PULMONARY TUBERCULOSIS PULMONARY TUBERCULOSIS Hamdi turkey - Pulmonologist Hamdi turkey - Pulmonologist

HISTORY OF TBHISTORY OF TB AN OLD DISEASE AN OLD DISEASE

• May have evolved from May have evolved from M bovisM bovis; ; acquired by humans from domesticated acquired by humans from domesticated animals ~15,000 years agoanimals ~15,000 years ago

• Endemic in humans when stable Endemic in humans when stable networks of 200-440 people networks of 200-440 people established (villages) ~ 10,000 years established (villages) ~ 10,000 years ago; Epidemic in Europe after 1600 ago; Epidemic in Europe after 1600 (cities)(cities)

• 354-322 BC - Aristotle – “When one 354-322 BC - Aristotle – “When one comes near consumptives… one does comes near consumptives… one does contract their disease… The reason is contract their disease… The reason is that the breath is bad and heavy…In that the breath is bad and heavy…In approaching the consumptive, one approaching the consumptive, one breathes this pernicious air. One takes breathes this pernicious air. One takes the disease because in this air there is the disease because in this air there is something disease producing.”something disease producing.”

TB is an ancient disease. Signs of skeletal TB (Pott disease) have TB is an ancient disease. Signs of skeletal TB (Pott disease) have been found in remains from Europe from Neolithic times (8000 BCE), been found in remains from Europe from Neolithic times (8000 BCE), ancient Egypt (1000 BCE), and the pre-Columbian New World. ancient Egypt (1000 BCE), and the pre-Columbian New World.

TB was recognized as a contagious disease by the time of TB was recognized as a contagious disease by the time of Hippocrates (400 BCE), when it was termed "phthisis" (Greek from Hippocrates (400 BCE), when it was termed "phthisis" (Greek from phthinein, to waste away). phthinein, to waste away).

In English, pulmonary TB was long known by the term In English, pulmonary TB was long known by the term “consumption.” “consumption.”

German physician Robert Koch discovered and isolated M German physician Robert Koch discovered and isolated M tuberculosis in 1882.tuberculosis in 1882.

HISTORY OF TBHISTORY OF TB AN OLD DISEASE AN OLD DISEASE

PHTHISISPHTHISIS

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

Hamdi TurkeyHamdi Turkey

CDC Tuberculosis Case CDC Tuberculosis Case Definition for Public Definition for Public Health SurveillanceHealth Surveillance

M TUBERCULOSIS AS CAUSATIVE M TUBERCULOSIS AS CAUSATIVE AGENT FOR TUBERCULOSISAGENT FOR TUBERCULOSIS

1882 – 1882 – Robert KochRobert Koch – – “one seventh of all “one seventh of all human beings die of human beings die of tuberculosis and… if one tuberculosis and… if one considers only the considers only the productive middle-age productive middle-age groups, tuberculosis groups, tuberculosis carries away one-third carries away one-third and often more of and often more of these…”these…”

OBJECTIVESOBJECTIVES

The TB ScenarioThe TB Scenario Defining TB: Cause, Transmission, and Defining TB: Cause, Transmission, and ManifestationsManifestationsRisk of TB infectionRisk of TB infectionDiagnosing Pulmonary TuberculosisDiagnosing Pulmonary TuberculosisTB Treatment and CureTB Treatment and CurePreventing transmissionPreventing transmissionProper Management of TB casesProper Management of TB cases

THE BURDEN OF TBTHE BURDEN OF TBTB remains the leading cause of death worldwide from a TB remains the leading cause of death worldwide from a single infectious agentsingle infectious agent

It is estimated that between 2000-2020, nearly It is estimated that between 2000-2020, nearly one one billion people billion people will be newly infected, will be newly infected, 200 million 200 million peoplepeople will get sick, and will get sick, and 35 million35 million will die from TB- if will die from TB- if control is not further strengthened control is not further strengthened

With the increased incidence of AIDS, TB has become With the increased incidence of AIDS, TB has become more a problem in the US and the worldmore a problem in the US and the world

It is currently estimated that 1/2 of the world population It is currently estimated that 1/2 of the world population (3.1 billion) is infected with TB(3.1 billion) is infected with TB

EPIDEMIOLOGY EPIDEMIOLOGY Tuberculosis (TB), which is caused by a complex of organisms, Tuberculosis (TB), which is caused by a complex of organisms, Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium africanum, is an ancient human disease. africanum, is an ancient human disease.

Evidence of TB can be found in human remains dating back to Neolithic Evidence of TB can be found in human remains dating back to Neolithic times. The most recent World Health Organization data estimate that times. The most recent World Health Organization data estimate that 1.86 billion persons are currently infected with TB. 1.86 billion persons are currently infected with TB.

At any time, an estimated 16 million persons worldwide demonstrate At any time, an estimated 16 million persons worldwide demonstrate active disease, and 8 million new active cases develop each year, of which active disease, and 8 million new active cases develop each year, of which 3.5 million manifest as the infectious pulmonary form of the disease. 3.5 million manifest as the infectious pulmonary form of the disease.

This remarkable prevalence of disease is estimated to be responsible for This remarkable prevalence of disease is estimated to be responsible for at least 2 million deaths each year, making TB the most frequent at least 2 million deaths each year, making TB the most frequent infectious cause of death in the world and the seventh most frequent infectious cause of death in the world and the seventh most frequent cause of morbidity among all diseases.cause of morbidity among all diseases.

The World Health Organization declared TB a world The World Health Organization declared TB a world global emergency in 1993; however, economic and global emergency in 1993; however, economic and political commitment to TB control programs is political commitment to TB control programs is lacking in many countries, and it is estimated that lacking in many countries, and it is estimated that 95% of new cases of TB occur in countries with 95% of new cases of TB occur in countries with limited resources. limited resources.

This situation facilitates inappropriate or unsustained This situation facilitates inappropriate or unsustained TB therapy, which in turn has promoted a rise in the TB therapy, which in turn has promoted a rise in the rates of multidrug-resistant TB (MDR-TB) rates of multidrug-resistant TB (MDR-TB)

EPIDEMIOLOGY EPIDEMIOLOGY

ETIOLOGYETIOLOGYMycobacterium tuberculosis is the Mycobacterium tuberculosis is the causative organism of pulmonary causative organism of pulmonary tuberculosis tuberculosis

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 stained Appear beaded or clumped in stained clinical specimens or culture media clinical specimens or culture media

Grow best at 37-41 cGrow best at 37-41 c

Grow slowly, their generation time Grow slowly, their generation time being 12-24 hourbeing 12-24 hour

MODE OF TRANSMISSION MODE OF TRANSMISSION

Airway droplets: the main Airway droplets: the main mode of transmission from mode of transmission from person infected with person infected with pulmonary TB to others by pulmonary TB to others by respiratory droplets.respiratory droplets.

Ingestion: Less frequently Ingestion: Less frequently transmitted by ingestion of transmitted by ingestion of mycobacterium bovis found in mycobacterium bovis found in unpasteurized milk products unpasteurized milk products

Direct inoculation Direct 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 patients with active disease expel bacilli into the air by:by:

CoughingCoughing

Sneezing Sneezing

ShoutingShouting

Or any other way that will expel bacilli into the airOr any other way that will expel bacilli into the air

MODE OF TRANSMISSION MODE OF TRANSMISSION

Millions of tubercle bacilli in Millions of tubercle bacilli in lungs ( mainly in cavities)lungs ( mainly in cavities)

Coughing projects droplets Coughing projects droplets nuclei into the air that contain nuclei into the air that contain tubercle bacillitubercle bacilli

One cough can release 3,000 One cough can release 3,000 droplet nuclei droplet nuclei

One sneeze can release tens of One sneeze can release tens of thousands of droplet nucleithousands of droplet nuclei

As few as five M. tuberculosis As few as five M. tuberculosis (MTB) bacilli are necessary for (MTB) bacilli are necessary for human infectionhuman infection

MODE OF TRANSMISSION MODE OF TRANSMISSION

Optimal conditions for transmission include:Optimal conditions for transmission include:

Overcrowding Overcrowding

Poor personal hygienePoor personal hygiene

Poor public hygiene Poor public hygiene

MODE OF TRANSMISSION MODE OF TRANSMISSION

FATE OF M. TB AEROSOLS FATE OF M. TB AEROSOLS

Large droplets settle to the ground quickly Large droplets settle to the ground quickly

Smaller droplets form " droplet nuclei" of 1-5 µm in Smaller droplets form " droplet nuclei" of 1-5 µm in diameter, only TB-containing particles small enough to diameter, only TB-containing particles small enough to reach the vulnerable environment of the alveolar space reach the vulnerable environment of the alveolar space (typically <5–10 µm) are considered infectious. After (typically <5–10 µm) are considered infectious. After inhalation, these infectious particles deposit preferentially inhalation, these infectious particles deposit preferentially in the dependent lower half of the lung, where they in the dependent lower half of the lung, where they subsequently initiate a primary focus of infection.subsequently initiate a primary focus of infection.

Droplet nuclei can remain airborne Droplet nuclei can remain airborne

NOT EVERYONE WHO IS EXPOSED NOT EVERYONE WHO IS EXPOSED TO TB WILL BECOME INFECTED TO TB WILL BECOME INFECTED

Exposure Exposure

Infection (30%)Infection (30%)

No infection No infection (70%)(70%)

Non specific Non specific immunityimmunity

Adequate Adequate

InadequatInadequate e

Early progression Early progression (5%) (5%)

Containment Containment (95%)(95%)

Latent TBLatent TB

immunological immunological defenses defenses

AdequaAdequate te

Inadequate Inadequate

HIGH RISK FOR PROGRESSION HIGH 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 persons HIV infected persons

Persons with a history of prior, untreated TB or fibrotic lesions on Persons with a history of prior, untreated TB or fibrotic lesions on CXRCXR

Recent TB infection (within the past 2 years)Recent TB infection (within the past 2 years)

Injection drug users Injection 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 hemodialysis, solid organ transplantation, cancer, malnourished patient, silicosis) patient, silicosis)

LTBI VS TB DISEASELTBI VS TB DISEASE

LTBILTBI TB diseaseTB disease

Tubercle bacilli in the body Tubercle bacilli in the body

TST or QFT-Gold results usually positive TST or QFT-Gold results usually positive

CXR usually normal CXR usually normal CXR usually abnormal CXR usually abnormal

Sputum smear and cultures Sputum smear and cultures negative negative

Sputum smear and cultures Sputum smear and cultures positive positive

No symptomsNo symptoms Symptoms such as Symptoms such as cough,fever, weight losscough,fever, weight loss

Not infectious Not infectious Often infectious before Often infectious before treatmenttreatment

Not a case of TBNot a case of TB A case of TBA case of TB

SPREAD OF TB TO OTHER SPREAD OF TB TO OTHER PARTS OF THE BODYPARTS OF THE BODY

Lungs (85% of all cases)Lungs (85% of all cases)

PleuraPleura

CNSCNS

Lymph nodes Lymph nodes

Genitourinary systemGenitourinary system

Bones and jointsBones and joints

Disseminated ( eg Disseminated ( eg miliary)miliary)

TB CAN AFFECT ANY PART TB CAN AFFECT ANY PART OF THE BODYOF THE BODY

PATHOGENESIS PATHOGENESIS

The bacilli implant in areas of high partial pressure of oxygen:The bacilli implant in areas of high partial pressure of oxygen:

•Lung Lung

•Renal cortexRenal cortex

•Reticule endothelial system Reticule endothelial system

The principal cause of tissue destruction from M tuberculosis The principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intense infection 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

PATHOGENESIS PATHOGENESIS

This is known as the primary infection, the patient will This is known as the primary infection, the patient will heal and a scar will appear in the affected loci.heal and a scar will appear in the affected loci.

There will also be a few viable bacilli/spores may remain in There will also be a few viable bacilli/spores may remain in these areas( particularly in the lung), the bacteria at this these areas( particularly in the lung), the bacteria at this time goes into a dormant state, as long as the person's time goes into a dormant state, as long as the person's immune system remains active and functions normally immune system remains active and functions normally

When a person immune system is depressed, a secondary When a person immune system is depressed, a secondary reactivation occurs. 85-90% this reactivation occurs in the reactivation occurs. 85-90% this reactivation occurs in the lungslungs

About 90% of those infected with mycobacterium tuberculosis About 90% of those infected with mycobacterium tuberculosis are asymptomatic (latent TB infection), with only a 10% lifetime are asymptomatic (latent TB infection), with only a 10% lifetime chance that latent infection will progress to TB disease.chance that 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 When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow for 2-12 terminal airspaces of the lung. The organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is weeks, until they reach 1000-10,000 in number, which is sufficient to elicit a cellular immune response that can be sufficient to elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test.detected by a reaction to the tuberculin skin test.

Mycobacteria are highly antigenic, and they promote a Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear Langerhans cells, lymphocytes, and polymorphonuclear leukocytesleukocytes

MICROSCOPIC PICTURE MICROSCOPIC PICTURE

The Ghon focus The Ghon focus consists of a central consists of a central area of pink caseous area of pink caseous necrosis surrounded necrosis surrounded by inflammatory by inflammatory infiltrate and walled infiltrate and walled of by an area of of by an area of granulation tissue granulation tissue containing containing multinucleated multinucleated Langhans giant cellsLanghans giant cells

FATE OF PRIMARY TB FATE 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 host Degree of resistance of the host

A.A.If the patient resistance is good and the organism is of low virulence, If the patient resistance is good and the organism is of low virulence, Ghon complex undergo healing and over time usually evolve to Ghon complex undergo healing and over time usually evolve to fibrocalcific nodules 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 progressive pulmonary tuberculosis will develop, the primary Ghon focus in the lung enlarges rapidly, erodes the bronchial tree, and spread focus in the lung enlarges rapidly, erodes the bronchial tree, and spread

HOST'S IMMUNE HOST'S IMMUNE SYSTEM AND TB DISEASE SYSTEM AND TB DISEASE

More important than the virulence of the infecting strain, More important than the virulence of the infecting strain, however, may be genetic differences in the host’s immune system. however, may be genetic differences in the host’s immune system.

IL-12 is important for the development of cell-mediated immunity, IL-12 is important for the development of cell-mediated immunity, and defects in the IL-12 receptor have been associated with and defects in the IL-12 receptor have been associated with disseminated mycobacterial infection following bacille Calmette-disseminated mycobacterial infection following bacille Calmette-Guérin (BCG) vaccination. Guérin (BCG) vaccination.

Tumor necrosis factor-α (TNF-α) is responsible for granuloma Tumor necrosis factor-α (TNF-α) is responsible for granuloma formation and also for the production of reactive nitrogen formation and also for the production of reactive nitrogen intermediates needed to kill intracellular bacilli, and high rates of intermediates needed to kill intracellular bacilli, and high rates of active TB have been described following the administration of active TB have been described following the administration of anti–TNF-α antibodies. anti–TNF-α antibodies.

IFN-α is necessary for the production of TNF-α by macrophages, IFN-α is necessary for the production of TNF-α by macrophages, and genetic absence of the IFN-γ receptor has been associated and genetic absence of the IFN-γ receptor has been associated with disseminated nontuberculous mycobacterial infections in with disseminated nontuberculous mycobacterial infections in humans. Some have hypothesized that subtle alterations in the humans. Some have hypothesized that subtle alterations in the IFN-γ receptor may be responsible forIFN-γ receptor may be responsible for

variations in susceptibility to the development of TB: variability in variations in susceptibility to the development of TB: variability in the HLA-D gene locus, possibly related to a reduced affinity of the the HLA-D gene locus, possibly related to a reduced affinity of the class II major histocompatibility complex for mycobacterial class II major histocompatibility complex for mycobacterial antigens, in addition to genetic polymorphisms in the natural antigens, in addition to genetic polymorphisms in the natural resistance–associated macrophage protein-1 (NRAMP-1) , have resistance–associated macrophage protein-1 (NRAMP-1) , have been associated with an increased likelihood for the development been associated with an increased likelihood for the development of clinically apparent disease.of clinically apparent disease.

HOST'S IMMUNE HOST'S IMMUNE SYSTEM AND TB DISEASE SYSTEM AND TB DISEASE

PATHOGENESIS PATHOGENESIS

TB disease TB disease

Immunity Immunity Hypersensitivity Hypersensitivity

Healing Healing DiseaseDisease

Type IV hypersensitivity reaction: Type IV hypersensitivity reaction:

T cells ----->macrophages----> granuloma T cells ----->macrophages----> granuloma

Activated macrophages -----> epithelioid cellsActivated macrophages -----> epithelioid cells

Self destruction by lysosomal enzymes Self destruction by lysosomal enzymes

Infected macrophages secrete interleukin-12 (IL-12), Infected macrophages secrete interleukin-12 (IL-12), which promotes a nonspecific immune response which promotes a nonspecific immune response mediated primarily by natural killer cells and γ/δ T cells. mediated primarily by natural killer cells and γ/δ T cells.

The nonspecific immune response may retard the local The nonspecific immune response may retard the local infection but is usually unable to control it, and bacilli infection but is usually unable to control it, and bacilli spread to local lymph nodes, where they may enter the spread to local lymph nodes, where they may enter the blood (bacillemia). From this point, TB infection is a blood (bacillemia). From this point, TB infection is a systemic process characterized by lymphatic and systemic process characterized by lymphatic and hematogenous spread and the deposition of bacilli in hematogenous 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 creating the potential for disease in virtually any anatomic location.anatomic location.

MTB antigens in association with the class II major histocompatibility MTB antigens in association with the class II major histocompatibility complex are presented to naive CD4+ T cells, heralding the onset of complex are presented to naive CD4+ T cells, heralding the onset of specific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cell specific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cell immunity). immunity).

Anti-TB CD4+ T cells coordinate the specific immune response by two Anti-TB CD4+ T cells coordinate the specific immune response by two routes:routes:

The onset of the cytotoxic T-lymphocyte response several weeks after The onset of the cytotoxic T-lymphocyte response several weeks after infection coincides with the development of caseous necrosis at the infection coincides with the development of caseous necrosis at the site of primary infection and the development of delayed-type site of primary infection and the development of delayed-type hypersensitivity hypersensitivity

(a)(a)secretion of IL-2 supports cytotoxic T-lymphocyte function, secretion of IL-2 supports cytotoxic T-lymphocyte function, allowing these cells to kill other cells already infected with allowing these cells to kill other cells already infected with MTB directly MTB directly

(b)(b)secretion of interferon-γ (IFN-γ) primes uninfected secretion of interferon-γ (IFN-γ) primes uninfected macrophages, allowing them to kill the intracellular pathogen macrophages, allowing them to kill the intracellular pathogen efficiently. efficiently.

Primary pulmonary TB is an infection of persons who Primary pulmonary TB is an infection of persons who have not had prior contact with the tubercle bacillushave not had prior contact with the tubercle bacillus

Inhaled bacilli are commonly deposited in alveoli Inhaled bacilli are commonly deposited in alveoli immediately beneath the pleura, usually in the lower immediately beneath the pleura, usually in the lower part of the upper lobes or the upper part of the lower part of the upper lobes or the upper part of the lower lobeslobes

When inhaled, droplet nuclei are deposited in When inhaled, droplet nuclei are deposited in terminal airspaces of the lungterminal airspaces of the lung

Macrophages ingest the bacilli and transport them to Macrophages ingest the bacilli and transport them to regional lymph nodesregional lymph nodes

PRIMARY PULMONARY PRIMARY PULMONARY TBTB

PRIMARY PULMONARY TBPRIMARY PULMONARY TB

The primary infection characteristically The primary infection characteristically produces a " Ghon complex" formed of:produces a " Ghon complex" formed of:

1.1. Ghon focus: small area of pneumonic Ghon focus: small area of pneumonic consolidation about 1-3 cm in diameter, consolidation about 1-3 cm in diameter, sub-pleural in location present in the base sub-pleural in location present in the base of the upper lobe or apex of the lower lobeof the upper lobe or apex of the lower lobe

2.2. Tuberculous lymphangitis: of the draining Tuberculous lymphangitis: of the draining lymphatic channels lymphatic channels

3.3. Tuberculous lymphadenitis: of the Tuberculous lymphadenitis: of the tracheobronchial nodes which are tracheobronchial nodes which are enlarged, matted together and their cut enlarged, matted together and their cut surface show areas of caseous necrosis surface show areas of caseous necrosis

PRIMARY PULMONARY TB PRIMARY PULMONARY TB PATHOGENESIS PATHOGENESIS

Spread if infection will take place by:Spread if infection will take place by:

A.A.Local spread: to the surrounding lung tissue and Local spread: to the surrounding lung tissue and pleurapleura

B.B.Lymphatic spread: along bronchi, leading to Lymphatic spread: along bronchi, leading to tuberculous bronchopneumonia tuberculous bronchopneumonia

C.C.Hematogenous spread: leading to miliary TB or Hematogenous spread: leading to miliary TB or isolated organ TB or miliary TB of the lungisolated organ TB or miliary TB of the lung

PRIMARY PULMONARY TBPRIMARY PULMONARY TB• • Most often a childhood infection in endemic Most often a childhood infection in endemic settingssettings

•Few clinical symptoms in immunocompetent Few clinical symptoms in immunocompetent hostshosts

•Lymphangitic spread to hilar and paratracheal Lymphangitic spread to hilar and paratracheal nodes result in enlargement of these structuresnodes result in enlargement of these structures

•Often the only residua of primary infection is a Often the only residua of primary infection is a positive skin test and the Ranke complexpositive skin test and the Ranke complex

•Primary progressive tuberculosis occurs in a Primary progressive tuberculosis occurs in a minority of casesminority of cases

The natural history of primary pulmonary tuberculosis The natural history of primary pulmonary tuberculosis in adultsin adults

Event Event TimeTime CommentCommentAlveolar Alveolar

deposition of deposition of tubercle bacillitubercle bacilli

00Bacilli engulfed Bacilli engulfed by alveolar by alveolar

macrophagesmacrophages

Bacilli proliferate Bacilli proliferate and disseminateand disseminate 3-8 weeks3-8 weeks

Tuberculin skin Tuberculin skin test becomes test becomes

reactive; CXR may reactive; CXR may become abnormal become abnormal

Some patients Some patients develop pleurisy; a develop pleurisy; a minority develop minority develop miliary diseasemiliary disease

8-26 weeks8-26 weeks

High risk period High risk period for pulmonary and for pulmonary and extra pulmonary extra pulmonary

diseasedisease26-156 weeks 26-156 weeks 10% infected will 10% infected will

develop TB develop TB

COMPLICATIONS OF COMPLICATIONS OF PRIMARY TUBERCULOSIS PRIMARY TUBERCULOSIS

Collapse/ consolidationCollapse/ consolidation

BronchiectasisBronchiectasis

Obstructive emphysema Obstructive emphysema

BroncholithBroncholith

Erythema nodosum Erythema nodosum

Phlyctenular conjunctivitis Phlyctenular conjunctivitis

Pleural effusionPleural effusion

Miliary TB Miliary TB

Progressive primary tuberculosis Progressive primary tuberculosis

Secondary(cavitary) TB usually results from Secondary(cavitary) TB usually results from reactivation of a dormant, endogenous tubercle bacilli reactivation of a dormant, endogenous tubercle bacilli in a sensitized patient who has had previous contact in a sensitized patient who has had previous contact with the tubercle bacillus with the tubercle bacillus

In some cases the disease is caused by reinfection with In some cases the disease is caused by reinfection with exogenous bacilli exogenous bacilli

The lesion begins as a tubercle, the micro-organisms The lesion begins as a tubercle, the micro-organisms searching for a high oxygen tension, usually settle in searching for a high oxygen tension, usually settle in the apical portion of one or both lungs the apical portion of one or both lungs

SECONDARY PULMONARY TB SECONDARY PULMONARY TB PATHOGENESIS PATHOGENESIS

A tubercle is no larger than A tubercle is no larger than 3 cm and consists of a 3 cm and consists of a central area of caseous central area of caseous necrosis surrounded by necrosis surrounded by granulomatous tissue granulomatous tissue containing the typical containing the typical Langhans giant cellsLanghans giant cells

The tubercle is separated The tubercle is separated from the surrounding tissue from the surrounding tissue by a layer of fibrous tissue by a layer of fibrous tissue infiltrated with lymphocytes infiltrated with lymphocytes

SECONDARY PULMONARY TB SECONDARY PULMONARY TB PATHOGENESIS PATHOGENESIS

FATE OF SECONDARY FATE OF SECONDARY PULMONARY TB PULMONARY TB

Healing by fibrosis with dystrophic calcification occurs in Healing by fibrosis with dystrophic calcification occurs in most cases when the dose of infection is small, virulence of most cases when the dose of infection is small, virulence of the organism is low and the patient resistance is goodthe organism is low and the patient resistance is good

Spread of infection occurs when the patient resistance is Spread of infection occurs when the patient resistance is poor and the virulence of the organism is high, spread poor and the virulence of the organism is high, spread occurs directly by lymphatic,natural passages and blood occurs directly by lymphatic,natural passages and blood streamstream

Fibrocaseous tuberculosis with cavitation occurs with Fibrocaseous tuberculosis with cavitation occurs with moderate dose of the organism and moderate resistance of moderate dose of the organism and moderate resistance of the patient the patient

Primary pulmonary TB Primary pulmonary TB Secondary pulmonary TB Secondary pulmonary TB

Mainly occurs in children but Mainly occurs in children but can occasionally occurs in elderly can occasionally occurs in elderly

and adults and adults Mainly occurs in adults Mainly occurs in adults

Mainly Asymptomatic or with Mainly Asymptomatic or with minimal symptoms and may goes minimal symptoms and may goes

unrecognized unrecognized Symptomatic Symptomatic

Septum for AFB is rarely Septum for AFB is rarely positive positive Usually positive Usually positive

Associated with Associated with hypersensitivity phenomenon hypersensitivity phenomenon

( erythema noduom) ( erythema noduom) Not associated with Not associated with hypersensitivity hypersensitivity

Site of involvement on is the Site of involvement on is the lower portion of the upper lobe lower portion of the upper lobe

and the upper portion of the and the upper portion of the lower lobe lower lobe

Apex of both lungs and the Apex of both lungs and the upper portion of the lower lobe upper portion of the lower lobe

On CXR : an area of On CXR : an area of consolidation or pleural effusion consolidation or pleural effusion

Typically cavitary lesion over Typically cavitary lesion over the apex the apex

Non infectious Non infectious Highly infectious in sputum Highly infectious in sputum positive cases positive cases

FIBROCASEOUS TB WITH FIBROCASEOUS TB WITH CAVITATIONCAVITATION

The cavity is chronic The cavity is chronic with fibrotic walls, lined with fibrotic walls, lined by caseous material and by caseous material and is traversed by blood is traversed by blood vessels and bronchivessels and bronchi

The surrounding lung The surrounding lung tissue shows multiple tissue shows multiple focal areas of caseation focal areas of caseation and other cavities and other cavities

COMPLICATIONS OF COMPLICATIONS OF FIBROCASEOUS TBFIBROCASEOUS TB

Spread to the pleura causing----> pleural effusion, Spread to the pleura causing----> pleural effusion, fibrinous pleurisy, tuberculous empyema, fibrinous pleurisy, tuberculous empyema, pneumothorax, pyopneumothoraxpneumothorax, pyopneumothorax

Coughing of the content of the cavity leads to: Coughing of the content of the cavity leads to: tuberculous tracheobronchitis, tuberculous laryngitis, tuberculous tracheobronchitis, tuberculous laryngitis, tuberculous glossitis and tuberculous enteritistuberculous glossitis and tuberculous enteritis

Erosion of the traversing blood vessels leads to: Erosion of the traversing blood vessels leads to: hemoptysis, hematogenous spread hemoptysis, hematogenous spread

Secondary amyloidosis Secondary amyloidosis

MILIARY TUBERCULOSIS MILIARY TUBERCULOSIS

It is the disseminated form of tuberculosis and is caused by It is the disseminated form of tuberculosis and is caused by seeding of the bacilli through lymphatic a or blood vessels seeding of the bacilli through lymphatic a or blood vessels

Sites : the lung, lymph nodes, kidneys, adrenals, bone Sites : the lung, lymph nodes, kidneys, adrenals, bone marrow, spleen, liver, meninges, brain, eye grounds, and marrow, spleen, liver, meninges, brain, eye grounds, and genitalia genitalia

Fate: all granulomas have similar features and follow the Fate: all granulomas have similar features and follow the same progression, namely focal collections of histocytes, same progression, namely focal collections of histocytes, followed by epithelioid cells, Langhans giant cells, central followed by epithelioid cells, Langhans giant cells, central caseation necrosis and eventually fibrosis and caseation necrosis and eventually fibrosis and mineralizationmineralization

Gross picture: Gross picture:

Minute, yellow-white lesions resembling millet seeds ( hence miliary)Minute, yellow-white lesions resembling millet seeds ( hence miliary)

MILIARY TUBERCULOSIS MILIARY TUBERCULOSIS

CLINICAL FEATURES CLINICAL FEATURES

Symptoms and signs of primary pulmonary Symptoms and signs of primary pulmonary Tuberclosis Tuberclosis

AsymptomaAsymptomatictic A great majority especially adults A great majority especially adults

Brief Brief febrile illness febrile illness At the time of tuberculin conversion At the time of tuberculin conversion

Anorexia, Anorexia, failure to gain failure to gain

weight weight In few cases with more severe infection In few cases with more severe infection

or low host resistance or low host resistance

CoughCough If LN or granulation tissue impinge on If LN or granulation tissue impinge on bronchial wallbronchial wall

SputumSputum Rare in children Rare in children

HypersensitHypersensitivity ivity

phenomenon phenomenon Erythema nodosum, phlyctenular Erythema nodosum, phlyctenular

conjunctivitis , dactalitisconjunctivitis , dactalitis

Symptoms and signs of secondary pulmonary Symptoms and signs of secondary pulmonary tuberculosistuberculosis

Cough Cough Initially minimal and dry at early morning, then Initially minimal and dry at early morning, then

productive of small amount of sputum and present productive of small amount of sputum and present all the day all the day

Fever Fever Diurnal with early morning and late afternoon Diurnal with early morning and late afternoon

rise, Low grade fever and in advanced cases rise, Low grade fever and in advanced cases associated with drenching night sweats and associated with drenching night sweats and diaphoresisdiaphoresis

Hemoptysis Hemoptysis Blood streak sputum and occasionally massive Blood streak sputum and occasionally massive hemoptysis in complicated caseshemoptysis in complicated cases

Loss of Loss of weight weight

Hence the name phthisis or wasting in advanced Hence the name phthisis or wasting in advanced untreated casesuntreated cases

Anorexia Anorexia and fatigue and fatigue Systemic manifestation of the disease Systemic manifestation of the disease

Crackles Crackles Characteristically post tussive over the involved Characteristically post tussive over the involved areaarea

Amorphic Amorphic breath sound breath sound

Or cavernous breath sound over a large cavity Or cavernous breath sound over a large cavity communicating with a patent bronchuscommunicating with a patent bronchus

DIAGNOSIS DIAGNOSIS

DIAGNOSIS DIAGNOSIS

Any cough that persists more than 2 weeks should be Any cough that persists more than 2 weeks should be evaluated for pulmonary TB in the appropriate clinical evaluated 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 be A full history and physical examination should be undertaken undertaken

A minimum of 2 sputum samples, ( the first on spot and A minimum of 2 sputum samples, ( the first on spot and the second in the early morning preferably fasting ) the second in the early morning preferably fasting ) should be examined, the sputum sample should be of a should be examined, the sputum sample should be of a good quality representative of lower respiratory tract. good quality representative of lower respiratory tract.

RADIOLOGYRADIOLOGY

The following characteristics of chest radiograph favor the The following characteristics of chest radiograph favor the diagnosis of tuberculosis diagnosis of tuberculosis

Shadows mainly in the upper zonesShadows mainly in the upper zones

Patchy or nodular shadows Patchy or nodular shadows

The presence of a cavity or cavities The 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 TB PRIMARY PULMONARY TB

Lymphadenopathy is the hallmark of primary Lymphadenopathy 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 paratracheal Usually affects the hilum and right paratracheal regionsregions

Bilateral adenopathy occurs in one third of Bilateral adenopathy occurs in one third of casescases

Adenopathy usually seen in association with Adenopathy usually seen in association with parenchymal consolidation or atelectasisparenchymal consolidation or atelectasis

Lymphadenopathy can be the only manifestation Lymphadenopathy can be the only manifestation of TB in young childrenof TB in young children

Adenopathy resolves slowly, and nodal Adenopathy resolves slowly, and nodal calcification may occur six months after the calcification may occur six months after the initial infectioninitial infection

Pleural effusion may occur in a minority of casesPleural effusion may occur in a minority of cases

RADIOGRAPHIC RESIDUAL OF RADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TB PRIMARY PULMONARY TB

Ranke's Complex Ranke's Complex Simon fociSimon foci

RADIOGRAPHIC RESIDUAL OF RADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TB PRIMARY PULMONARY TB

POST PRIMARY POST PRIMARY PULMONARY TB PULMONARY TB

Post-primary TB represents 90 percent of adult cases in the non-HIV-Post-primary TB represents 90 percent of adult cases in the non-HIV-infected populationinfected population

Results from reactivation of a previously dormant focus seeded at the Results from reactivation of a previously dormant focus seeded at the time of primary infectiontime of primary infection

Apical-posterior segments of the upper lobes (80 to 90 percent of Apical-posterior segments of the upper lobes (80 to 90 percent of patients), followed in frequency by the superior segment of the lower patients), followed in frequency by the superior segment of the lower lobes and the anterior segment of the upper lobeslobes and the anterior segment of the upper lobes

The original site of spread is occasionally associated with Simon foci—The original site of spread is occasionally associated with Simon foci—residual uni- or bilateral apical fibronodular shadows from primary residual uni- or bilateral apical fibronodular shadows from primary infectioninfection

Post-primary disease also known as reactivation TB, recrudescent TB, Post-primary disease also known as reactivation TB, recrudescent TB, chronic TB, endogenous reinfection, and adult type progressive TBchronic TB, endogenous reinfection, and adult type progressive TB

THE RADIOGRAPHIC APPEARANCE THE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASE OF POST-PRIMARY DISEASE

Upper lobe infiltratesUpper lobe infiltrates

Cavitary lesionsCavitary lesions

TuberculomasTuberculomas

Absence of lymphadenopathyAbsence of lymphadenopathy

Complete lobar or lung opacification and lobar Complete lobar or lung opacification and lobar

collapse in severe casescollapse in severe cases

Pleural effusion, empyemaPleural effusion, empyema

bronchiectasis, mililary patternbronchiectasis, mililary pattern

pneumothoraxpneumothorax

THE RADIOGRAPHIC APPEARANCE THE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASE OF POST-PRIMARY DISEASE

CAVITARY DISEASE CAVITARY DISEASE

A characteristic finding of post-A characteristic finding of post-primary diseaseprimary disease

Cavitation implies a high Cavitation implies a high bacillary burden and high bacillary burden and high infectivityinfectivity

Cavity size ranges from a few Cavity size ranges from a few mm to several cmmm to several cm

Variable wall thicknessVariable wall thickness

Air fluid levels rare, and may be Air fluid levels rare, and may be an indication of bacterial or an indication of bacterial or fungal superinfectionfungal superinfection

Bilateral upper lobe Bilateral upper lobe involvement involvement

seen in this patient with seen in this patient with post- post-

primary diseaseprimary disease

Advanced post-primary Advanced post-primary tuberculosis tuberculosis

in an immunocompetent in an immunocompetent hosthost

TUBECULOMATUBECULOMA

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-primary diseaseprimary disease

Easily mistaken for coin lesions or Easily mistaken for coin lesions or metastatic disease on chest metastatic disease on chest

Vary in size from a few millimeters Vary in size from a few millimeters to 5 or 6 cm in diameter but to 5 or 6 cm in diameter but usually range from 1 to 3 cm. usually range from 1 to 3 cm.

They may or may not contain They may or may not contain calciumcalcium

CHEST CT IN PULOMNARY TB CHEST CT IN PULOMNARY TB

Characterize the cavity Characterize the cavity

Tree in bud nodules Tree in bud nodules indicating endo-bronchial indicating endo-bronchial spread of infection spread of infection

Detects complications:Detects complications:

1.1. PneumothoraxPneumothorax

2.2. Empyema Empyema

3.3. BronchiectasisBronchiectasis

4.4. Tracheo-bronchial stenosis Tracheo-bronchial stenosis

5.5. Miliary TB Miliary TB

SPUTUM EXAMINATIONSPUTUM EXAMINATION

For patients with suspected pulmonary TB, at least For patients with suspected pulmonary TB, at least three freshly expectorated first morning sputum three freshly expectorated first morning sputum samples should be collected from a deep, productive samples should be collected from a deep, productive cough in a sterile container with a wide mouth. Ideally, cough in a sterile container with a wide mouth. Ideally, the volume of each sample should be more than 5 mL the volume of each sample should be more than 5 mL

Induction of sputum with aerosolized hypertonic saline Induction of sputum with aerosolized hypertonic saline solution may be required if the patient is having solution may be required if the patient is having difficulty producing sputum; serial morning gastric difficulty producing sputum; serial morning gastric lavage and bronchoalveolar lavage are alternative lavage and bronchoalveolar lavage are alternative methods of obtaining clinical specimens.methods of obtaining clinical specimens.

Examination of stained smears for AFB remains the most rapid and inexpensive Examination of stained smears for AFB remains the most rapid and inexpensive method for detecting mycobacteria. method for 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 has rhodamine) 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 a Staining 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 positive 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 ranges from 45% to 75%, and specificity is reported to be greater than 97% in most studies. studies.

The yield of a single specimen is low and can be improved by submitting multiple The yield of a single specimen is low and can be improved by submitting multiple samples of adequate volume. samples of adequate volume.

Patients with cavitary TB are more likely to have a positive AFB smear because of Patients 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 the high number 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 smear is less likely in most types of extrapulmonary disease given the relatively low numbers of organisms in these forms of TB numbers of organisms in these forms of TB

STAINING FOR ACID-STAINING FOR ACID-FAST BACILLIFAST BACILLI

DIRECT SMEAR DIRECT SMEAR EXAMINATION EXAMINATION

Is only positive when large number of Is only positive when large number of bacilli are present ( 10,000), so bacilli are present ( 10,000), so negative smear doesn't exclude negative smear doesn't exclude tuberculosis tuberculosis

A negative smear in the presence of A negative smear in the presence of extensive disease and cavitation extensive disease and cavitation makes the diagnosis less likely, makes the diagnosis less likely, particularly if the negatives are particularly if the negatives are frequently repeated frequently repeated

Sputum for AFBSputum for AFB

• Ziehl-Neelsen staining Ziehl-Neelsen staining

• Flurochrome staining- Auramine-Flurochrome staining- Auramine-RhodamineRhodamine

CULTURE CULTURE The AFB smear is limited by its poor sensitivity and inability to differentiate The AFB smear is limited by its poor sensitivity and inability to differentiate between MTB, nontuberculous mycobacterial species, and other acid-fast between MTB, nontuberculous mycobacterial species, and other acid-fast organisms. organisms.

Mycobacterial culture is able to detect as few as 10 organisms per milliliter and Mycobacterial culture is able to detect as few as 10 organisms per milliliter and overcomes many of the limitations of AFB staining. overcomes many of the limitations of AFB staining.

Several types of culture media have been developed for the isolation of Several types of culture media have been developed for the isolation of mycobacteria, including agar-based media (Middlebrook 7H10-selective 7H11), mycobacteria, including agar-based media (Middlebrook 7H10-selective 7H11), egg-based media (Lowenstein-Jensen), and liquid media (Middlebrook 7H12). egg-based media (Lowenstein-Jensen), and liquid media (Middlebrook 7H12).

The development of automated broth culture systems, such as BACTEC 460, The development of automated broth culture systems, such as BACTEC 460, BACTEC 960 mycobacterial growth indicator tube (MGIT) systems, Septi-Check BACTEC 960 mycobacterial growth indicator tube (MGIT) systems, Septi-Check ESP, and MB/BacT, has been a major step in accelerating the diagnosis of MTBESP, and MB/BacT, has been a major step in accelerating the diagnosis of MTB

traditional solid media–based systems require 3 to 8 weeks for organism growth, traditional solid media–based systems require 3 to 8 weeks for organism growth, whereas broth culture methods require 1 to 3 weeks; however, because some whereas broth culture methods require 1 to 3 weeks; however, because some species of the MTB complex may grow only on solid media, inoculation of both species of the MTB complex may grow only on solid media, inoculation of both types of media is recommendedtypes of media is recommended

Even with the use of broth-based culture systems, confirming Even with the use of broth-based culture systems, confirming the presence of MTB from the time of specimen collection the presence of MTB from the time of specimen collection takes at least a week and more often 2 to 3 weeks. takes at least a week and more often 2 to 3 weeks.

Methods to detect the presence of TB directly from clinical Methods to detect the presence of TB directly from clinical specimens more rapidly have been a significant advance in specimens more rapidly have been a significant advance in the treatment of TB. the treatment of TB.

Current direct methods are based on nucleic acid Current direct methods are based on nucleic acid amplification techniques, and two different tests are amplification techniques, and two different tests are commercially available: a transcription-mediated commercially available: a transcription-mediated amplification method (Amplified Mycobacterium tuberculosis amplification method (Amplified Mycobacterium tuberculosis Direct [MTD] Test) and a polymerase chain reaction–based Direct [MTD] Test) and a polymerase chain reaction–based assay (Amplicor; Roche Diagnostic Systems)assay (Amplicor; Roche Diagnostic Systems)

DIRECT AMPLIFICATION DIRECT AMPLIFICATION TECHNIQUETECHNIQUE

The performance of nucleic acid amplification techniques has been The performance of nucleic acid amplification techniques has been most rigorously evaluated in respiratory samples, in which both tests most rigorously evaluated in respiratory samples, in which both tests have a sensitivity of about 96% and a specificity of 100% for AFB have a sensitivity of about 96% and a specificity of 100% for AFB smear-positive samples when combined with appropriate nucleic acid smear-positive samples when combined with appropriate nucleic acid probes. probes.

Their performance in AFB smear-negative specimens is significantly Their performance in AFB smear-negative specimens is significantly less impressive, with sensitivities ranging from 48% to 53%, although less impressive, with sensitivities ranging from 48% to 53%, although their specificity remains high, at 96% to 99%. their specificity remains high, at 96% to 99%.

The accuracy of nucleic acid amplification testing may be reduced by The accuracy of nucleic acid amplification testing may be reduced by the concurrent use of antituberculous therapy, and inhibitors in the the concurrent use of antituberculous therapy, and inhibitors in the patient’s sputum may also cause a false-negative result.patient’s sputum may also cause a false-negative result.

nucleic acid amplification tests offer the opportunity to diagnose nucleic acid amplification tests offer the opportunity to diagnose pulmonary TB within several hours, and their application to the first pulmonary TB within several hours, and their application to the first specimen of all clinically suspected cases is recommended specimen of all clinically suspected cases is recommended

DIRECT AMPLIFICATION DIRECT AMPLIFICATION TECHNIQUETECHNIQUE

The use of nucleic acid amplification tests in the The use of nucleic acid amplification tests in the diagnostic evaluation of patients with suspected diagnostic evaluation of patients with suspected

pulmonary tuberculosispulmonary tuberculosis

NUCLEIC ACID PROBESNUCLEIC ACID PROBES

Nucleic acid probes have been developed that can Nucleic acid probes have been developed that can specifically hybridize with DNA or RNA from MTB, M. specifically hybridize with DNA or RNA from MTB, M. avium, M. intracellulare, M. kansasii, and M. gordonae. The avium, M. intracellulare, M. kansasii, and M. gordonae. The rapidity of this test allows for species identification within 2 rapidity of this test allows for species identification within 2 hours and has a sensitivity and specificity that approaches hours and has a sensitivity and specificity that approaches 100% for MTB 100% for MTB

Although the test requires more than 105 organisms or the Although the test requires more than 105 organisms or the use of an amplification technique to achieve an adequate use of an amplification technique to achieve an adequate yield, when it is combined with automated broth culture yield, when it is combined with automated broth culture methods, the time for detecting and identifying MTB can be methods, the time for detecting and identifying MTB can be reduced to as little as 4 to 7 days reduced to as little as 4 to 7 days

IDENTIFICATION OF IDENTIFICATION OF RESISTANCERESISTANCE

The identification of antimicrobial resistance among clinical isolates is The identification of antimicrobial resistance among clinical isolates is necessary to ensure optimal therapy and prevent the spread of these necessary to ensure optimal therapy and prevent the spread of these organisms to others. Traditionally, agar- and broth-based methods have organisms to others. Traditionally, agar- and broth-based methods have been used to detect drug resistance. been used to detect drug 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 a containing 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 medium containing a drug that equals 1% or more of the growth of the organisms on a medium without the drug indicates resistance to that drugorganisms on a medium without the drug indicates resistance to that drug

Broth-based radiometric methods use a similar process and correlate well Broth-based radiometric methods use a similar process and correlate well with agar-based methods (95%–100%) but allow resistance to be detected with agar-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 much earlier than do solid media (4–7 days vs. 14–21 days). Because of the importance of resistance, it is recommended that both media be used importance of resistance, it is recommended that both media be used

ANTIGEN DETECTION ANTIGEN 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 TESTS INDIRECT TESTS

Tuberculin skin test Tuberculin skin test

TB serological tests ( antibody detection )TB serological tests ( antibody detection )

Mycobacteriophage assaysMycobacteriophage assays

Cytokine detectionCytokine detection

HistopathologyHistopathology

ADENOSINE ADENOSINE DEAMINASEDEAMINASE

Adenosine deaminase is an enzyme produced by activated T Adenosine deaminase is an enzyme produced by activated T lymphocytes, and measurement of the adenosine deaminase level in lymphocytes, and measurement of the adenosine deaminase level in certain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) certain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) has been evaluated as a diagnostic test for TB. In several studies, the has been evaluated as a diagnostic test for TB. In several studies, the sensitivity of the adenosine deaminase level in pleural fluid ranged sensitivity of the adenosine deaminase level in pleural fluid ranged from 83% to 99%, with a specificity that ranged from 89% to 97% from 83% 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 when cutoff levels of 45 to 60 U/L were used; however, many of these studies were based on highly selected populations in areas where TB studies were based on highly selected populations in areas where TB was endemic. was endemic.

The positive predictive value of the test would be much lower in areas The positive predictive value of the test would be much lower in areas like the United States, where the prevalence of TB and hence the like the United States, where the prevalence of TB and hence the pretest probability are lower (e.g., the positive predictive value is 50% pretest probability are lower (e.g., the positive predictive value is 50% when the pretest probability is 5%) when the pretest probability is 5%)

TUBERCULIN TESTING TUBERCULIN 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 arm Injected 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 erythema Measure induration not erythema

The TST is the standard method for identifying patients with latent The TST is the standard method for identifying patients with latent TB infection. TB infection.

Currently available test preparations of tuberculin use purified Currently available test preparations of tuberculin use purified protein derivative (PPD) standardized for potency. Local induration protein derivative (PPD) standardized for potency. Local induration develops within 48 to 72 hours at the site of intradermal PPD develops within 48 to 72 hours at the site of intradermal PPD injection (Mantoux method) in patients with sensitivity to the injection (Mantoux method) in patients with sensitivity to the antigen.antigen.

The largest reactions to PPD-tuberculin are expected in persons The largest reactions to PPD-tuberculin are expected in persons infected with MTB. However, cross-reaction with some infected with MTB. However, cross-reaction with some nontuberculous mycobacteria takes place, and some persons infected nontuberculous mycobacteria takes place, and some persons infected with MTB may be anergic and unable to respond as expected.with MTB may be anergic and unable to respond as expected.

TUBERCULIN TESTING TUBERCULIN TESTING

FACTORS ASSOCIATED WITH A FACTORS ASSOCIATED WITH A FALSE-NEGATIVE TUBERCULIN FALSE-NEGATIVE TUBERCULIN

SKIN TESTSKIN TESTHost factorsHost factorsInfectionsInfections

Viral (e.g., measles, mumps, HIV)Viral (e.g., measles, mumps, HIV) Bacterial (e.g., typhoid fever, Bacterial (e.g., typhoid fever, miliary TB, TB meningitis)miliary TB, TB meningitis)

Fungal (e.g., blastomycosis)Fungal (e.g., blastomycosis)Live viral vaccinesLive viral vaccinesChronic renal failureChronic renal failureMalnutrition and low protein Malnutrition and low protein statesstates

• Neoplastic disease (e.g., Hodgkin Neoplastic disease (e.g., Hodgkin disease, lymphoma)disease, lymphoma)Corticosteroids and other Corticosteroids and other immunosuppressantsimmunosuppressants

• Booster phenomenonBooster phenomenon• Severe stress (e.g., trauma, burn Severe stress (e.g., trauma, burn victims)victims)

• Recent exposure (within 4–7 Recent exposure (within 4–7 weeks)weeks)

Improper administrationImproper administrationInjection of inadequate volumeInjection of inadequate volumeSubcutaneous injectionSubcutaneous injectionInexperienced readerInexperienced reader

Problems with tuberculinProblems with tuberculinImproper storage (i.e., Improper storage (i.e., exposure to heat and light)exposure to heat and light)Improper dilutionImproper dilutionContaminationContamination

in vitro assay thet in vitro assay thet measure interferon measure interferon gamma released by gamma released by sensitized T cells after sensitized T cells after stimulation by M. stimulation by M. Tuberculosis antigensTuberculosis antigens

Measures immune Measures immune reactivity to M. TB.reactivity to M. TB.

PREVENTION PREVENTION

Prevention of infection Prevention of infection

General hygiene measuresGeneral hygiene measures

Effective treatment of infected patients Effective treatment of infected patients

Vaccine Vaccine

BCG vaccination: live attenuated strain of mycobacterium bovis, given BCG vaccination: live attenuated strain of mycobacterium bovis, given 2-45 days after birth; prevents complications 2-45 days after birth; prevents complications

Chemo prophylaxis Chemo prophylaxis

INH as a mono therapy for 6 months INH as a mono therapy for 6 months