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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