Pulmonary Tuberculosis
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Pulmonary Tuberculosis

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These lecture notes were prepared by Dr. Hamdi Turkey- Pulmonologist- Department of internal medicine - Taiz university ...

These lecture notes were prepared by Dr. Hamdi Turkey- Pulmonologist- Department of internal medicine - Taiz university

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Pulmonary Tuberculosis Pulmonary Tuberculosis Presentation Transcript

  • PULMONARY TUBERCULOSISPULMONARY TUBERCULOSIS Hamdi turkey - PulmonologistHamdi turkey - PulmonologistHamdi turkey - PulmonologistHamdi turkey - Pulmonologist
  • HISTORY OF TBHISTORY OF TB AN OLD DISEASEAN OLD DISEASE AN OLD DISEASEAN OLD DISEASE HISTORY OF TBHISTORY OF TB AN OLD DISEASEAN OLD DISEASE AN OLD DISEASEAN OLD DISEASE • May have evolved fromMay have evolved from M bovisM bovis; acquired; acquired by humans from domesticated animalsby humans from domesticated animals ~15,000 years ago~15,000 years ago • Endemic in humans when stable networksEndemic in humans when stable networks of 200-440 people established (villages) ~of 200-440 people established (villages) ~ 10,000 years ago; Epidemic in Europe after10,000 years ago; Epidemic in Europe after 1600 (cities)1600 (cities) • 354-322 BC - Aristotle – “When one comes354-322 BC - Aristotle – “When one comes near consumptives… one does contract theirnear consumptives… one does contract their disease… The reason is that the breath isdisease… The reason is that the breath is bad and heavy…In approaching thebad and heavy…In approaching the consumptive, one breathes this perniciousconsumptive, one breathes this pernicious air. One takes the disease because in thisair. One takes the disease because in this air there is something disease producing.”air there is something disease producing.”
  • TB is an ancient disease. Signs of skeletal TB (Pott disease) have beenTB is an ancient disease. Signs of skeletal TB (Pott disease) have been found in remains from Europe from Neolithic times (8000 BCE), ancientfound in remains from Europe from Neolithic times (8000 BCE), ancient Egypt (1000 BCE), and the pre-Columbian New World.Egypt (1000 BCE), and the pre-Columbian New World. TB was recognized as a contagious disease by the time of HippocratesTB was recognized as a contagious disease by the time of Hippocrates (400 BCE), when it was termed "phthisis" (Greek from phthinein, to(400 BCE), when it was termed "phthisis" (Greek from phthinein, to waste away).waste away). In English, pulmonary TB was long known by the term “consumption.”In English, pulmonary TB was long known by the term “consumption.” German physician Robert Koch discovered and isolated M tuberculosisGerman physician Robert Koch discovered and isolated M tuberculosis in 1882.in 1882. HISTORY OF TBHISTORY OF TB AN OLD DISEASEAN OLD DISEASE HISTORY OF TBHISTORY OF TB AN OLD DISEASEAN OLD DISEASE
  • PHTHISISPHTHISISPHTHISISPHTHISIS In 46o B.C.,the Greek physician Hippocrates described tuberculosisIn 46o B.C.,the Greek physician Hippocrates described tuberculosis as an "almost always fatal disease of the lungs."The Greeks calledas an "almost always fatal disease of the lungs."The Greeks called the disease phthisis(pronounced "TEE-sis"),which means wasting orthe disease phthisis(pronounced "TEE-sis"),which means wasting or decay.decay. In 46o B.C.,the Greek physician Hippocrates described tuberculosisIn 46o B.C.,the Greek physician Hippocrates described tuberculosis as an "almost always fatal disease of the lungs."The Greeks calledas an "almost always fatal disease of the lungs."The Greeks called the disease phthisis(pronounced "TEE-sis"),which means wasting orthe disease phthisis(pronounced "TEE-sis"),which means wasting or decay.decay. Hamdi TurkeyHamdi Turkey
  • CDC Tuberculosis CaseCDC Tuberculosis Case Definition for Public HealthDefinition for Public Health SurveillanceSurveillance CDC Tuberculosis CaseCDC Tuberculosis Case Definition for Public HealthDefinition for Public Health SurveillanceSurveillance
  • M TUBERCULOSIS AS CAUSATIVEM TUBERCULOSIS AS CAUSATIVE AGENT FOR TUBERCULOSISAGENT FOR TUBERCULOSIS M TUBERCULOSIS AS CAUSATIVEM TUBERCULOSIS AS CAUSATIVE AGENT FOR TUBERCULOSISAGENT FOR TUBERCULOSIS 1882 –1882 – Robert KochRobert Koch – “one– “one seventh of all human beingsseventh of all human beings die of tuberculosis and… if onedie of tuberculosis and… if one considers only the productiveconsiders only the productive middle-age groups,middle-age groups, tuberculosis carries away one-tuberculosis carries away one- third and often more ofthird and often more of these…”these…”
  • OBJECTIVESOBJECTIVESOBJECTIVESOBJECTIVES The TB ScenarioThe TB Scenario Defining TB: Cause, Transmission, andDefining TB: Cause, Transmission, and ManifestationsManifestations Risk of TB infectionRisk of TB infection Diagnosing Pulmonary TuberculosisDiagnosing Pulmonary Tuberculosis TB Treatment and CureTB Treatment and Cure Preventing transmissionPreventing transmission Proper Management of TB casesProper Management of TB cases
  • THE BURDEN OF TBTHE BURDEN OF TBTHE BURDEN OF TBTHE BURDEN OF TB TB remains the leading cause of death worldwide from aTB remains the leading cause of death worldwide from a single infectious agentsingle infectious agent It is estimated that between 2000-2020, nearlyIt is estimated that between 2000-2020, nearly one billionone billion peoplepeople will be newly infected,will be newly infected, 200 million people200 million people will getwill get sick, andsick, and 35 million35 million will die from TB- if control is notwill die from TB- if control is not further strengthenedfurther strengthened With the increased incidence of AIDS, TB has become more aWith the increased incidence of AIDS, TB has become more a problem in the US and the worldproblem in the US and the world It is currently estimated that 1/2 of the world populationIt is currently estimated that 1/2 of the world population (3.1(3.1 billion) is infected with TBbillion) is infected with TB
  • EPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGY Tuberculosis (TB), which is caused by a complex of organisms, MycobacteriumTuberculosis (TB), which is caused by a complex of organisms, Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium africanum, is antuberculosis, Mycobacterium bovis, and Mycobacterium africanum, is an ancient human disease.ancient human disease. Evidence of TB can be found in human remains dating back to Neolithic times.Evidence of TB can be found in human remains dating back to Neolithic times. The most recent World Health Organization data estimate that 1.86 billionThe most recent World Health Organization data estimate that 1.86 billion persons are currently infected with TB.persons are currently infected with TB. At any time, an estimated 16 million persons worldwide demonstrate activeAt any time, an estimated 16 million persons worldwide demonstrate active disease, and 8 million new active cases develop each year, of which 3.5 milliondisease, and 8 million new active cases develop each year, of which 3.5 million manifest as the infectious pulmonary form of the disease.manifest as the infectious pulmonary form of the disease. This remarkable prevalence of disease is estimated to be responsible for at leastThis remarkable prevalence of disease is estimated to be responsible for at least 2 million deaths each year, making TB the most frequent infectious cause of2 million deaths each year, making TB the most frequent infectious cause of death in the world and the seventh most frequent cause of morbidity among alldeath in the world and the seventh most frequent cause of morbidity among all diseases.diseases.
  • The World Health Organization declared TB a worldThe World Health Organization declared TB a world global emergency in 1993; however, economic andglobal emergency in 1993; however, economic and political commitment to TB control programs is lackingpolitical commitment to TB control programs is lacking in many countries, and it is estimated that 95% of newin many countries, and it is estimated that 95% of new cases of TB occur in countries with limited resources.cases of TB occur in countries with limited resources. This situation facilitates inappropriate or unsustainedThis situation facilitates inappropriate or unsustained TB therapy, which in turn has promoted a rise in theTB therapy, which in turn has promoted a rise in the rates of multidrug-resistant TB (MDR-TB)rates of multidrug-resistant TB (MDR-TB) EPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGYEPIDEMIOLOGY
  • ETIOLOGYETIOLOGYETIOLOGYETIOLOGY Mycobacterium tuberculosis is theMycobacterium tuberculosis is the causative organism of pulmonarycausative organism of pulmonary tuberculosistuberculosis Non-spore forming, non motile,Non-spore forming, non motile, pleiomorphic, weakly gram-positive,pleiomorphic, weakly gram-positive, curved rod about 2-4 um longcurved rod about 2-4 um long Appear beaded or clumped in stainedAppear beaded or clumped in stained clinical specimens or culture mediaclinical specimens or culture media Grow best at 37-41 cGrow best at 37-41 c Grow slowly, their generation time beingGrow slowly, their generation time being 12-24 hour12-24 hour
  • MODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSION Airway droplets: the main modeAirway droplets: the main mode of transmission from personof transmission from person infected with pulmonary TB toinfected with pulmonary TB to others by respiratory droplets.others by respiratory droplets. Ingestion: Less frequentlyIngestion: Less frequently transmitted by ingestion oftransmitted by ingestion of mycobacterium bovis found inmycobacterium bovis found in unpasteurized milk productsunpasteurized milk products Direct inoculationDirect inoculation
  • Pulmonary TB is a disease of respiratory transmission,Pulmonary TB is a disease of respiratory transmission, patients with active disease expel bacilli into the air by:patients with active disease expel bacilli into the air by: CoughingCoughing SneezingSneezing ShoutingShouting Or any other way that will expel bacilli into the airOr any other way that will expel bacilli into the air MODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSION
  • Millions of tubercle bacilli in lungsMillions of tubercle bacilli in lungs ( mainly in cavities)( mainly in cavities) Coughing projects droplets nucleiCoughing projects droplets nuclei into the air that contain tubercleinto the air that contain tubercle bacillibacilli One cough can release 3,000One cough can release 3,000 droplet nucleidroplet nuclei One sneeze can release tens ofOne sneeze can release tens of thousands of droplet nucleithousands of droplet nuclei As few as five M. tuberculosisAs few as five M. tuberculosis (MTB) bacilli are necessary for(MTB) bacilli are necessary for human infectionhuman infection MODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSION
  • Optimal conditions for transmission include:Optimal conditions for transmission include: OvercrowdingOvercrowding Poor personal hygienePoor personal hygiene Poor public hygienePoor public hygiene MODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSIONMODE OF TRANSMISSION
  • FATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLSFATE OF M. TB AEROSOLS Large droplets settle to the ground quicklyLarge droplets settle to the ground quickly Smaller droplets form " droplet nuclei" of 1-5 µm inSmaller droplets form " droplet nuclei" of 1-5 µm in diameter, only TB-containing particles small enough to reachdiameter, only TB-containing particles small enough to reach the vulnerable environment of the alveolar space (typicallythe vulnerable environment of the alveolar space (typically <5–10 µm) are considered infectious. After inhalation, these<5–10 µm) are considered infectious. After inhalation, these infectious particles deposit preferentially in the dependentinfectious particles deposit preferentially in the dependent lower half of the lung, where they subsequently initiate alower half of the lung, where they subsequently initiate a primary focus of infection.primary focus of infection. Droplet nuclei can remain airborneDroplet nuclei can remain airborne
  • NOT EVERYONE WHO IS EXPOSED TONOT EVERYONE WHO IS EXPOSED TO TB WILL BECOME INFECTEDTB WILL BECOME INFECTED NOT EVERYONE WHO IS EXPOSED TONOT EVERYONE WHO IS EXPOSED TO TB WILL BECOME INFECTEDTB WILL BECOME INFECTED ExposureExposureExposureExposure Infection (30%)Infection (30%)Infection (30%)Infection (30%) No infection (70%)No infection (70%)No infection (70%)No infection (70%) Non specificNon specific immunityimmunity AdequateAdequate InadequateInadequate Early progression (5%)Early progression (5%)Early progression (5%)Early progression (5%) Containment (95%)Containment (95%) Latent TBLatent TB Containment (95%)Containment (95%) Latent TBLatent TB immunologicalimmunological defensesdefenses immunologicalimmunological defensesdefenses AdequateAdequate InadequateInadequate
  • HIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSIONHIGH RISK FOR PROGRESSION Persons more likely to progress from LTBI to TB disease includesPersons more likely to progress from LTBI to TB disease includes:: HIV infected personsHIV infected persons Persons with a history of prior, untreated TB or fibrotic lesions on CXRPersons with a history of prior, untreated TB or fibrotic lesions on CXR Recent TB infection (within the past 2 years)Recent TB infection (within the past 2 years) Injection drug usersInjection drug users Age ( very young or very old)Age ( very young or very old) Patients with certain medical conditions ( DM, chronic renal failure,Patients with certain medical conditions ( DM, chronic renal failure, hemodialysis, solid organ transplantation, cancer, malnourished patient,hemodialysis, solid organ transplantation, cancer, malnourished patient, silicosis)silicosis)
  • LTBI VS TB DISEASELTBI VS TB DISEASELTBI VS TB DISEASELTBI VS TB DISEASE LTBILTBI TB diseaseTB disease Tubercle bacilli in the bodyTubercle bacilli in the body TST or QFT-Gold results usually positiveTST or QFT-Gold results usually positive CXR usually normalCXR usually normal CXR usually abnormalCXR usually abnormal Sputum smear and culturesSputum smear and cultures negativenegative Sputum smear and culturesSputum smear and cultures positivepositive No symptomsNo symptoms Symptoms such as cough,fever,Symptoms such as cough,fever, weight lossweight loss Not infectiousNot infectious Often infectious before treatmentOften infectious before treatment Not a case of TBNot a case of TB A case of TBA case of TB
  • SPREAD OF TB TO OTHERSPREAD OF TB TO OTHER PARTS OF THE BODYPARTS OF THE BODY SPREAD OF TB TO OTHERSPREAD OF TB TO OTHER PARTS OF THE BODYPARTS OF THE BODY Lungs (85% of all cases)Lungs (85% of all cases) PleuraPleura CNSCNS Lymph nodesLymph nodes Genitourinary systemGenitourinary system Bones and jointsBones and joints Disseminated ( eg miliary)Disseminated ( eg miliary)
  • TB CAN AFFECT ANY PART OFTB CAN AFFECT ANY PART OF THE BODYTHE BODY TB CAN AFFECT ANY PART OFTB CAN AFFECT ANY PART OF THE BODYTHE BODY
  • PATHOGENESISPATHOGENESIS The bacilli implant in areas of high partial pressure of oxygen:The bacilli implant in areas of high partial pressure of oxygen: •LungLung •Renal cortexRenal cortex •Reticule endothelial systemReticule endothelial system The principal cause of tissue destruction from M tuberculosisThe principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intenseinfection is related to the organism's ability to incite intense host immune reactions to antigenic cell wall proteinshost immune reactions to antigenic cell wall proteins
  • PATHOGENESISPATHOGENESIS This is known as the primary infection, the patient will healThis is known as the primary infection, the patient will heal and a scar will appear in the affected loci.and a scar will appear in the affected loci. There will also be a few viable bacilli/spores may remain inThere will also be a few viable bacilli/spores may remain in these areas( particularly in the lung), the bacteria at this timethese areas( particularly in the lung), the bacteria at this time goes into a dormant state, as long as the person's immunegoes into a dormant state, as long as the person's immune system remains active and functions normallysystem remains active and functions normally When a person immune system is depressed, a secondaryWhen a person immune system is depressed, a secondary reactivation occurs. 85-90% this reactivation occurs in thereactivation occurs. 85-90% this reactivation occurs in the lungslungs
  • About 90% of those infected with mycobacterium tuberculosis areAbout 90% of those infected with mycobacterium tuberculosis are asymptomatic (latent TB infection), with only a 10% lifetime chance thatasymptomatic (latent TB infection), with only a 10% lifetime chance that latent infection will progress to TB disease.latent infection will progress to TB disease. Tuberculosis is classified into:Tuberculosis is classified into: A.A. Primary pulmonary TBPrimary pulmonary TB B.B. Secondary pulmonary TBSecondary pulmonary TB C.C. Miliary TBMiliary TB D.D. Extra pulmonary TB ( CNS, Bones, joints, adrenal, renal etc...)Extra pulmonary TB ( CNS, Bones, joints, adrenal, renal etc...)
  • When inhaled, droplet nuclei are deposited within the terminalWhen inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow for 2-12 weeks, untilairspaces of the lung. The organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to elicitthey reach 1000-10,000 in number, which is sufficient to elicit a cellular immune response that can be detected by a reactiona cellular immune response that can be detected by a reaction to the tuberculin skin test.to the tuberculin skin test. Mycobacteria are highly antigenic, and they promote aMycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity isvigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins,due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells,phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocyteslymphocytes, and polymorphonuclear leukocytes
  • MICROSCOPIC PICTUREMICROSCOPIC PICTURE The Ghon focus consistsThe Ghon focus consists of a central area of pinkof a central area of pink caseous necrosiscaseous necrosis surrounded bysurrounded by inflammatory infiltrateinflammatory infiltrate and walled of by an areaand walled of by an area of granulation tissueof granulation tissue containing multinucleatedcontaining multinucleated Langhans giant cellsLanghans giant cells
  • FATE OF PRIMARY TBFATE OF PRIMARY TB This depends on:This depends on: Virulence of the organismVirulence of the organism Dose of infectionDose of infection Degree of resistance of the hostDegree of resistance of the host A.A.If the patient resistance is good and the organism is of low virulence, GhonIf the patient resistance is good and the organism is of low virulence, Ghon complex undergo healing and over time usually evolve to fibrocalcific nodulescomplex undergo healing and over time usually evolve to fibrocalcific nodules B.B.If the patient resistance is poor and/or the organism of high virulence,If the patient resistance is poor and/or the organism of high virulence, progressive pulmonary tuberculosis will develop, the primary Ghon focus in theprogressive pulmonary tuberculosis will develop, the primary Ghon focus in the lung enlarges rapidly, erodes the bronchial tree, and spreadlung enlarges rapidly, erodes the bronchial tree, and spread
  • HOST'S IMMUNE SYSTEMHOST'S IMMUNE SYSTEM AND TB DISEASEAND TB DISEASE More important than the virulence of the infecting strain, however, mayMore important than the virulence of the infecting strain, however, may be genetic differences in the host’s immune system.be genetic differences in the host’s immune system. IL-12 is important for the development of cell-mediated immunity, andIL-12 is important for the development of cell-mediated immunity, and defects in the IL-12 receptor have been associated with disseminateddefects in the IL-12 receptor have been associated with disseminated mycobacterial infection following bacille Calmette-Guérin (BCG)mycobacterial infection following bacille Calmette-Guérin (BCG) vaccination.vaccination. Tumor necrosis factor-α (TNF-α) is responsible for granuloma formationTumor necrosis factor-α (TNF-α) is responsible for granuloma formation and also for the production of reactive nitrogen intermediates needed toand also for the production of reactive nitrogen intermediates needed to kill intracellular bacilli, and high rates of active TB have been describedkill intracellular bacilli, and high rates of active TB have been described following the administration of anti–TNF-α antibodies.following the administration of anti–TNF-α antibodies.
  • IFN-α is necessary for the production of TNF-α by macrophages, andIFN-α is necessary for the production of TNF-α by macrophages, and genetic absence of the IFN-γ receptor has been associated withgenetic absence of the IFN-γ receptor has been associated with disseminated nontuberculous mycobacterial infections in humans. Somedisseminated nontuberculous mycobacterial infections in humans. Some have hypothesized that subtle alterations in the IFN-γ receptor may behave hypothesized that subtle alterations in the IFN-γ receptor may be responsible forresponsible for variations in susceptibility to the development of TB: variability in thevariations in susceptibility to the development of TB: variability in the HLA-D gene locus, possibly related to a reduced affinity of the class IIHLA-D gene locus, possibly related to a reduced affinity of the class II major histocompatibility complex for mycobacterial antigens, inmajor histocompatibility complex for mycobacterial antigens, in addition to genetic polymorphisms in the natural resistance–associatedaddition to genetic polymorphisms in the natural resistance–associated macrophage protein-1 (NRAMP-1) , have been associated with anmacrophage protein-1 (NRAMP-1) , have been associated with an increased likelihood for the development of clinically apparent disease.increased likelihood for the development of clinically apparent disease. HOST'S IMMUNE SYSTEMHOST'S IMMUNE SYSTEM AND TB DISEASEAND TB DISEASE
  • PATHOGENESISPATHOGENESISPATHOGENESISPATHOGENESIS TB diseaseTB diseaseTB diseaseTB disease ImmunityImmunityImmunityImmunityHypersensitivityHypersensitivityHypersensitivityHypersensitivity HealingHealingDiseaseDisease
  • Type IV hypersensitivity reaction:Type IV hypersensitivity reaction: T cells ----->macrophages----> granulomaT cells ----->macrophages----> granuloma Activated macrophages -----> epithelioid cellsActivated macrophages -----> epithelioid cells Self destruction by lysosomal enzymesSelf destruction by lysosomal enzymes
  • Infected macrophages secrete interleukin-12 (IL-12), whichInfected macrophages secrete interleukin-12 (IL-12), which promotes a nonspecific immune response mediatedpromotes a nonspecific immune response mediated primarily by natural killer cells and / T cells.γ δprimarily by natural killer cells and / T cells.γ δ The nonspecific immune response may retard the localThe nonspecific immune response may retard the local infection but is usually unable to control it, and bacilliinfection but is usually unable to control it, and bacilli spread to local lymph nodes, where they may enter thespread to local lymph nodes, where they may enter the blood (bacillemia). From this point, TB infection is ablood (bacillemia). From this point, TB infection is a systemic process characterized by lymphatic andsystemic process characterized by lymphatic and hematogenous spread and the deposition of bacilli inhematogenous spread and the deposition of bacilli in multiple extrapulmonary sites (i.e., bones, meninges,multiple extrapulmonary sites (i.e., bones, meninges, kidney, and the posterior apical segment of the lungs),kidney, and the posterior apical segment of the lungs), creating the potential for disease in virtually any anatomiccreating the potential for disease in virtually any anatomic location.location.
  • MTB antigens in association with the class II major histocompatibilityMTB antigens in association with the class II major histocompatibility complex are presented to naive CD4+ T cells, heralding the onset ofcomplex are presented to naive CD4+ T cells, heralding the onset of specific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cellspecific anti-TB cell-mediated immunity (T helper subset 1 [Th1] cell immunity).immunity). Anti-TB CD4+ T cells coordinate the specific immune response by twoAnti-TB CD4+ T cells coordinate the specific immune response by two routes:routes: The onset of the cytotoxic T-lymphocyte response several weeks afterThe onset of the cytotoxic T-lymphocyte response several weeks after infection coincides with the development of caseous necrosis at the site ofinfection coincides with the development of caseous necrosis at the site of primary infection and the development of delayed-type hypersensitivityprimary infection and the development of delayed-type hypersensitivity (a)(a) secretion of IL-2 supports cytotoxic T-lymphocyte function, allowingsecretion of IL-2 supports cytotoxic T-lymphocyte function, allowing these cells to kill other cells already infected with MTB directlythese cells to kill other cells already infected with MTB directly (b)(b) secretion of interferon-γ (IFN-γ) primes uninfected macrophages,secretion of interferon-γ (IFN-γ) primes uninfected macrophages, allowing them to kill the intracellular pathogen efficiently.allowing them to kill the intracellular pathogen efficiently. (a)(a) secretion of IL-2 supports cytotoxic T-lymphocyte function, allowingsecretion of IL-2 supports cytotoxic T-lymphocyte function, allowing these cells to kill other cells already infected with MTB directlythese cells to kill other cells already infected with MTB directly (b)(b) secretion of interferon-γ (IFN-γ) primes uninfected macrophages,secretion of interferon-γ (IFN-γ) primes uninfected macrophages, allowing them to kill the intracellular pathogen efficiently.allowing them to kill the intracellular pathogen efficiently.
  • Primary pulmonary TB is an infection of persons who havePrimary pulmonary TB is an infection of persons who have not had prior contact with the tubercle bacillusnot had prior contact with the tubercle bacillus Inhaled bacilli are commonly deposited in alveoliInhaled bacilli are commonly deposited in alveoli immediately beneath the pleura, usually in the lower partimmediately beneath the pleura, usually in the lower part of the upper lobes or the upper part of the lower lobesof the upper lobes or the upper part of the lower lobes When inhaled, droplet nuclei are deposited in terminalWhen inhaled, droplet nuclei are deposited in terminal airspaces of the lungairspaces of the lung Macrophages ingest the bacilli and transport them toMacrophages ingest the bacilli and transport them to regional lymph nodesregional lymph nodes PRIMARY PULMONARY TBPRIMARY PULMONARY TB
  • PRIMARY PULMONARY TBPRIMARY PULMONARY TB The primary infection characteristicallyThe primary infection characteristically produces a " Ghon complex" formed of:produces a " Ghon complex" formed of: 1.1. Ghon focus: small area of pneumonicGhon focus: small area of pneumonic consolidation about 1-3 cm in diameter, sub-consolidation about 1-3 cm in diameter, sub- pleural in location present in the base of thepleural in location present in the base of the upper lobe or apex of the lower lobeupper lobe or apex of the lower lobe 2.2. Tuberculous lymphangitis: of the drainingTuberculous lymphangitis: of the draining lymphatic channelslymphatic channels 3.3. Tuberculous lymphadenitis: of theTuberculous lymphadenitis: of the tracheobronchial nodes which are enlarged,tracheobronchial nodes which are enlarged, matted together and their cut surface showmatted together and their cut surface show areas of caseous necrosisareas of caseous necrosis
  • PRIMARY PULMONARY TBPRIMARY PULMONARY TB PATHOGENESISPATHOGENESIS PRIMARY PULMONARY TBPRIMARY PULMONARY TB PATHOGENESISPATHOGENESIS Spread if infection will take place by:Spread if infection will take place by: A.A. Local spread: to the surrounding lung tissue and pleuraLocal spread: to the surrounding lung tissue and pleura B.B. Lymphatic spread: along bronchi, leading toLymphatic spread: along bronchi, leading to tuberculous bronchopneumoniatuberculous bronchopneumonia C.C. Hematogenous spread: leading to miliary TB orHematogenous spread: leading to miliary TB or isolated organ TB or miliary TB of the lungisolated organ TB or miliary TB of the lung
  • PRIMARY PULMONARY TBPRIMARY PULMONARY TB •• Most often a childhood infection in endemic settingsMost often a childhood infection in endemic settings •Few clinical symptoms in immunocompetent hostsFew clinical symptoms in immunocompetent hosts •Lymphangitic spread to hilar and paratracheal nodes resultLymphangitic spread to hilar and paratracheal nodes result in enlargement of these structuresin enlargement of these structures •Often the only residua of primary infection is a positive skinOften the only residua of primary infection is a positive skin test and the Ranke complextest and the Ranke complex •Primary progressive tuberculosis occurs in a minority ofPrimary progressive tuberculosis occurs in a minority of casescases
  • The natural history of primary pulmonary tuberculosis in adultsThe natural history of primary pulmonary tuberculosis in adults EventEvent TimeTime CommentComment Alveolar depositionAlveolar deposition of tubercle bacilliof tubercle bacilli 00 Bacilli engulfed byBacilli engulfed by alveolar macrophagesalveolar macrophages Bacilli proliferateBacilli proliferate and disseminateand disseminate 3-8 weeks3-8 weeks Tuberculin skin testTuberculin skin test becomes reactive;becomes reactive; CXR may becomeCXR may become abnormalabnormal Some patientsSome patients develop pleurisy; adevelop pleurisy; a minority developminority develop miliary diseasemiliary disease 8-26 weeks8-26 weeks High risk period forHigh risk period for pulmonary and extrapulmonary and extra pulmonary diseasepulmonary disease 26-156 weeks26-156 weeks 10% infected will10% infected will develop TBdevelop TB
  • COMPLICATIONS OFCOMPLICATIONS OF PRIMARY TUBERCULOSISPRIMARY TUBERCULOSIS COMPLICATIONS OFCOMPLICATIONS OF PRIMARY TUBERCULOSISPRIMARY TUBERCULOSIS Collapse/ consolidationCollapse/ consolidation BronchiectasisBronchiectasis Obstructive emphysemaObstructive emphysema BroncholithBroncholith Erythema nodosumErythema nodosum Phlyctenular conjunctivitisPhlyctenular conjunctivitis Pleural effusionPleural effusion Miliary TBMiliary TB Progressive primary tuberculosisProgressive primary tuberculosis
  • Secondary(cavitary) TB usually results from reactivation of aSecondary(cavitary) TB usually results from reactivation of a dormant, endogenous tubercle bacilli in a sensitized patientdormant, endogenous tubercle bacilli in a sensitized patient who has had previous contact with the tubercle bacilluswho has had previous contact with the tubercle bacillus In some cases the disease is caused by reinfection withIn some cases the disease is caused by reinfection with exogenous bacilliexogenous bacilli The lesion begins as a tubercle, the micro-organismsThe lesion begins as a tubercle, the micro-organisms searching for a high oxygen tension, usually settle in thesearching for a high oxygen tension, usually settle in the apical portion of one or both lungsapical portion of one or both lungs SECONDARY PULMONARY TBSECONDARY PULMONARY TB PATHOGENESISPATHOGENESIS SECONDARY PULMONARY TBSECONDARY PULMONARY TB PATHOGENESISPATHOGENESIS
  • A tubercle is no larger than 3A tubercle is no larger than 3 cm and consists of a centralcm and consists of a central area of caseous necrosisarea of caseous necrosis surrounded by granulomatoussurrounded by granulomatous tissue containing the typicaltissue containing the typical Langhans giant cellsLanghans giant cells The tubercle is separated fromThe tubercle is separated from the surrounding tissue by athe surrounding tissue by a layer of fibrous tissuelayer of fibrous tissue infiltrated with lymphocytesinfiltrated with lymphocytes SECONDARY PULMONARY TBSECONDARY PULMONARY TB PATHOGENESISPATHOGENESIS SECONDARY PULMONARY TBSECONDARY PULMONARY TB PATHOGENESISPATHOGENESIS
  • FATE OF SECONDARYFATE OF SECONDARY PULMONARY TBPULMONARY TB Healing by fibrosis with dystrophic calcification occurs in mostHealing by fibrosis with dystrophic calcification occurs in most cases when the dose of infection is small, virulence of thecases when the dose of infection is small, virulence of the organism is low and the patient resistance is goodorganism is low and the patient resistance is good Spread of infection occurs when the patient resistance is poorSpread of infection occurs when the patient resistance is poor and the virulence of the organism is high, spread occursand the virulence of the organism is high, spread occurs directly by lymphatic,natural passages and blood streamdirectly by lymphatic,natural passages and blood stream Fibrocaseous tuberculosis with cavitation occurs withFibrocaseous tuberculosis with cavitation occurs with moderate dose of the organism and moderate resistance of themoderate dose of the organism and moderate resistance of the patientpatient
  • Primary pulmonary TBPrimary pulmonary TB Secondary pulmonary TBSecondary pulmonary TB Mainly occurs in children but canMainly occurs in children but can occasionally occurs in elderly andoccasionally occurs in elderly and adultsadults Mainly occurs in adultsMainly occurs in adults Mainly Asymptomatic or withMainly Asymptomatic or with minimal symptoms and may goesminimal symptoms and may goes unrecognizedunrecognized SymptomaticSymptomatic Septum for AFB is rarely positiveSeptum for AFB is rarely positive Usually positiveUsually positive Associated with hypersensitivityAssociated with hypersensitivity phenomenon ( erythema noduom)phenomenon ( erythema noduom) Not associated withNot associated with hypersensitivityhypersensitivity Site of involvement on is the lowerSite of involvement on is the lower portion of the upper lobe and theportion of the upper lobe and the upper portion of the lower lobeupper portion of the lower lobe Apex of both lungs and the upperApex of both lungs and the upper portion of the lower lobeportion of the lower lobe On CXR : an area of consolidationOn CXR : an area of consolidation or pleural effusionor pleural effusion Typically cavitary lesion over theTypically cavitary lesion over the apexapex Non infectiousNon infectious Highly infectious in sputumHighly infectious in sputum positive casespositive cases
  • FIBROCASEOUS TB WITHFIBROCASEOUS TB WITH CAVITATIONCAVITATION FIBROCASEOUS TB WITHFIBROCASEOUS TB WITH CAVITATIONCAVITATION The cavity is chronic withThe cavity is chronic with fibrotic walls, lined byfibrotic walls, lined by caseous material and iscaseous material and is traversed by blood vesselstraversed by blood vessels and bronchiand bronchi The surrounding lung tissueThe surrounding lung tissue shows multiple focal areasshows multiple focal areas of caseation and otherof caseation and other cavitiescavities
  • COMPLICATIONS OFCOMPLICATIONS OF FIBROCASEOUS TBFIBROCASEOUS TB COMPLICATIONS OFCOMPLICATIONS OF FIBROCASEOUS TBFIBROCASEOUS TB Spread to the pleura causing----> pleural effusion, fibrinousSpread to the pleura causing----> pleural effusion, fibrinous pleurisy, tuberculous empyema, pneumothorax,pleurisy, tuberculous empyema, pneumothorax, pyopneumothoraxpyopneumothorax Coughing of the content of the cavity leads to: tuberculousCoughing of the content of the cavity leads to: tuberculous tracheobronchitis, tuberculous laryngitis, tuberculoustracheobronchitis, tuberculous laryngitis, tuberculous glossitis and tuberculous enteritisglossitis and tuberculous enteritis Erosion of the traversing blood vessels leads to: hemoptysis,Erosion of the traversing blood vessels leads to: hemoptysis, hematogenous spreadhematogenous spread Secondary amyloidosisSecondary amyloidosis
  • MILIARY TUBERCULOSISMILIARY TUBERCULOSIS It is the disseminated form of tuberculosis and is caused byIt is the disseminated form of tuberculosis and is caused by seeding of the bacilli through lymphatic a or blood vesselsseeding of the bacilli through lymphatic a or blood vessels Sites : the lung, lymph nodes, kidneys, adrenals, bone marrow,Sites : the lung, lymph nodes, kidneys, adrenals, bone marrow, spleen, liver, meninges, brain, eye grounds, and genitaliaspleen, liver, meninges, brain, eye grounds, and genitalia Fate: all granulomas have similar features and follow the sameFate: all granulomas have similar features and follow the same progression, namely focal collections of histocytes, followed byprogression, namely focal collections of histocytes, followed by epithelioid cells, Langhans giant cells, central caseationepithelioid cells, Langhans giant cells, central caseation necrosis and eventually fibrosis and mineralizationnecrosis and eventually fibrosis and mineralization
  • Gross picture:Gross picture: Minute, yellow-white lesions resembling millet seeds ( hence miliary)Minute, yellow-white lesions resembling millet seeds ( hence miliary) Gross picture:Gross picture: Minute, yellow-white lesions resembling millet seeds ( hence miliary)Minute, yellow-white lesions resembling millet seeds ( hence miliary) MILIARY TUBERCULOSISMILIARY TUBERCULOSISMILIARY TUBERCULOSISMILIARY TUBERCULOSIS
  • CLINICAL FEATURESCLINICAL FEATURES
  • Symptoms and signs of primary pulmonarySymptoms and signs of primary pulmonary TuberclosisTuberclosis AsymptomatAsymptomat icic A great majority especially adultsA great majority especially adults Brief febrileBrief febrile illnessillness At the time of tuberculin conversionAt the time of tuberculin conversion Anorexia,Anorexia, failure to gainfailure to gain weightweight In few cases with more severe infection or lowIn few cases with more severe infection or low host resistancehost resistance CoughCough If LN or granulation tissue impinge onIf LN or granulation tissue impinge on bronchial wallbronchial wall SputumSputum Rare in childrenRare in children HypersensitiHypersensiti vityvity phenomenonphenomenon Erythema nodosum, phlyctenularErythema nodosum, phlyctenular conjunctivitis , dactalitisconjunctivitis , dactalitis
  • Symptoms and signs of secondary pulmonarySymptoms and signs of secondary pulmonary tuberculosistuberculosis CoughCough Initially minimal and dry at early morning, thenInitially minimal and dry at early morning, then productive of small amount of sputum and present all theproductive of small amount of sputum and present all the dayday FeverFever Diurnal with early morning and late afternoon rise, LowDiurnal with early morning and late afternoon rise, Low grade fever and in advanced cases associated withgrade fever and in advanced cases associated with drenching night sweats and diaphoresisdrenching night sweats and diaphoresis HemoptysisHemoptysis Blood streak sputum and occasionally massiveBlood streak sputum and occasionally massive hemoptysis in complicated caseshemoptysis in complicated cases Loss ofLoss of weightweight Hence the name phthisis or wasting in advancedHence the name phthisis or wasting in advanced untreated casesuntreated cases AnorexiaAnorexia and fatigueand fatigue Systemic manifestation of the diseaseSystemic manifestation of the disease CracklesCrackles Characteristically post tussive over the involved areaCharacteristically post tussive over the involved area AmorphicAmorphic breath soundbreath sound Or cavernous breath sound over a large cavityOr cavernous breath sound over a large cavity communicating with a patent bronchuscommunicating with a patent bronchus
  • DIAGNOSISDIAGNOSISDIAGNOSISDIAGNOSIS
  • DIAGNOSISDIAGNOSIS Any cough that persists more than 2 weeks should beAny cough that persists more than 2 weeks should be evaluated for pulmonary TB in the appropriate clinicalevaluated for pulmonary TB in the appropriate clinical context ( poor patient, overcrowded, bad hygiene etc)context ( poor patient, overcrowded, bad hygiene etc) A full history and physical examination should beA full history and physical examination should be undertakenundertaken A minimum of 2 sputum samples, ( the first on spot and theA minimum of 2 sputum samples, ( the first on spot and the second in the early morning preferably fasting ) should besecond in the early morning preferably fasting ) should be examined, the sputum sample should be of a good qualityexamined, the sputum sample should be of a good quality representative of lower respiratory tract.representative of lower respiratory tract.
  • RADIOLOGYRADIOLOGY The following characteristics of chest radiograph favor theThe following characteristics of chest radiograph favor the diagnosis of tuberculosisdiagnosis of tuberculosis Shadows mainly in the upper zonesShadows mainly in the upper zones Patchy or nodular shadowsPatchy or nodular shadows The presence of a cavity or cavitiesThe presence of a cavity or cavities The presence of calcificationThe presence of calcification Bilateral shadows especially if theses are in the upper zonesBilateral shadows especially if theses are in the upper zones
  • PRIMARY PULMONARY TBPRIMARY PULMONARY TBPRIMARY PULMONARY TBPRIMARY PULMONARY TB Lymphadenopathy is the hallmark of primaryLymphadenopathy is the hallmark of primary disease in childhood, seen in up to 90% of casesdisease in childhood, seen in up to 90% of cases Usually affects the hilum and right paratrachealUsually affects the hilum and right paratracheal regionsregions Bilateral adenopathy occurs in one third of casesBilateral adenopathy occurs in one third of cases Adenopathy usually seen in association withAdenopathy usually seen in association with parenchymal consolidation or atelectasisparenchymal consolidation or atelectasis Lymphadenopathy can be the only manifestationLymphadenopathy can be the only manifestation of TB in young childrenof TB in young children Adenopathy resolves slowly, and nodalAdenopathy resolves slowly, and nodal calcification may occur six months after the initialcalcification may occur six months after the initial infectioninfection Pleural effusion may occur in a minority of casesPleural effusion may occur in a minority of cases
  • RADIOGRAPHIC RESIDUAL OFRADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TBPRIMARY PULMONARY TB RADIOGRAPHIC RESIDUAL OFRADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TBPRIMARY PULMONARY TB
  • Ranke's ComplexRanke's ComplexRanke's ComplexRanke's Complex Simon fociSimon fociSimon fociSimon foci RADIOGRAPHIC RESIDUAL OFRADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TBPRIMARY PULMONARY TB RADIOGRAPHIC RESIDUAL OFRADIOGRAPHIC RESIDUAL OF PRIMARY PULMONARY TBPRIMARY PULMONARY TB
  • POST PRIMARY PULMONARYPOST PRIMARY PULMONARY TBTB Post-primary TB represents 90 percent of adult cases in the non-HIV-infectedPost-primary TB represents 90 percent of adult cases in the non-HIV-infected populationpopulation Results from reactivation of a previously dormant focus seeded at the time ofResults from reactivation of a previously dormant focus seeded at the time of primary infectionprimary infection Apical-posterior segments of the upper lobes (80 to 90 percent of patients),Apical-posterior segments of the upper lobes (80 to 90 percent of patients), followed in frequency by the superior segment of the lower lobes and thefollowed in frequency by the superior segment of the lower lobes and the anterior segment of the upper lobesanterior segment of the upper lobes The original site of spread is occasionally associated with Simon foci—residualThe original site of spread is occasionally associated with Simon foci—residual uni- or bilateral apical fibronodular shadows from primary infectionuni- or bilateral apical fibronodular shadows from primary infection Post-primary disease also known as reactivation TB, recrudescent TB, chronicPost-primary disease also known as reactivation TB, recrudescent TB, chronic TB, endogenous reinfection, and adult type progressive TBTB, endogenous reinfection, and adult type progressive TB
  • THE RADIOGRAPHIC APPEARANCETHE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASEOF POST-PRIMARY DISEASE THE RADIOGRAPHIC APPEARANCETHE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASEOF POST-PRIMARY DISEASE Upper lobe infiltratesUpper lobe infiltrates Cavitary lesionsCavitary lesions TuberculomasTuberculomas Absence of lymphadenopathyAbsence of lymphadenopathy Complete lobar or lung opacification and lobarComplete lobar or lung opacification and lobar collapse in severe casescollapse in severe cases Pleural effusion, empyemaPleural effusion, empyema bronchiectasis, mililary patternbronchiectasis, mililary pattern pneumothoraxpneumothorax
  • THE RADIOGRAPHIC APPEARANCETHE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASEOF POST-PRIMARY DISEASE THE RADIOGRAPHIC APPEARANCETHE RADIOGRAPHIC APPEARANCE OF POST-PRIMARY DISEASEOF POST-PRIMARY DISEASE
  • CAVITARY DISEASECAVITARY DISEASECAVITARY DISEASECAVITARY DISEASE A characteristic finding of post-A characteristic finding of post- primary diseaseprimary disease Cavitation implies a high bacillaryCavitation implies a high bacillary burden and high infectivityburden and high infectivity Cavity size ranges from a few mmCavity size ranges from a few mm to several cmto several cm Variable wall thicknessVariable wall thickness Air fluid levels rare, and may be anAir fluid levels rare, and may be an indication of bacterial or fungalindication of bacterial or fungal superinfectionsuperinfection
  • Bilateral upper lobeBilateral upper lobe involvementinvolvement seen in this patient with post-seen in this patient with post- primary diseaseprimary disease Bilateral upper lobeBilateral upper lobe involvementinvolvement seen in this patient with post-seen in this patient with post- primary diseaseprimary disease Advanced post-primaryAdvanced post-primary tuberculosistuberculosis in an immunocompetent hostin an immunocompetent host Advanced post-primaryAdvanced post-primary tuberculosistuberculosis in an immunocompetent hostin an immunocompetent host
  • TUBECULOMATUBECULOMATUBECULOMATUBECULOMA Single or multiple rounded, well-Single or multiple rounded, well- circumscribed, focal lesionscircumscribed, focal lesions Manifestation of primary or post-Manifestation of primary or post- primary diseaseprimary disease Easily mistaken for coin lesions orEasily mistaken for coin lesions or metastatic disease on chestmetastatic disease on chest Vary in size from a few millimeters toVary in size from a few millimeters to 5 or 6 cm in diameter but usually5 or 6 cm in diameter but usually range from 1 to 3 cm.range from 1 to 3 cm. They may or may not contain calciumThey may or may not contain calcium
  • CHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TBCHEST CT IN PULOMNARY TB Characterize the cavityCharacterize the cavity Tree in bud nodules indicatingTree in bud nodules indicating endo-bronchial spread ofendo-bronchial spread of infectioninfection Detects complications:Detects complications: 1.1. PneumothoraxPneumothorax 2.2. EmpyemaEmpyema 3.3. BronchiectasisBronchiectasis 4.4. Tracheo-bronchial stenosisTracheo-bronchial stenosis 5.5. Miliary TBMiliary TB
  • SPUTUM EXAMINATIONSPUTUM EXAMINATION For patients with suspected pulmonary TB, at least threeFor patients with suspected pulmonary TB, at least three freshly expectorated first morning sputum samples shouldfreshly expectorated first morning sputum samples should be collected from a deep, productive cough in a sterilebe collected from a deep, productive cough in a sterile container with a wide mouth. Ideally, the volume of eachcontainer with a wide mouth. Ideally, the volume of each sample should be more than 5 mLsample should be more than 5 mL Induction of sputum with aerosolized hypertonic salineInduction of sputum with aerosolized hypertonic saline solution may be required if the patient is having difficultysolution may be required if the patient is having difficulty producing sputum; serial morning gastric lavage andproducing sputum; serial morning gastric lavage and bronchoalveolar lavage are alternative methods of obtainingbronchoalveolar lavage are alternative methods of obtaining clinical specimens.clinical specimens.
  • Examination of stained smears for AFB remains the most rapid and inexpensive method forExamination of stained smears for AFB remains the most rapid and inexpensive method for detecting mycobacteria.detecting mycobacteria. Both carbolfuchsin (Ziehl-Neelson or Kinyoun method) and fluorochrome (auramine–Both carbolfuchsin (Ziehl-Neelson or Kinyoun method) and fluorochrome (auramine– rhodamine) stains are available, but fluorochrome staining is more sensitive and hasrhodamine) stains are available, but fluorochrome staining is more sensitive and has become the standard staining method used in the United States.become the standard staining method used in the United States. Staining techniques require the presence of at least 5,000 to 10,000 organisms for aStaining techniques require the presence of at least 5,000 to 10,000 organisms for a positive result. The reported sensitivity of the AFB smear for respiratory samples rangespositive result. The reported sensitivity of the AFB smear for respiratory samples ranges from 45% to 75%, and specificity is reported to be greater than 97% in most studies.from 45% to 75%, and specificity is reported to be greater than 97% in most studies. The yield of a single specimen is low and can be improved by submitting multiple samplesThe yield of a single specimen is low and can be improved by submitting multiple samples of adequate volume.of adequate volume. Patients with cavitary TB are more likely to have a positive AFB smear because of the highPatients with cavitary TB are more likely to have a positive AFB smear because of the high number of organisms present in this form of TB, whereas a positive AFB smear is less likelynumber of organisms present in this form of TB, whereas a positive AFB smear is less likely in most types of extrapulmonary disease given the relatively low numbers of organisms inin most types of extrapulmonary disease given the relatively low numbers of organisms in these forms of TBthese forms of TB STAINING FOR ACID-FASTSTAINING FOR ACID-FAST BACILLIBACILLI
  • DIRECT SMEARDIRECT SMEAR EXAMINATIONEXAMINATION Is only positive when large number ofIs only positive when large number of bacilli are present ( 10,000), sobacilli are present ( 10,000), so negative smear doesn't excludenegative smear doesn't exclude tuberculosistuberculosis A negative smear in the presence ofA negative smear in the presence of extensive disease and cavitation makesextensive disease and cavitation makes the diagnosis less likely, particularly ifthe diagnosis less likely, particularly if the negatives are frequently repeatedthe negatives are frequently repeated Sputum for AFBSputum for AFB • Ziehl-Neelsen stainingZiehl-Neelsen staining • Flurochrome staining- Auramine-Flurochrome staining- Auramine- RhodamineRhodamine
  • CULTURECULTURE The AFB smear is limited by its poor sensitivity and inability to differentiate betweenThe AFB smear is limited by its poor sensitivity and inability to differentiate between MTB, nontuberculous mycobacterial species, and other acid-fast organisms.MTB, nontuberculous mycobacterial species, and other acid-fast organisms. Mycobacterial culture is able to detect as few as 10 organisms per milliliter and overcomesMycobacterial culture is able to detect as few as 10 organisms per milliliter and overcomes many of the limitations of AFB staining.many of the limitations of AFB staining. Several types of culture media have been developed for the isolation of mycobacteria,Several types of culture media have been developed for the isolation of mycobacteria, including agar-based media (Middlebrook 7H10-selective 7H11), egg-based mediaincluding agar-based media (Middlebrook 7H10-selective 7H11), egg-based media (Lowenstein-Jensen), and liquid media (Middlebrook 7H12).(Lowenstein-Jensen), and liquid media (Middlebrook 7H12). The development of automated broth culture systems, such as BACTEC 460, BACTEC 960The development of automated broth culture systems, such as BACTEC 460, BACTEC 960 mycobacterial growth indicator tube (MGIT) systems, Septi-Check ESP, and MB/BacT,mycobacterial growth indicator tube (MGIT) systems, Septi-Check ESP, and MB/BacT, has been a major step in accelerating the diagnosis of MTBhas been a major step in accelerating the diagnosis of MTB traditional solid media–based systems require 3 to 8 weeks for organism growth, whereastraditional solid media–based systems require 3 to 8 weeks for organism growth, whereas broth culture methods require 1 to 3 weeks; however, because some species of the MTBbroth culture methods require 1 to 3 weeks; however, because some species of the MTB complex may grow only on solid media, inoculation of both types of media iscomplex may grow only on solid media, inoculation of both types of media is recommendedrecommended
  • Even with the use of broth-based culture systems, confirming theEven with the use of broth-based culture systems, confirming the presence of MTB from the time of specimen collection takes at least apresence of MTB from the time of specimen collection takes at least a week and more often 2 to 3 weeks.week and more often 2 to 3 weeks. Methods to detect the presence of TB directly from clinical specimensMethods to detect the presence of TB directly from clinical specimens more rapidly have been a significant advance in the treatment of TB.more rapidly have been a significant advance in the treatment of TB. Current direct methods are based on nucleic acid amplificationCurrent direct methods are based on nucleic acid amplification techniques, and two different tests are commercially available: atechniques, and two different tests are commercially available: a transcription-mediated amplification method (Amplifiedtranscription-mediated amplification method (Amplified Mycobacterium tuberculosis Direct [MTD] Test) and a polymeraseMycobacterium tuberculosis Direct [MTD] Test) and a polymerase chain reaction–based assay (Amplicor; Roche Diagnostic Systems)chain reaction–based assay (Amplicor; Roche Diagnostic Systems) DIRECT AMPLIFICATIONDIRECT AMPLIFICATION TECHNIQUETECHNIQUE
  • The performance of nucleic acid amplification techniques has been most rigorouslyThe performance of nucleic acid amplification techniques has been most rigorously evaluated in respiratory samples, in which both tests have a sensitivity of about 96%evaluated in respiratory samples, in which both tests have a sensitivity of about 96% and a specificity of 100% for AFB smear-positive samples when combined withand a specificity of 100% for AFB smear-positive samples when combined with appropriate nucleic acid probes.appropriate nucleic acid probes. Their performance in AFB smear-negative specimens is significantly lessTheir performance in AFB smear-negative specimens is significantly less impressive, with sensitivities ranging from 48% to 53%, although their specificityimpressive, with sensitivities ranging from 48% to 53%, although their specificity remains high, at 96% to 99%.remains high, at 96% to 99%. The accuracy of nucleic acid amplification testing may be reduced by theThe accuracy of nucleic acid amplification testing may be reduced by the concurrent use of antituberculous therapy, and inhibitors in the patient’s sputumconcurrent use of antituberculous therapy, and inhibitors in the patient’s sputum may also cause a false-negative result.may also cause a false-negative result. nucleic acid amplification tests offer the opportunity to diagnose pulmonary TBnucleic acid amplification tests offer the opportunity to diagnose pulmonary TB within several hours, and their application to the first specimen of all clinicallywithin several hours, and their application to the first specimen of all clinically suspected cases is recommendedsuspected cases is recommended DIRECT AMPLIFICATIONDIRECT AMPLIFICATION TECHNIQUETECHNIQUE
  • The use of nucleic acid amplification tests in the diagnosticThe use of nucleic acid amplification tests in the diagnostic evaluation of patients with suspected pulmonary tuberculosisevaluation of patients with suspected pulmonary tuberculosis The use of nucleic acid amplification tests in the diagnosticThe use of nucleic acid amplification tests in the diagnostic evaluation of patients with suspected pulmonary tuberculosisevaluation of patients with suspected pulmonary tuberculosis
  • NUCLEIC ACID PROBESNUCLEIC ACID PROBES Nucleic acid probes have been developed that can specificallyNucleic acid probes have been developed that can specifically hybridize with DNA or RNA from MTB, M. avium, M.hybridize with DNA or RNA from MTB, M. avium, M. intracellulare, M. kansasii, and M. gordonae. The rapidity of thisintracellulare, M. kansasii, and M. gordonae. The rapidity of this test allows for species identification within 2 hours and has atest allows for species identification within 2 hours and has a sensitivity and specificity that approaches 100% for MTBsensitivity and specificity that approaches 100% for MTB Although the test requires more than 105 organisms or the useAlthough the test requires more than 105 organisms or the use of an amplification technique to achieve an adequate yield, whenof an amplification technique to achieve an adequate yield, when it is combined with automated broth culture methods, the timeit is combined with automated broth culture methods, the time for detecting and identifying MTB can be reduced to as little as 4for detecting and identifying MTB can be reduced to as little as 4 to 7 daysto 7 days
  • IDENTIFICATION OFIDENTIFICATION OF RESISTANCERESISTANCE The identification of antimicrobial resistance among clinical isolates is necessaryThe identification of antimicrobial resistance among clinical isolates is necessary to ensure optimal therapy and prevent the spread of these organisms to others.to ensure optimal therapy and prevent the spread of these organisms to others. Traditionally, agar- and broth-based methods have been used to detect drugTraditionally, agar- and broth-based methods have been used to detect drug resistance.resistance. In the agar-based method, organisms are allowed to grow on both a drug-In the agar-based method, organisms are allowed to grow on both a drug- containing medium and a drug-free medium. Growth of the organisms on acontaining medium and a drug-free medium. Growth of the organisms on a medium containing a drug that equals 1% or more of the growth of the organismsmedium containing a drug that equals 1% or more of the growth of the organisms on a medium without the drug indicates resistance to that drugon a medium without the drug indicates resistance to that drug Broth-based radiometric methods use a similar process and correlate well withBroth-based radiometric methods use a similar process and correlate well with agar-based methods (95%–100%) but allow resistance to be detected much earlieragar-based methods (95%–100%) but allow resistance to be detected much earlier than do solid media (4–7 days vs. 14–21 days). Because of the importance ofthan do solid media (4–7 days vs. 14–21 days). Because of the importance of resistance, it is recommended that both media be usedresistance, it is recommended that both media be used
  • ANTIGEN DETECTIONANTIGEN DETECTION Tuberculostearic acid in sputumTuberculostearic acid in sputum Membrane antigens in CSFMembrane antigens in CSF Lipoarabinomannan in serum and sputumLipoarabinomannan in serum and sputum
  • INDIRECT TESTSINDIRECT TESTS Tuberculin skin testTuberculin skin test TB serological tests ( antibody detection )TB serological tests ( antibody detection ) Mycobacteriophage assaysMycobacteriophage assays Cytokine detectionCytokine detection HistopathologyHistopathology
  • ADENOSINE DEAMINASEADENOSINE DEAMINASE Adenosine deaminase is an enzyme produced by activated TAdenosine deaminase is an enzyme produced by activated T lymphocytes, and measurement of the adenosine deaminase level inlymphocytes, and measurement of the adenosine deaminase level in certain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) hascertain extrapulmonary body fluids (pleural fluid, ascitic fluid, CSF) has been evaluated as a diagnostic test for TB. In several studies, thebeen evaluated as a diagnostic test for TB. In several studies, the sensitivity of the adenosine deaminase level in pleural fluid ranged fromsensitivity of the adenosine deaminase level in pleural fluid ranged from 83% to 99%, with a specificity that ranged from 89% to 97% when cutoff83% to 99%, with a specificity that ranged from 89% to 97% when cutoff levels of 45 to 60 U/L were used; however, many of these studies werelevels of 45 to 60 U/L were used; however, many of these studies were based on highly selected populations in areas where TB was endemic.based on highly selected populations in areas where TB was endemic. The positive predictive value of the test would be much lower in areasThe positive predictive value of the test would be much lower in areas like the United States, where the prevalence of TB and hence the pretestlike the United States, where the prevalence of TB and hence the pretest probability are lower (e.g., the positive predictive value is 50% when theprobability are lower (e.g., the positive predictive value is 50% when the pretest probability is 5%)pretest probability is 5%)
  • TUBERCULIN TESTINGTUBERCULIN TESTING 0.1 ml of 5 tuberculin units ( TU) PPD0.1 ml of 5 tuberculin units ( TU) PPD Injected intra dermally over the volar aspect of the armInjected intra dermally over the volar aspect of the arm Should be read in 48-72 hoursShould be read in 48-72 hours Measure induration not erythemaMeasure induration not erythema
  • The TST is the standard method for identifying patients with latent TBThe TST is the standard method for identifying patients with latent TB infection.infection. Currently available test preparations of tuberculin use purified proteinCurrently available test preparations of tuberculin use purified protein derivative (PPD) standardized for potency. Local induration developsderivative (PPD) standardized for potency. Local induration develops within 48 to 72 hours at the site of intradermal PPD injection (Mantouxwithin 48 to 72 hours at the site of intradermal PPD injection (Mantoux method) in patients with sensitivity to the antigen.method) in patients with sensitivity to the antigen. The largest reactions to PPD-tuberculin are expected in persons infectedThe largest reactions to PPD-tuberculin are expected in persons infected with MTB. However, cross-reaction with some nontuberculouswith MTB. However, cross-reaction with some nontuberculous mycobacteria takes place, and some persons infected with MTB may bemycobacteria takes place, and some persons infected with MTB may be anergic and unable to respond as expected.anergic and unable to respond as expected. TUBERCULIN TESTINGTUBERCULIN TESTING
  • FACTORS ASSOCIATED WITH AFACTORS ASSOCIATED WITH A FALSE-NEGATIVE TUBERCULINFALSE-NEGATIVE TUBERCULIN SKIN TESTSKIN TEST Host factorsHost factors InfectionsInfections Viral (e.g., measles, mumps, HIV)Viral (e.g., measles, mumps, HIV) Bacterial (e.g., typhoid fever, miliaryBacterial (e.g., typhoid fever, miliary TB, TB meningitis)TB, TB meningitis) Fungal (e.g., blastomycosis)Fungal (e.g., blastomycosis) Live viral vaccinesLive viral vaccines Chronic renal failureChronic renal failure Malnutrition and low protein statesMalnutrition and low protein states • Neoplastic disease (e.g., HodgkinNeoplastic disease (e.g., Hodgkin disease, lymphoma)disease, lymphoma) Corticosteroids and otherCorticosteroids and other immunosuppressantsimmunosuppressants • Booster phenomenonBooster phenomenon • Severe stress (e.g., trauma, burnSevere stress (e.g., trauma, burn victims)victims) • Recent exposure (within 4–7 weeks)Recent exposure (within 4–7 weeks) Host factorsHost factors InfectionsInfections Viral (e.g., measles, mumps, HIV)Viral (e.g., measles, mumps, HIV) Bacterial (e.g., typhoid fever, miliaryBacterial (e.g., typhoid fever, miliary TB, TB meningitis)TB, TB meningitis) Fungal (e.g., blastomycosis)Fungal (e.g., blastomycosis) Live viral vaccinesLive viral vaccines Chronic renal failureChronic renal failure Malnutrition and low protein statesMalnutrition and low protein states • Neoplastic disease (e.g., HodgkinNeoplastic disease (e.g., Hodgkin disease, lymphoma)disease, lymphoma) Corticosteroids and otherCorticosteroids and other immunosuppressantsimmunosuppressants • Booster phenomenonBooster phenomenon • Severe stress (e.g., trauma, burnSevere stress (e.g., trauma, burn victims)victims) • Recent exposure (within 4–7 weeks)Recent exposure (within 4–7 weeks) Improper administrationImproper administration Injection of inadequate volumeInjection of inadequate volume Subcutaneous injectionSubcutaneous injection Inexperienced readerInexperienced reader Problems with tuberculinProblems with tuberculin Improper storage (i.e., exposureImproper storage (i.e., exposure to heat and light)to heat and light) Improper dilutionImproper dilution ContaminationContamination Improper administrationImproper administration Injection of inadequate volumeInjection of inadequate volume Subcutaneous injectionSubcutaneous injection Inexperienced readerInexperienced reader Problems with tuberculinProblems with tuberculin Improper storage (i.e., exposureImproper storage (i.e., exposure to heat and light)to heat and light) Improper dilutionImproper dilution ContaminationContamination
  • in vitro assay thet measurein vitro assay thet measure interferon gamma releasedinterferon gamma released by sensitized T cells afterby sensitized T cells after stimulation by M.stimulation by M. Tuberculosis antigensTuberculosis antigens Measures immuneMeasures immune reactivity to M. TB.reactivity to M. TB.
  • PREVENTIONPREVENTION Prevention of infectionPrevention of infection General hygiene measuresGeneral hygiene measures Effective treatment of infected patientsEffective treatment of infected patients VaccineVaccine BCG vaccination: live attenuated strain of mycobacterium bovis, given 2-45 daysBCG vaccination: live attenuated strain of mycobacterium bovis, given 2-45 days after birth; prevents complicationsafter birth; prevents complications Chemo prophylaxisChemo prophylaxis INH as a mono therapy for 6 monthsINH as a mono therapy for 6 months