence of lymphadenopathy
Complete lobar or lung opacification and lobarComplete lobar or lung opacification and lobar
collapse in severe casescollapse in severe cases
Pleural effusion, empyemaPleural effusion, empyema
bronchiectasis, mililary patternbronchiectasis, mililary pattern
pneumothoraxpneumothorax

CAVITARY DISEASECAVITARY DISEASECAVITARY DISEASECAVITARY DISEASE
A characteristic finding of post-A characteristic finding of post-
primary diseaseprimary disease
Cavitation implies a high bacillaryCavitation implies a high bacillary
burden and high infectivityburden and high infectivity
Cavity size ranges from a few mmCavity size ranges from a few mm
to several cmto several cm
Variable wall thicknessVariable wall thickness
Air fluid levels rare, and may be anAir fluid levels rare, and may be an
indication of bacterial or fungalindication of bacterial or fungal
superinfectionsuperinfection

Bilateral upper lobeBilateral upper lobe
involvementinvolvement
seen in this patient with post-seen in this patient with post-
Bilateral upper lobeBilateral upper lobe
involvementinvolvement
seen in this patient with post-seen in this patient with post-
Advanced post-primaryAdvanced post-primary
in an immunocompetent hostin an immunocompetent host
Advanced post-primaryAdvanced post-primary
in an immunocompetent hostin an immunocompetent host

TUBECULOMATUBECULOMATUBECULOMATUBECULOMA
Single or multiple rounded, well-Single or multiple rounded, well-
circumscribed, focal lesionscircumscribed, focal lesions
Manifestation of primary or post-Manifestation of primary or post-
Easily mistaken for coin lesions orEasily mistaken for coin lesions or
metastatic disease on chestmetastatic disease on chest
Vary in size from a few millimeters toVary in size from a few millimeters to
5 or 6 cm in diameter but usually5 or 6 cm in diameter but usually
range from 1 to 3 cm.range from 1 to 3 cm.
They may or may not contain calciumThey may or may not contain calcium

CHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TB
Characterize the cavityCharacterize the cavity
Tree in bud nodules indicatingTree in bud nodules indicating
endo-bronchial spread ofendo-bronchial spread of
infectioninfection
Detects complications:Detects complications:
1.1. PneumothoraxPneumothorax
2.2. EmpyemaEmpyema
3.3. BronchiectasisBronchiectasis
4.4. Tracheo-bronchial stenosisTracheo-bronchial stenosis
5.5. Miliary TBMiliary TB

SPUTUM EXAMINATIONSPUTUM EXAMINATION
For patients with suspected pulmonary TB, at least threeFor patients with suspected pulmonary TB, at least three
freshly expectorated first morning sputum samples shouldfreshly expectorated first morning sputum samples should
be collected from a deep, productive cough in a sterilebe collected from a deep, productive cough in a sterile
container with a wide mouth. Ideally, the volume of eachcontainer with a wide mouth. Ideally, the volume of each
sample should be more than 5 mLsample should be more than 5 mL
Induction of sputum with aerosolized hypertonic salineInduction of sputum with aerosolized hypertonic saline
solution may be required if the patient is having difficultysolution may be required if the patient is having difficulty
producing sputum; serial morning gastric lavage andproducing sputum; serial morning gastric lavage and
bronchoalveolar lavage are alternative methods of obtainingbronchoalveolar lavage are alternative methods of obtaining
clinical specimens.clinical specimens.

Examination of stained smears for AFB remains the most rapid and inexpensive method forExamination of stained smears for AFB remains the most rapid and inexpensive method for
detecting mycobacteria.detecting mycobacteria.
Both carbolfuchsin (Ziehl-Neelson or Kinyoun method) and fluorochrome (auramine–Both carbolfuchsin (Ziehl-Neelson or Kinyoun method) and fluorochrome (auramine–
rhodamine) stains are available, but fluorochrome staining is more sensitive and hasrhodamine) stains are available, but fluorochrome staining is more sensitive and has
become the standard staining method used in the United States.become the standard staining method used in the United States.
Staining techniques require the presence of at least 5,000 to 10,000 organisms for aStaining techniques require the presence of at least 5,000 to 10,000 organisms for a
positive result. The reported sensitivity of the AFB smear for respiratory samples rangespositive result. The reported sensitivity of the AFB smear for respiratory samples ranges
from 45% to 75%, and specificity is reported to be greater than 97% in most studies.from 45% to 75%, and specificity is reported to be greater than 97% in most studies.
The yield of a single specimen is low and can be improved by submitting multiple samplesThe yield of a single specimen is low and can be improved by submitting multiple samples
of adequate volume.of adequate volume.
Patients with cavitary TB are more likely to have a positive AFB smear because of the highPatients with cavitary TB are more likely to have a positive AFB smear because of the high
number of organisms present in this form of TB, whereas a positive AFB smear is less likelynumber of organisms present in this form of TB, whereas a positive AFB smear is less likely
in most types of extrapulmonary disease given the relatively low numbers of organisms inin most types of extrapulmonary disease given the relatively low numbers of organisms in
these forms of TBthese forms of TB
STAINING FOR ACID-FASTSTAINING FOR ACID-FAST
BACILLIBACILLI

DIRECT SMEARDIRECT SMEAR
EXAMINATIONEXAMINATION
Is only positive when large number ofIs only positive when large number of
bacilli are present ( 10,000), sobacilli are present ( 10,000), so
negative smear doesn't excludenegative smear doesn't exclude
A negative smear in the presence ofA negative smear in the presence of
extensive disease and cavitation makesextensive disease and cavitation makes
the diagnosis less likely, particularly ifthe diagnosis less likely, particularly if
the negatives are frequently repeatedthe negatives are frequently repeated
Sputum for AFBSputum for AFB
• Ziehl-Neelsen stainingZiehl-Neelsen staining
• Flurochrome staining- Auramine-Flurochrome staining- Auramine-
RhodamineRhodamine

CULTURECULTURE
The AFB smear is limited by its poor sensitivity and inability to differentiate betweenThe AFB smear is limited by its poor sensitivity and inability to differentiate between
MTB, nontuberculous mycobacterial species, and other acid-fast organisms.MTB, nontuberculous mycobacterial species, and other acid-fast organisms.
Mycobacterial culture is able to detect as few as 10 organisms per milliliter and overcomesMycobacterial culture is able to detect as few as 10 organisms per milliliter and overcomes
many of the limitations of AFB staining.many of the limitations of AFB staining.
Several types of culture media have been developed for the isolation of mycobacteria,Several types of culture media have been developed for the isolation of mycobacteria,
including agar-based media (Middlebrook 7H10-selective 7H11), egg-based mediaincluding agar-based media (Middlebrook 7H10-selective 7H11), egg-based media
(Lowenstein-Jensen), and liquid media (Middlebrook 7H12).(Lowenstein-Jensen), and liquid media (Middlebrook 7H12).
The development of automated broth culture systems, such as BACTEC 460, BACTEC 960The development of automated broth culture systems, such as BACTEC 460, BACTEC 960
mycobacterial growth indicator tube (MGIT) systems, Septi-Check ESP, and MB/BacT,mycobacterial growth indicator tube (MGIT) systems, Septi-Check ESP, and MB/BacT,
has been a major step in accelerating the diagnosis of MTBhas been a major step in accelerating the diagnosis of MTB
traditional solid media–based systems require 3 to 8 weeks for organism growth, whereastraditional solid media–based systems require 3 to 8 weeks for organism growth, whereas
broth culture methods require 1 to 3 weeks; however, because some species of the MTBbroth culture methods require 1 to 3 weeks; however, because some species of the MTB
complex may grow only on solid media, inoculation of both types of media iscomplex may grow only on solid media, inoculation of both types of media is
recommendedrecommended

Even with the use of broth-based culture systems, confirming theEven with the use of broth-based culture systems, confirming the
presence of MTB from the time of specimen collection takes at least apresence of MTB from the time of specimen collection takes at least a
week and more often 2 to 3 weeks.week and more often 2 to 3 weeks.
Methods to detect the presence of TB directly from clinical specimensMethods to detect the presence of TB directly from clinical specimens
more rapidly have been a significant advance in the treatment of TB.more rapidly have been a significant advance in the treatment of TB.
Current direct methods are based on nucleic acid amplificationCurrent direct methods are based on nucleic acid amplification
techniques, and two different tests are commercially available: atechniques, and two different tests are commercially available: a
transcription-mediated amplification method (Amplifiedtranscription-mediated amplification method (Amplified
Mycobacterium tuberculosis Direct [MTD] Test) and a polymeraseMycobacterium tuberculosis Direct [MTD] Test) and a polymerase
chain reaction–based assay (Amplicor; Roche Diagnostic Systems)chain reaction–based assay (Amplicor; Roche Diagnostic Systems)
DIRECT AMPLIFICATIONDIRECT AMPLIFICATION
TECHNIQUETECHNIQUE

The performance of nucleic acid amplification techniques has been most rigorouslyThe performance of nucleic acid amplification techniques has been most rigorously
evaluated in respiratory samples, in which both tests have a sensitivity of about 96%evaluated in respiratory samples, in which both tests have a sensitivity of about 96%
and a specificity of 100% for AFB smear-positive samples when combined withand a specificity of 100% for AFB smear-positive samples when combined with
appropriate nucleic acid probes.appropriate nucleic acid probes.
Their performance in AFB smear-negative specimens is significantly lessTheir performance in AFB smear-negative specimens is significantly less
impressive, with sensitivities ranging from 48% to 53%, although their specificityimpressive, with sensitivities ranging from 48% to 53%, although their specificity
remains high, at 96% to 99%.remains high, at 96% to 99%.
The accuracy of nucleic acid amplification testing may be reduced by theThe accuracy of nucleic acid amplification testing may be reduced by the
concurrent use of antituberculous therapy, and inhibitors in the patient’s sputumconcurrent use of antituberculous therapy, and inhibitors in the patient’s sputum
may also cause a false-negative result.may also cause a false-negative result.
nucleic acid amplification tests offer the opportunity to diagnose pulmonary TBnucleic acid amplification tests offer the opportunity to diagnose pulmonary TB
within several hours, and their application to the first specimen of all clinicallywithin several hours, and their application to the first specimen of all clinically
suspected cases is recommendedsuspected cases is recommended
DIRECT AMPLIFICATIONDIRECT AMPLIFICATION
TECHNIQUETECHNIQUE

The use of nucleic acid amplification tests in the diagnosticThe use of nucleic acid amplification tests in the diagnostic
evaluation of patients with suspected pulmonary tuberculosisevaluation of patients with suspected pulmonary tuberculosis
The use of nucleic acid amplification tests in the diagnosticThe use of nucleic acid amplification tests in the diagnostic
evaluation of patients with suspected pulmonary tuberculosisevaluation of patients with suspected pulmonary tuberculosis

NUCLEIC ACID PROBESNUCLEIC ACID PROBES
Nucleic acid probes have been developed that can specificallyNucleic acid probes have been developed that can specifically
hybridize with DNA or RNA from MTB, M. avium, M.hybridize with DNA or RNA from MTB, M. avium, M.
intracellulare, M. kansasii, and M. gordonae. The rapidity of thisintracellulare, M. kansasii, and M. gordonae. The rapidity of this
test allows for species identification within 2 hours and has atest allows for species identification within 2 hours and has a
sensitivity and specificity that approaches 100% for MTBsensitivity and specificity that approaches 100% for MTB
Although the test requires more than 105 organisms or the useAlthough the test requires more than 105 organisms or the use
of an amplification technique to achieve an adequate yield, whenof an amplification technique to achieve an adequate yield, when
it is combined with automated broth culture methods, the timeit is combined with automated broth culture methods, the time
for detecting and identifying MTB can be reduced to as little as 4for detecting and identifying MTB can be reduced to as little as 4
to 7 daysto 7 days

IDENTIFICATION OFIDENTIFICATION OF
RESISTANCERESISTANCE
The identification of antimicrobial resistance among clinical isolates is necessaryThe identification of antimicrobial resistance among clinical isolates is necessary
to ensure optimal therapy and prevent the spread of these organisms to others.to ensure optimal therapy and prevent the spread of these organisms to others.
Traditionally, agar- and broth-based methods have been used to detect drugTraditionally, agar- and broth-based methods have been used to detect drug
resistance.resistance.
In the agar-based method, organisms are allowed to grow on both a drug-In the agar-based method, organisms are allowed to grow on both a drug-
containing medium and a drug-free medium. Growth of the organisms on acontaining medium and a drug-free medium. Growth of the organisms on a
medium containing a drug that equals 1% or more of the growth of the organismsmedium containing a drug that equals 1% or more of the growth of the organisms
on a medium without the drug indicates resistance to that drugon a medium without the drug indicates resistance to that drug
Broth-based radiometric methods use a similar process and correlate well withBroth-based radiometric methods use a similar process and correlate well with
agar-based methods (95%–100%) but allow resistance to be detected much earlieragar-based methods (95%–100%) but allow resistance to be detected much earlier
than do solid media (4–7 days vs. 14–21 days). Because of the importance ofthan do solid media (4–7 days vs. 14–21 days). Because of the importance of
resistance, it is recommended that both media be usedresistance, it is recommended that both media be used

ANTIGEN DETECTIONANTIGEN DETECTION
Tuberculostearic acid in sputumTuberculostearic acid in sputum
Membrane antigens in CSFMembrane antigens in CSF
Lipoarabinomannan in serum and sputumLipoarabinomannan in serum and sputum

INDIRECT TESTSINDIRECT TESTS
Tuberculin skin testTuberculin skin test
TB serological tests ( antibody detection )TB serological tests ( antibody detection )
Mycobacteriophage assaysMycobacteriophage assays
Cytokine detectionCytokine detection
HistopathologyHistopathology

ADENOSINE DEAMINASEADENOSINE DEAMINASE
Adenosine deaminase is an enzyme produced by activated TAdenosine deaminase is an enzyme produced by activated T
lymphocytes, and measurement of the adenosine deaminase level inlymphocytes, and measurement of the adenosine deaminase level in
certain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) hascertain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) has
been evaluated as a diagnostic test for TB. In several studies, thebeen evaluated as a diagnostic test for TB. In several studies, the
sensitivity of the adenosine deaminase level in pleural fluid ranged fromsensitivity of the adenosine deaminase level in pleural fluid ranged from
83% to 99%, with a specificity that ranged from 89% to 97% when cutoff83% to 99%, with a specificity that ranged from 89% to 97% when cutoff
levels of 45 to 60 U/L were used; however, many of these studies werelevels of 45 to 60 U/L were used; however, many of these studies were
based on highly selected populations in areas where TB was endemic.based on highly selected populations in areas where TB was endemic.
The positive predictive value of the test would be much lower in areasThe positive predictive value of the test would be much lower in areas
like the United States, where the prevalence of TB and hence the pretestlike the United States, where the prevalence of TB and hence the pretest
probability are lower (e.g., the positive predictive value is 50% when theprobability are lower (e.g., the positive predictive value is 50% when the
pretest probability is 5%)pretest probability is 5%)

TUBERCULIN TESTINGTUBERCULIN TESTING
0.1 ml of 5 tuberculin units ( TU) PPD0.1 ml of 5 tuberculin units ( TU) PPD
Injected intra dermally over the volar aspect of the armInjected intra dermally over the volar aspect of the arm
Should be read in 48-72 hoursShould be read in 48-72 hours
Measure induration not erythemaMeasure induration not erythema

The TST is the standard method for identifying patients with latent TBThe TST is the standard method for identifying patients with latent TB
infection.infection.
Currently available test preparations of tuberculin use purified proteinCurrently available test preparations of tuberculin use purified protein
derivative (PPD) standardized for potency. Local induration developsderivative (PPD) standardized for potency. Local induration develops
within 48 to 72 hours at the site of intradermal PPD injection (Mantouxwithin 48 to 72 hours at the site of intradermal PPD injection (Mantoux
method) in patients with sensitivity to the antigen.method) in patients with sensitivity to the antigen.
The largest reactions to PPD-tuberculin are expected in persons infectedThe largest reactions to PPD-tuberculin are expected in persons infected
with MTB. However, cross-reaction with some nontuberculouswith MTB. However, cross-reaction with some nontuberculous
mycobacteria takes place, and some persons infected with MTB may bemycobacteria takes place, and some persons infected with MTB may be
anergic and unable to respond as expected.anergic and unable to respond as expected.
TUBERCULIN TESTINGTUBERCULIN TESTING

FACTORS ASSOCIATED WITH AFACTORS ASSOCIATED WITH A
FALSE-NEGATIVE TUBERCULINFALSE-NEGATIVE TUBERCULIN
SKIN TESTSKIN TEST
Host factorsHost factors
InfectionsInfections
Viral (e.g., measles, mumps, HIV)Viral (e.g., measles, mumps, HIV)
Bacterial (e.g., typhoid fever, miliaryBacterial (e.g., typhoid fever, miliary
TB, TB meningitis)TB, TB meningitis)
Fungal (e.g., blastomycosis)Fungal (e.g., blastomycosis)
Live viral vaccinesLive viral vaccines
Chronic renal failureChronic renal failure
Malnutrition and low protein statesMalnutrition and low protein states
•
Neoplastic disease (e.g., HodgkinNeoplastic disease (e.g., Hodgkin
disease, lymphoma)disease, lymphoma)
Corticosteroids and otherCorticosteroids and other
immunosuppressantsimmunosuppressants
•
Booster phenomenonBooster phenomenon
•
Severe stress (e.g., trauma, burnSevere stress (e.g., trauma, burn
victims)victims)
•
Recent exposure (within 4–7 weeks)Recent exposure (within 4–7 weeks)
Host factorsHost factors
InfectionsInfections
Viral (e.g., measles, mumps, HIV)Viral (e.g., measles, mumps, HIV)
Bacterial (e.g., typhoid fever, miliaryBacterial (e.g., typhoid fever, miliary
TB, TB meningitis)TB, TB meningitis)
Fungal (e.g., blastomycosis)Fungal (e.g., blastomycosis)
Live viral vaccinesLive viral vaccines
Chronic renal failureChronic renal failure
Malnutrition and low protein statesMalnutrition and low protein states
•
Neoplastic disease (e.g., HodgkinNeoplastic disease (e.g., Hodgkin
disease, lymphoma)disease, lymphoma)
Corticosteroids and otherCorticosteroids and other
immunosuppressantsimmunosuppressants
•
Booster phenomenonBooster phenomenon
•
Severe stress (e.g., trauma, burnSevere stress (e.g., trauma, burn
victims)victims)
•
Recent exposure (within 4–7 weeks)Recent exposure (within 4–7 weeks)
Improper administrationImproper administration
Injection of inadequate volumeInjection of inadequate volume
Subcutaneous injectionSubcutaneous injection
Inexperienced readerInexperienced reader
Problems with tuberculinProblems with tuberculin
Improper storage (i.e., exposureImproper storage (i.e., exposure
to heat and light)to heat and light)
Improper dilutionImproper dilution
ContaminationContamination
Improper administrationImproper administration
Injection of inadequate volumeInjection of inadequate volume
Subcutaneous injectionSubcutaneous injection
Inexperienced readerInexperienced reader
Problems with tuberculinProblems with tuberculin
Improper storage (i.e., exposureImproper storage (i.e., exposure
to heat and light)to heat and light)
Improper dilutionImproper dilution
ContaminationContamination

in vitro assay thet measurein vitro assay thet measure
interferon gamma releasedinterferon gamma released
by sensitized T cells afterby sensitized T cells after
stimulation by M.stimulation by M.
Tuberculosis antigensTuberculosis antigens
Measures immuneMeasures immune
reactivity to M. TB.reactivity to M. TB.

PREVENTIONPREVENTION
Prevention of infectionPrevention of infection
General hygiene measuresGeneral hygiene measures
Effective treatment of infected patientsEffective treatment of infected patients
VaccineVaccine
BCG vaccination: live attenuated strain of mycobacterium bovis, given 2-45 daysBCG vaccination: live attenuated strain of mycobacterium bovis, given 2-45 days
after birth; prevents complicationsafter birth; prevents complications
Chemo prophylaxisChemo prophylaxis
INH as a mono therapy for 6 monthsINH as a mono therapy for 6 months

Pulmonary Tuberculosis

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