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Tuberculosis Teaching Basics

This document provides information on the history, classification, morphology, culture characteristics, and pathogenesis of Mycobacterium tuberculosis and other mycobacteria. It discusses how tuberculosis spreads through airborne droplets expelled from infected individuals. Key points include: 1) Tuberculosis is caused by Mycobacterium tuberculosis and other members of the M. tuberculosis complex. It has been identified in Egyptian mummies from 1550-1080 BC. 2) Mycobacteria are acid-fast bacilli with a waxy, lipid-rich cell wall. They grow slowly and can survive in sputum and other environments. 3) Tuberculosis spreads when people with active lung TB expel bacteria into the air through

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Dr.T.V.Rao MD 1
HISTORY of Tuberculosis Tuberculosis Is an Ancient Disease Spinal Tuberculosis in Egyptian Mummies History dates to 1550 – 1080 BC Identified by PCR Dr.T.V.Rao MD 2
Robert Koch Discoverer of Mycobacterium Tuberculosis Dr.T.V.Rao MD 3
What are Mycobacteria? • Obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lungs. • Facultative intracellular pathogens usually infecting mononuclear phagocytes (e.g. macrophages). Dr.T.V.Rao MD 4
Classification of Mycobacteria 1. Tubercle bacilli a) Human – MTB b) Bovine – M. bovis c) Murine – M. microti d) Avian – M. avium e) Cold blooded – M. marinum 2. Lepra bacilli a) Human – M. leprae b) Rat – M. leprae murium 3. Mycobacteria causing skin ulcers a) M. ulcerans b) M. belnei 4. Atypical Mycobacteria (Runyon Groups) a) Photochromogens b) Scotochromogens c) Nonphotochromogens d) Rapid growers 4. Johne’s bacillus M. paratuberculosis 6. Saprophytic mycobacteria a) M. butyricum b) M. phlei c) M. stercoralis d) M. smegmatis e) Others Dr.T.V.Rao MD 5
Mycobacterium differ from other routinely isolated Bacteria • Slow-growing with a generation time of 12 to 18 hours (c.f. 20-30 minutes for Escherichia coli). • Hydrophobic with a high lipid content in the cell wall. Because the cells are hydrophobic and tend to clump together, they are impermeable to the usual stains, e.g. Gram's stain Dr.T.V.Rao MD 6
Acid fast bacilli • Known as “Acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Dr.T.V.Rao MD 7
How they are Acid fast • Once stained, the cells resist decolourization with acidified organic solvents and are therefore called "acid-fast". (Other bacteria which also contain mycolic acids, such as Nocardia, can also exhibit this feature.) Dr.T.V.Rao MD 8
Mycobacterium tuberculosis complex • Includes Human and Bovine mycobacterium • M .Africanism Tropical Africa • M.microti do not cause human infections but in small mammals Dr.T.V.Rao MD 9
M.bovis • Primarily infection among the cattle • M.bovis infects Tonsils, Cervical nodes, can produce Scrofula. • Enter through Intestines – infects the Ileocecal region. Dr.T.V.Rao MD 10
What are atypical MycobacteriumWhat are atypical Mycobacterium • Infects birds, cold blooded animals worm blooded animals • Present in environment • Opportunistic pathogens • Others – Saprophytic bacteria M butryicum present in butter M.phlei M smegmatis – present in Smegma Dr.T.V.Rao MD 11
Atypical Mycobacterium • 1 Photochromogens • 2 Scotochromogens • 3 Non Photochromogens • 4 Rapid growers Dr.T.V.Rao MD 12
MOST IMPORTANT AMONG INFECTIOUS DISEASES • Tuberculosis (TB) is the leading cause of death in the world from a bacterial infectious disease. The disease affects 1.8 billion people/year which is equal to one- third of the entire world population. Dr.T.V.Rao MD 13
Poverty and Crowded living spreads Tuberculosis Dr.T.V.Rao MD 14
Tuberculosis infects Famous people too Dr.T.V.Rao MD 15
What are Mycobacteria? • Obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lungs. • Facultative intracellular pathogens usually infecting mononuclear phagocytes (e.g. macrophages). Dr.T.V.Rao MD 16
General characters of the genus • Slender rods • Resist staining but once stained, resist decolonization by dilute mineral acids; hence called ACID FAST BACILLI (AFB) • Aerobic, Non-motile, Non-sporing, Non- capsulated. • Growth generally slow • Genus includes – Obligate parasites – Opportunist pathogens – Saprophytes Dr.T.V.Rao MD 17
Morphology of Mycobacterium tuberculosis • Straight, slightly curved Rod shaped 3 x 0.3microns • May be single, in pairs or in small clumps • On conditions in growth appears as filamentous, club shaped, or in Branched forms. Dr.T.V.Rao MD 18
ACID FAST BACILLI • Known as “Acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Dr.T.V.Rao MD 19
Important MycobacteriumImportant Mycobacterium • Mycobacterium tuberculosis, along with M. bovis, M. africanum, and M. microti all cause the disease known as tuberculosis (TB) and are members of the tuberculosis species complex. Each member of the TB complex is pathogenic, but M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic for animalsDr.T.V.Rao MD 20
Avian Tuberculosis • Transmitted by ingestion and inhalation of aerosolized infectious organisms from feces. • Oral ingestion of food and water contaminated with feces is the most common method of infection. • Once ingested, the organism spreads throughout the bird's body and is shed in large numbers in the feces. • If the bacterium is inhaled, pulmonary lesions and skin invasions may occur • transmission of avian TB is from bird to human not from human to human. Dr.T.V.Rao MD 21
Acid Fast Bacilli seen in a specimen of Sputum Dr.T.V.Rao MD 22
Acid fast bacilli Dr.T.V.Rao MD 23
Acid fast Bacilli seen as in Florescent Microscope • After staining with Ziehl Neelsen method or Fluorescent method ( Auramine or Rhodamine they resist decolonization by 20% Sulphuric acid and absolute alcohol for 10 mt, • So called as Acid and Alchool fast. Dr.T.V.Rao MD 24
Why they are Acid Fast • The character of Acid fastness is due to presence of Unsapnofiable wax ( Mcolic acid and semi permeable membrane around the cell)Dr.T.V.Rao MD 25
MTB : Cultural characters • Grow slowly. Generation time 14-15 hrs • Colonies appear after 2 weeks or at 6-8 weeks • MTB - Obligate aerobe • MTB grows more luxuriantly (eugonic) than M. bovis (dysgonic). • Addition of 0.5% Glycerol supports growth of human strains. No effect or inhibitory effect on bovine strains. Dr.T.V.Rao MD 26
Culturing Acid Fast Bacilli • Slow to grow , • Generation time is 14 – 15 hours • > 2 weeks minimal required period • Grows at 370 c do not grow below 250 c • Ph between 6.4 to 7.0 Dr.T.V.Rao MD 27
Eight Week Growth of Mycobacterium tuberculosis on Lowenstein-Jensen Agar Dr.T.V.Rao MD 28
Nature of Media Used • Helps the growth needs • Solid Medium is commonly used • Lowenstein Jensen’s medium • Petrangini • Middle brook mediumDr.T.V.Rao MD 29
Lowenstein Jensen’s Medium • Contain coagulated egg • Mineral salt solution • Asparagine's • Malachite green • Agar Dr.T.V.Rao MD 30
Other Medium •Middle brook •Sula's medium •But not routinely used Dr.T.V.Rao MD 31
Nature of Growth CharactersNature of Growth Characters • M tuberculosis is obligate aerobe • M.bovis Microaerophilic • M.tuberculosis growth luxierently • M.tuberculosis eugonic • M bovis is dysgonic • When grown on 0.5% glycerin M tuberculosis growth improves • Sodium pyruvate improves the growth of both organism. Dr.T.V.Rao MD 32
On L J Medium • M.tuberculosis appear dry, rough raised irregular colonies • Appear wrinkled • They appear creamy white • Become yellowish • M.bovis appear as flat smooth, moist, white and break up easily Dr.T.V.Rao MD 33
Lowenstein Jensen Medium – Selective. Always in screw capped bottle. Bluish Green. Contains – Egg protein – Solidifying agent Mineral salts – Mg Sulphate, Mg citrate Asparagine Malachite Green – Selective agent Dr.T.V.Rao MD 34
On Liquid Medium •Appear as long serpentine cords in liquid medium •Virulent strains grow in a more dispersedDr.T.V.Rao MD 35
Resistance of Mycobacterium • Mycobacterium are killed at 600 c in 15 – 20 mt • In sputum they survive for 10 – 30 mt • Relatively resistant to several chemicals including Phenol 5 % • Sensitive to Glutaraldehyde and Formaldehyde • Ethanol is suitable application to superficial surfaces and skin gloves Dr.T.V.Rao MD 36
Resistance to several agents • Bacilli survive in Droplets for 8 – 10 days • Survive in 5% phenol, 15% Sulphuric acid 3% Nitric acid,5% oxalic acid, 4% Sodium hydroxide Dr.T.V.Rao MD 37
Biochemical Tests on Mycobacterium spp • Niacin test – 10% cyanogen's bromide and 4% Aniline in 96% ethanol are added to suspension of – C canary yellow color indicates positive test. Dr.T.V.Rao MD 38
Other Tests • Aryl sulphatase test – Positive in Atypical Mycobacterium • Bacilli grown in 0.001 tripotassium phenolpthalein disulphide / 2 N. Sodium hydroxide added drop by drop a pink color develops • Catalase peroxidase test – Differentiates Atypical from Typical Most Atypical are strongly Catalase positive Tubercle bacilli are weakly positive Tubercle bacilli are peroxidase positive – not atypical INH resistant strains are negative for testDr.T.V.Rao MD 39
Catalase Test • 30 Vol of H2O2 and 0.2 % alcohol in distilled water is added to 5 ml of test culture • Effervescence indicates Catalase positive • Other test Amidase test Nitrate reduction test Dr.T.V.Rao MD 40
Antigenic Characters • Group specificity due to Polysaccharides • Type specificity to protein antigens • Delayed hypersensitivity to proteins • Related to each other species • Some relation between lepra and tubercle bacilli • Serology – Tests not useful Antigenic homogeneity between < bovis and M.microti Dr.T.V.Rao MD 41
Bacteriophages • There are 4 Bacteriophages A B C D • A worldwide • B. Europe and -American • C rare • I type nature between A and B and common in India • Phage 33 D M tuberculosis and not in BCG strains Dr.T.V.Rao MD 42
Molecular Typing • DNA finger printing differentiates different strains of Mycobacterium species • Treating the organism with Restriction endonuclease yields Nucleic acid fragments of varying length and strain specific • Use in epidemiological studies Dr.T.V.Rao MD 43
Finger printing Methods • Finger printing is done with Chromosomal insertion sequence IS 6110 present in most strains of Tubercle bacilli • Now entire genome of M tuberculosis is sequenced • Several Molecular methods are available for studies Dr.T.V.Rao MD 44
Genome of Mycobacterium tuberculosis Dr.T.V.Rao MD 45
How tuberculosis spreads• Tuberculosis (TB) is a contagious disease. Like the common cold, it spreads through the air. Only people who are sick with TB in their lungs are infectious. When infectious people cough, sneeze, talk or spit, they propel TB germs, known as bacilli, into the air. A person needs only to inhale a small number of these to be infected. Dr.T.V.Rao MD 46
Tuberculosis spread by Respiratory route Dr.T.V.Rao MD 47
Tuberculosis highly Communicable Disease. • Someone in the world is newly infected with TB bacilli every second. • Overall, one-third of the world's population is currently infected with the TB bacillus. • 5-10% of people who are infected with TB bacilli (but who are not infected with HIV) become sick or infectious at some time during their life. People with HIV and TB infection are much more likely to develop TB. Dr.T.V.Rao MD 48
In India 1 death / Minute • Half a million people die from disease every year in India one death every minute Dr.T.V.Rao MD 49
Pathology and Pathogenesis of Tuberculosis • Source of Infection – Open case of Pulmonary Tuberculosis. • Every open case has potential to infect 20 – 25 healthy persons before cured or dies • Coughing , Sneezing, or Talking. • Each act can spill 3000 infective nuclei in the air, • Infective particles are engulfed by Alveolar Macrophages. Dr.T.V.Rao MD 50
Spread of Tuberculosis Dr.T.V.Rao MD 51
Generation of Droplet Nuclei • One cough produces 500 droplets • The average TB patient generates 75,000 droplets per day before therapy • This falls to 25 infectious droplets per day within two weeks of effective therapy Dr.T.V.Rao MD 52
Dr.T.V.Rao MD 53
Predisposing Factors • Genetic basis, • Age • Stress, • Nutrition, • Co existing infections Eg HIV Dr.T.V.Rao MD 54
Mechanisms of Infection • Mycobacterium do not produce toxins. • Allergy and Immunity plays the major role. • Only 1/10 of the infected will get disease. • Cell Mediated Immunity plays a crucial role. • Humoral Immunity – not Important. • CD4Cell plays role in Immune Mechanisms. Dr.T.V.Rao MD 55
Mechanisms of Infection • Within 10 days of entry of Bacilli clones of Antigen specific T Lymphocytes are produced • Can actively produce Cytokines, Interferon γ which activate Macrophages form cluster or Granuloma Dr.T.V.Rao MD 56
Tubercle with Caseous Necrosis Giant cells Tubercle bacilli Partially activated macrophage Lymphocyte Fully activated macrophage Dr.T.V.Rao MD 57
Basis of Tubercle formation. • Tubercle is a Avascular granuloma Contain central zone of giant cells with or without caseation and peripheral zone of Lymphocytes and Fibroblasts. • Produce lesions may be Exudative or Productive Dr.T.V.Rao MD 58
Diagram of a Granuloma NOTE: ultimately a fibrin layer develops around granuloma (fibrosis), further “walling off” the lesion. Typical progression in pulmonary TB involves caseation, calcification and cavity formation. Dr.T.V.Rao MD 59
Tubercle discharging Bronchial tree TNF- αTNF- α Dr.T.V.Rao MD 60
Immunity in Tuberculosis. • CD4 T Lymphocytes with Th 1 or Th 2 secrete - 1 Cytokines,2 Interleukin 1,and 2 , 3 Interferon's γ , 4.Tumor necrosis factor. • The mechanisms with Th 1 secrete Cytokines Activate Macrophages Results in protective Immunity, and contain Infection. Th 2 manifests with Delayed Hypersensitivity DTH causes Tissue destruction. and disease will progress. . Dr.T.V.Rao MD 61
Immunity in Tuberculosis Activated Macrophages - Epitheliod cells Forms cluster a granuloma Activated macrophages turn into Giant cells. Granuloma contains necrotic tissue Dead macrophages cheese like caseation. Apoptosis of bacteria laden cells Contribute to protective immunity. Dr.T.V.Rao MD 62
Lesions in Tuberculosis • Exudative – and Productive • Exudative – Acute inflammatory reaction with edema fluid – contains Polymorphs- Lymphocytes – later Mononuclear cells. Bacilli are virulent - Host responds with DTH Injurious. Productive Type protective ImmunityDr.T.V.Rao MD 63
Primary Tuberculosis • Initial response • In Endemic countries Young children • Events of Primary complex 1 Bacilli are engulfed by Alveolar Macrophages 2 Multiply and give raise to Sub pleural focus of Tuberculosis,Pneumonia,involve lower lobes and lower part of upper lobes. Called as Ghon’s focus. The Hilar Lymph nodes are also involved Dr.T.V.Rao MD 64
Primary complex • This is known as the primary complex or primary infection. The patient will heal and a scar will appear in the infected loci. There will also be a few viable bacilli/ may remain in these areas (particularly in the lung). The bacteria at this time goes into a dormant state, as long as the person's immune system remains active and functions normally this person isn't bothered by the dormant bacillus. Dr.T.V.Rao MD 65
Primary complex • Ghon’s focus with Enlarged lymph nodes appear after 3- 8 weeks after infection. • Heals in 2 – 6 months calcified, • Some bacteria remain alive and produce latent infections. • Infection activated in Immunosuppressed conditions Eg. HIV infections and AIDS • Can produce Meningitis, Miliary tuberculosis, other disseminated Tuberculosis. Dr.T.V.Rao MD 66
Reactivation of Tuberculosis • When a person's immune system is depressed., a secondary reactivation occurs. 85-90% of the cases seen which are of secondary reactivation type occurs in the lungs. Dr.T.V.Rao MD 67
Koch’s Phenomenon • Tuberculosis infected Guinea pig if injected with Living Tubercle bacilli • The site around the injection becomes necrotic. • Koch found the same reaction when injected with old Tuberculin ( heated and concentration of the tubercle bacilli ) • It has produced the same reaction • This is called as Koch’s Phenomenon. Dr.T.V.Rao MD 68
Post Primary Tuberculosis • Mainly occurs due to Reactivation of Latent infection. • May also due to Exogenous reinfection • Differs from Primary Infection. • Leads to – Cavitation's of Lungs, Enlargement of Lymph nodes, Expectoration of Bacteria laden sputum Dissemination into Lungs and other extra pulmonary areas. Dr.T.V.Rao MD 69
Majority of the Tuberculosis are Pulmonary Dr.T.V.Rao MD 70
Multiorgan Involvement in Tuberculosis. Dr.T.V.Rao MD 71
Complication of Tuberculosis. 1. Meningitis. 2. Pleurisy, 3. Involvement of Kidney, 4. Spine ( Potts spine ) 5. Bone Joints, 6. Miliary tuberculosis Dr.T.V.Rao MD 72
Symptoms and Sings of Tuberculosis Dr.T.V.Rao MD 73
Clinical Illness with Tuberculosis • Pulmonary Disease – Major manifestation with involvement of Lungs Hemoptysis, Chest pain Fever sweets Anorexia Cavity formation in Lungs Dr.T.V.Rao MD 74
Tuberculosis - Pneumothorax Dr.T.V.Rao MD 75
Extra pulmonary Tuberculosis • Bacteria on circulation leads to bacteremia leads to involvement of GUT, Genito urinary system, Meningitis Gastro Intestinal system, skin, Lymph nodes Bone marrow. Spinal infection Potts spine, Arthritis Dr.T.V.Rao MD 76
Tuberculosis - Lymphadenitis Dr.T.V.Rao MD 77
Multidrug-resistant tuberculosis (MDR-TB) • Drug resistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Dr.T.V.Rao MD 78
Definition of MDR Tuberculosis • MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD). XDR-TB is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin). Dr.T.V.Rao MD 79
MDR tuberculosis dangerous to Society too • Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals Dr.T.V.Rao MD 80
X- MDR • The term ‘totally drug resistant’ has not been clearly defined for tuberculosis. XDR-TB severely reduces the options for treatment although they have not been studied in large cohorts. Treatment options for XDR-TB patients who have resistance to additional second-line anti- TB drugs are even more limited. Dr.T.V.Rao MD 81
Epidemiology • An ancient disease, called as white plague • 1/3 of the world population is infected • 2 billion infected • Each year 9 lakhs to 1 million are infected • Poor nations phase the burnt of the disease. • In developing world > 4o% of the population is effected • 15 million suffer the disease • 3 million are highly infective. Dr.T.V.Rao MD 82
Diagnosis of Tuberculosis Dr.T.V.Rao MD 83
Types of specimens: -Sputum. - BAL. -Pleural effusions - Urine - Stool -CSF -Aspiration ( gastric – cold abscess) - Blood in case of haematogenous TB Dr.T.V.Rao MD 84
85 Sputum Collection • Sputum specimens are essential to confirm TB – Specimens should be from lung secretions, not saliva • Collect 3 specimens on 3 different days • Spontaneous morning sputum more desirable than induced specimens • Collect sputum before treatment is initiated
86 Culture • Used to confirm diagnosis of TB • Culture all specimens, even if smear is negative • Initial drug isolate should be used to determine drug susceptibility
Laboratory Diagnosis 1- Sputum smears stained by Z-N stain Three morning successive mucopurulent sputum samples are needed to diagnose pulmonary TB. Advantage: - cheap – rapid - Easy to perform - High predictive value > 90% - Specificity of 98% Disadvantages: - sputum ( need to contain 5000-10000 AFB/ ml.) - Young children, elderly & HIV infected persons may not produce cavities & sputum containing AFB. Dr.T.V.Rao MD 87
2- Detecting AFB by fluorochrome stain using fluorescence microscopy: The smear may be stained by aura mine-O dye. In this method the TB bacilli are stained yellow against dark background & easily visualized using florescent microscope. Advantages: - More sensitive - Rapid Disadvantages: - Hazards of dye toxicity - more expensive - must be confirmed by Z-N stain Dr.T.V.Rao MD 88
Quantitation of AFB in Sputum Smears • No of Bacilli No of Fields Report as • 0 300 Negative • 1-2 300 Doubtful • 1- 9 100 1+ • 1- 9 10 2+ • 1-9 1 3+ • 10 or >10 1 4+ Dr.T.V.Rao MD 89
Lowenstein–Jensen medium • When grown on LJ medium, M. tuberculosis appears as brown, granular colonies (sometimes called "buff, rough and tough"). The media must be incubated for a significant length of time, usually four weeks, due to the slow doubling time of M. tuberculosis Dr.T.V.Rao MD 90
3- Cultures on L J media Lowenstein –Jensen medium is an egg based media with addition of salts, 5 % glycerol, Malachite green. Advantages: - Specificity about 99 % - More sensitive (need lower no. of bacilli 10-100 / ml) - Can differentiate between TB complex & NTM using biochemical reactions - Sensitivity tests for antituberculous drugs ( St, INH, Rif., E) Disadvantages: Slowly growing ( up to 8 weeks ) Dr.T.V.Rao MD 91
Detection and identification of mycobacteria directly from clinical samples • Genotypic Methods : • 􀂄 PCR • 􀂄 LAMP • 􀂄 TMA / NAA • 􀂄 Ligase chain reaction • 􀂄 Phenotypic Methods : • 􀂄 FAST Plaque TB Dr.T.V.Rao MD 92
• Essentially PCR is a way to make millions of identical copies of a specific DNA sequence , which may be a gene, or a part of a gene, or simply a stretch of nucleotides with a known DNA sequence, the function of which may be unknown Polymerase Chain Reaction (PCR) Dr.T.V.Rao MD 93
• Interferon-γ assays measure cell- mediated immunity by quantifying IFN-γ released from sensitized T cells in whole blood/PBMCs incubated with TB antigens. Quantiferon-GOLD Dr.T.V.Rao MD 94
Tuberculin Test Interpretation: * A positive test indicates previous exposure and carriage of T.B. * A negative tuberculin test excludes infection in suspected persons * Tuberculin positive persons may develop reactivation type of T.B. * Tuberculin negative persons are at risk of gaining new infection * False positive reactions are mainly due to: - Infection with nontuberculous mycobacteria * Dr.T.V.Rao MD 95
* False negative reactions may be due to: - • False negative reactions may be due to: • - Sever tuberculosis infection (Miliary T.B.) - Hodgkin’s disease • - Corticosteroid therapy - Malnutrition - AIDS • * Children below 5 years of age with no exposure history: • - Positive test must be regarded suspicious Dr.T.V.Rao MD 96
Tuberculin Test ( Mantoux Test ) • Test to be interpreted in relation to clinical evaluation. • Even the induration of 5 mm to be considered positive when tested on HIV patients. • Lacks specificity.
Tuberculin Testing - Limitations • False positive reactions are mainly due to: • - Infection with nontuberculous mycobacteria • * False negative reactions may be due to: • - Sever tuberculosis infection (Miliary T.B.) - Hodgkin’s disease • - Corticosteroid therapy - Malnutrition - AIDS • * Children below 5 years of age with no exposure history: • - Positive test must be regarded suspicious Dr.T.V.Rao MD 98
Recent Methods for Diagnosis I – BACTEC 460 ( rapid radiometric culture system ) specimens are cultured in a liquid medium (Middle brook7H9 broth base )containing C14 – labeled palmitic acid & PANTA antibiotic mixture. Growing mycobacteria utilize the acid, releasing radioactive CO2 which is measured as growth index (GI) in the BACTEC instrument. The daily increase in GI output is directly proportional to the rate & amount of growth in the medium. Dr.T.V.Rao MD 99
III Polymerase Chain Reaction (PCR) & Gene probe Nucleic acid probes & nucleic acid amplification tests in which polymerase enzymes are used to amplify ( make many copies of specific DNA or RNA sequences extracted from mycobacterial cells. Advantages: - Rapid procedure - High sensitivity (1-10 ( 3 – 4 hours) bacilli / ml sputum) Dr.T.V.Rao MD 100
Tuberculosis and HIV infection • HIV association has become a threat to the developed countries too • HIV association will lead to rapid spread of tuberculosis Dr.T.V.Rao MD 101
HIV Considerations • HIV is the strongest risk factor for progression to active disease • HIV kills CD4+ T Helper cells which normally inhibit M. tuberculosis • HIV interferes with PPD skin test • Protease inhibitors interfere with rifampin Dr.T.V.Rao MD 102
MDR tuberculosis • Multidrug resistant tuberculosis has become a global threat. • In 1993 WHO declared Tuberculosis a Global emergency • Animals shed the bacilli in Milk, human’s get infected after drinking the unsterilized Milk • Pasteurization has reduced the incidence of Bovine tuberculosis. Dr.T.V.Rao MD 103
Second Line Drug Treatment (SLD’s) Less effective, more costly and more toxic, 50% cure rate • Four months intensive phase (5 drugs) – Kanamycin – Ethionamide – Pyrazinamide – Ofloxacin – Cycloserine or Ethambutol • 7X times p/w in hospital » Followed by
Why Tuberculosis continues to be Important • Someone in the world is newly infected with TB bacilli every second. • Overall, one-third of the world's population is currently infected with the TB bacillus. • 5-10% of people who are infected with TB bacilli (but who are not infected with HIV) become sick or infectious at some time during their life. People with HIV and TB infection are much more likely to develop TB. Dr.T.V.Rao MD 105
March 24th World TB Day Dr.T.V.Rao MD 106
Treatment Drugs used : 1- First line drugs : - Isoniazid - Rifampicin - Pyrazinamide - Ethambutol - Streptomycin 2- Second line drugs (more toxic and less effective): - Kanamycin - capreomycin - Cycloserin - ethionamide - ciprofloxacin - Ofloxacin * Noncompliance (failure to complete the course): Directly observed therapy (DOT) Health care workers observe the medication Dr.T.V.Rao MD 107
Directly Observed Therapy – Short Course • DOTS (directly observed treatment, short- course), is the name given to the World Health Organization-recommended tuberculosis control strategy that combines components: • Case detection by sputum smear microscopy • Standardized treatment regimen directly observed by a healthcare worker or community health worker for at least the first two months Dr.T.V.Rao MD 108
Immuno-prophylaxis • Intradermal injection of live attenuated vaccine Bacille Calmette-Guerin (BCG). • The strain causes self limited lesion and induces hypersensitivity & immunity. • Coverts tuberculin negative person to positive reactor. • Immunity lasts for 10-15 years. Immunity 60- 80% • Some studies proved BCG is doubtful value in prevention of Tuberculosis Dr.T.V.Rao MD 109
Bacillus Calmette-Guérin (BCG) • Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured (230 passages) in an artificial medium for 13 years, Dr.T.V.Rao MD 110
BCG • Given at birth without tuberculin testing • Protects against TB, the disease runs milder course in protected, prevents skeletal, meningeal & miliary forms. • Also found useful in leprosy, leukaemias and other malignancies by non-specific stimulation of RE system. Dr.T.V.Rao MD 111
• Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 112

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Tuberculosis Teaching Basics

  • 1.
  • 2.
    HISTORY of Tuberculosis Tuberculosis Isan Ancient Disease Spinal Tuberculosis in Egyptian Mummies History dates to 1550 – 1080 BC Identified by PCR Dr.T.V.Rao MD 2
  • 3.
  • 4.
    What are Mycobacteria? •Obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lungs. • Facultative intracellular pathogens usually infecting mononuclear phagocytes (e.g. macrophages). Dr.T.V.Rao MD 4
  • 5.
    Classification of Mycobacteria 1.Tubercle bacilli a) Human – MTB b) Bovine – M. bovis c) Murine – M. microti d) Avian – M. avium e) Cold blooded – M. marinum 2. Lepra bacilli a) Human – M. leprae b) Rat – M. leprae murium 3. Mycobacteria causing skin ulcers a) M. ulcerans b) M. belnei 4. Atypical Mycobacteria (Runyon Groups) a) Photochromogens b) Scotochromogens c) Nonphotochromogens d) Rapid growers 4. Johne’s bacillus M. paratuberculosis 6. Saprophytic mycobacteria a) M. butyricum b) M. phlei c) M. stercoralis d) M. smegmatis e) Others Dr.T.V.Rao MD 5
  • 6.
    Mycobacterium differ fromother routinely isolated Bacteria • Slow-growing with a generation time of 12 to 18 hours (c.f. 20-30 minutes for Escherichia coli). • Hydrophobic with a high lipid content in the cell wall. Because the cells are hydrophobic and tend to clump together, they are impermeable to the usual stains, e.g. Gram's stain Dr.T.V.Rao MD 6
  • 7.
    Acid fast bacilli •Known as “Acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Dr.T.V.Rao MD 7
  • 8.
    How they areAcid fast • Once stained, the cells resist decolourization with acidified organic solvents and are therefore called "acid-fast". (Other bacteria which also contain mycolic acids, such as Nocardia, can also exhibit this feature.) Dr.T.V.Rao MD 8
  • 9.
    Mycobacterium tuberculosis complex •Includes Human and Bovine mycobacterium • M .Africanism Tropical Africa • M.microti do not cause human infections but in small mammals Dr.T.V.Rao MD 9
  • 10.
    M.bovis • Primarily infectionamong the cattle • M.bovis infects Tonsils, Cervical nodes, can produce Scrofula. • Enter through Intestines – infects the Ileocecal region. Dr.T.V.Rao MD 10
  • 11.
    What are atypicalMycobacteriumWhat are atypical Mycobacterium • Infects birds, cold blooded animals worm blooded animals • Present in environment • Opportunistic pathogens • Others – Saprophytic bacteria M butryicum present in butter M.phlei M smegmatis – present in Smegma Dr.T.V.Rao MD 11
  • 12.
    Atypical Mycobacterium • 1Photochromogens • 2 Scotochromogens • 3 Non Photochromogens • 4 Rapid growers Dr.T.V.Rao MD 12
  • 13.
    MOST IMPORTANT AMONG INFECTIOUSDISEASES • Tuberculosis (TB) is the leading cause of death in the world from a bacterial infectious disease. The disease affects 1.8 billion people/year which is equal to one- third of the entire world population. Dr.T.V.Rao MD 13
  • 14.
    Poverty and Crowdedliving spreads Tuberculosis Dr.T.V.Rao MD 14
  • 15.
    Tuberculosis infects Famouspeople too Dr.T.V.Rao MD 15
  • 16.
    What are Mycobacteria? •Obligate aerobes growing most successfully in tissues with a high oxygen content, such as the lungs. • Facultative intracellular pathogens usually infecting mononuclear phagocytes (e.g. macrophages). Dr.T.V.Rao MD 16
  • 17.
    General characters ofthe genus • Slender rods • Resist staining but once stained, resist decolonization by dilute mineral acids; hence called ACID FAST BACILLI (AFB) • Aerobic, Non-motile, Non-sporing, Non- capsulated. • Growth generally slow • Genus includes – Obligate parasites – Opportunist pathogens – Saprophytes Dr.T.V.Rao MD 17
  • 18.
    Morphology of Mycobacterium tuberculosis •Straight, slightly curved Rod shaped 3 x 0.3microns • May be single, in pairs or in small clumps • On conditions in growth appears as filamentous, club shaped, or in Branched forms. Dr.T.V.Rao MD 18
  • 19.
    ACID FAST BACILLI •Known as “Acid-fast bacilli" because of their lipid-rich cell walls, which are relatively impermeable to various basic dyes unless the dyes are combined with phenol. Dr.T.V.Rao MD 19
  • 20.
    Important MycobacteriumImportant Mycobacterium •Mycobacterium tuberculosis, along with M. bovis, M. africanum, and M. microti all cause the disease known as tuberculosis (TB) and are members of the tuberculosis species complex. Each member of the TB complex is pathogenic, but M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic for animalsDr.T.V.Rao MD 20
  • 21.
    Avian Tuberculosis • Transmittedby ingestion and inhalation of aerosolized infectious organisms from feces. • Oral ingestion of food and water contaminated with feces is the most common method of infection. • Once ingested, the organism spreads throughout the bird's body and is shed in large numbers in the feces. • If the bacterium is inhaled, pulmonary lesions and skin invasions may occur • transmission of avian TB is from bird to human not from human to human. Dr.T.V.Rao MD 21
  • 22.
    Acid Fast Bacilliseen in a specimen of Sputum Dr.T.V.Rao MD 22
  • 23.
  • 24.
    Acid fast Bacilliseen as in Florescent Microscope • After staining with Ziehl Neelsen method or Fluorescent method ( Auramine or Rhodamine they resist decolonization by 20% Sulphuric acid and absolute alcohol for 10 mt, • So called as Acid and Alchool fast. Dr.T.V.Rao MD 24
  • 25.
    Why they areAcid Fast • The character of Acid fastness is due to presence of Unsapnofiable wax ( Mcolic acid and semi permeable membrane around the cell)Dr.T.V.Rao MD 25
  • 26.
    MTB : Culturalcharacters • Grow slowly. Generation time 14-15 hrs • Colonies appear after 2 weeks or at 6-8 weeks • MTB - Obligate aerobe • MTB grows more luxuriantly (eugonic) than M. bovis (dysgonic). • Addition of 0.5% Glycerol supports growth of human strains. No effect or inhibitory effect on bovine strains. Dr.T.V.Rao MD 26
  • 27.
    Culturing Acid FastBacilli • Slow to grow , • Generation time is 14 – 15 hours • > 2 weeks minimal required period • Grows at 370 c do not grow below 250 c • Ph between 6.4 to 7.0 Dr.T.V.Rao MD 27
  • 28.
    Eight Week Growthof Mycobacterium tuberculosis on Lowenstein-Jensen Agar Dr.T.V.Rao MD 28
  • 29.
    Nature of MediaUsed • Helps the growth needs • Solid Medium is commonly used • Lowenstein Jensen’s medium • Petrangini • Middle brook mediumDr.T.V.Rao MD 29
  • 30.
    Lowenstein Jensen’s Medium •Contain coagulated egg • Mineral salt solution • Asparagine's • Malachite green • Agar Dr.T.V.Rao MD 30
  • 31.
    Other Medium •Middle brook •Sula'smedium •But not routinely used Dr.T.V.Rao MD 31
  • 32.
    Nature of GrowthCharactersNature of Growth Characters • M tuberculosis is obligate aerobe • M.bovis Microaerophilic • M.tuberculosis growth luxierently • M.tuberculosis eugonic • M bovis is dysgonic • When grown on 0.5% glycerin M tuberculosis growth improves • Sodium pyruvate improves the growth of both organism. Dr.T.V.Rao MD 32
  • 33.
    On L JMedium • M.tuberculosis appear dry, rough raised irregular colonies • Appear wrinkled • They appear creamy white • Become yellowish • M.bovis appear as flat smooth, moist, white and break up easily Dr.T.V.Rao MD 33
  • 34.
    Lowenstein Jensen Medium– Selective. Always in screw capped bottle. Bluish Green. Contains – Egg protein – Solidifying agent Mineral salts – Mg Sulphate, Mg citrate Asparagine Malachite Green – Selective agent Dr.T.V.Rao MD 34
  • 35.
    On Liquid Medium •Appearas long serpentine cords in liquid medium •Virulent strains grow in a more dispersedDr.T.V.Rao MD 35
  • 36.
    Resistance of Mycobacterium •Mycobacterium are killed at 600 c in 15 – 20 mt • In sputum they survive for 10 – 30 mt • Relatively resistant to several chemicals including Phenol 5 % • Sensitive to Glutaraldehyde and Formaldehyde • Ethanol is suitable application to superficial surfaces and skin gloves Dr.T.V.Rao MD 36
  • 37.
    Resistance to severalagents • Bacilli survive in Droplets for 8 – 10 days • Survive in 5% phenol, 15% Sulphuric acid 3% Nitric acid,5% oxalic acid, 4% Sodium hydroxide Dr.T.V.Rao MD 37
  • 38.
    Biochemical Tests onMycobacterium spp • Niacin test – 10% cyanogen's bromide and 4% Aniline in 96% ethanol are added to suspension of – C canary yellow color indicates positive test. Dr.T.V.Rao MD 38
  • 39.
    Other Tests • Arylsulphatase test – Positive in Atypical Mycobacterium • Bacilli grown in 0.001 tripotassium phenolpthalein disulphide / 2 N. Sodium hydroxide added drop by drop a pink color develops • Catalase peroxidase test – Differentiates Atypical from Typical Most Atypical are strongly Catalase positive Tubercle bacilli are weakly positive Tubercle bacilli are peroxidase positive – not atypical INH resistant strains are negative for testDr.T.V.Rao MD 39
  • 40.
    Catalase Test • 30Vol of H2O2 and 0.2 % alcohol in distilled water is added to 5 ml of test culture • Effervescence indicates Catalase positive • Other test Amidase test Nitrate reduction test Dr.T.V.Rao MD 40
  • 41.
    Antigenic Characters • Groupspecificity due to Polysaccharides • Type specificity to protein antigens • Delayed hypersensitivity to proteins • Related to each other species • Some relation between lepra and tubercle bacilli • Serology – Tests not useful Antigenic homogeneity between < bovis and M.microti Dr.T.V.Rao MD 41
  • 42.
    Bacteriophages • There are4 Bacteriophages A B C D • A worldwide • B. Europe and -American • C rare • I type nature between A and B and common in India • Phage 33 D M tuberculosis and not in BCG strains Dr.T.V.Rao MD 42
  • 43.
    Molecular Typing • DNAfinger printing differentiates different strains of Mycobacterium species • Treating the organism with Restriction endonuclease yields Nucleic acid fragments of varying length and strain specific • Use in epidemiological studies Dr.T.V.Rao MD 43
  • 44.
    Finger printing Methods •Finger printing is done with Chromosomal insertion sequence IS 6110 present in most strains of Tubercle bacilli • Now entire genome of M tuberculosis is sequenced • Several Molecular methods are available for studies Dr.T.V.Rao MD 44
  • 45.
  • 46.
    How tuberculosis spreads• Tuberculosis(TB) is a contagious disease. Like the common cold, it spreads through the air. Only people who are sick with TB in their lungs are infectious. When infectious people cough, sneeze, talk or spit, they propel TB germs, known as bacilli, into the air. A person needs only to inhale a small number of these to be infected. Dr.T.V.Rao MD 46
  • 47.
    Tuberculosis spread byRespiratory route Dr.T.V.Rao MD 47
  • 48.
    Tuberculosis highly Communicable Disease. •Someone in the world is newly infected with TB bacilli every second. • Overall, one-third of the world's population is currently infected with the TB bacillus. • 5-10% of people who are infected with TB bacilli (but who are not infected with HIV) become sick or infectious at some time during their life. People with HIV and TB infection are much more likely to develop TB. Dr.T.V.Rao MD 48
  • 49.
    In India 1death / Minute • Half a million people die from disease every year in India one death every minute Dr.T.V.Rao MD 49
  • 50.
    Pathology and Pathogenesisof Tuberculosis • Source of Infection – Open case of Pulmonary Tuberculosis. • Every open case has potential to infect 20 – 25 healthy persons before cured or dies • Coughing , Sneezing, or Talking. • Each act can spill 3000 infective nuclei in the air, • Infective particles are engulfed by Alveolar Macrophages. Dr.T.V.Rao MD 50
  • 51.
  • 52.
    Generation of DropletNuclei • One cough produces 500 droplets • The average TB patient generates 75,000 droplets per day before therapy • This falls to 25 infectious droplets per day within two weeks of effective therapy Dr.T.V.Rao MD 52
  • 53.
  • 54.
    Predisposing Factors • Geneticbasis, • Age • Stress, • Nutrition, • Co existing infections Eg HIV Dr.T.V.Rao MD 54
  • 55.
    Mechanisms of Infection •Mycobacterium do not produce toxins. • Allergy and Immunity plays the major role. • Only 1/10 of the infected will get disease. • Cell Mediated Immunity plays a crucial role. • Humoral Immunity – not Important. • CD4Cell plays role in Immune Mechanisms. Dr.T.V.Rao MD 55
  • 56.
    Mechanisms of Infection •Within 10 days of entry of Bacilli clones of Antigen specific T Lymphocytes are produced • Can actively produce Cytokines, Interferon γ which activate Macrophages form cluster or Granuloma Dr.T.V.Rao MD 56
  • 57.
    Tubercle with CaseousNecrosis Giant cells Tubercle bacilli Partially activated macrophage Lymphocyte Fully activated macrophage Dr.T.V.Rao MD 57
  • 58.
    Basis of Tubercleformation. • Tubercle is a Avascular granuloma Contain central zone of giant cells with or without caseation and peripheral zone of Lymphocytes and Fibroblasts. • Produce lesions may be Exudative or Productive Dr.T.V.Rao MD 58
  • 59.
    Diagram of a Granuloma NOTE:ultimately a fibrin layer develops around granuloma (fibrosis), further “walling off” the lesion. Typical progression in pulmonary TB involves caseation, calcification and cavity formation. Dr.T.V.Rao MD 59
  • 60.
    Tubercle discharging Bronchial tree TNF-αTNF- α Dr.T.V.Rao MD 60
  • 61.
    Immunity in Tuberculosis. •CD4 T Lymphocytes with Th 1 or Th 2 secrete - 1 Cytokines,2 Interleukin 1,and 2 , 3 Interferon's γ , 4.Tumor necrosis factor. • The mechanisms with Th 1 secrete Cytokines Activate Macrophages Results in protective Immunity, and contain Infection. Th 2 manifests with Delayed Hypersensitivity DTH causes Tissue destruction. and disease will progress. . Dr.T.V.Rao MD 61
  • 62.
    Immunity in Tuberculosis ActivatedMacrophages - Epitheliod cells Forms cluster a granuloma Activated macrophages turn into Giant cells. Granuloma contains necrotic tissue Dead macrophages cheese like caseation. Apoptosis of bacteria laden cells Contribute to protective immunity. Dr.T.V.Rao MD 62
  • 63.
    Lesions in Tuberculosis •Exudative – and Productive • Exudative – Acute inflammatory reaction with edema fluid – contains Polymorphs- Lymphocytes – later Mononuclear cells. Bacilli are virulent - Host responds with DTH Injurious. Productive Type protective ImmunityDr.T.V.Rao MD 63
  • 64.
    Primary Tuberculosis • Initialresponse • In Endemic countries Young children • Events of Primary complex 1 Bacilli are engulfed by Alveolar Macrophages 2 Multiply and give raise to Sub pleural focus of Tuberculosis,Pneumonia,involve lower lobes and lower part of upper lobes. Called as Ghon’s focus. The Hilar Lymph nodes are also involved Dr.T.V.Rao MD 64
  • 65.
    Primary complex • Thisis known as the primary complex or primary infection. The patient will heal and a scar will appear in the infected loci. There will also be a few viable bacilli/ may remain in these areas (particularly in the lung). The bacteria at this time goes into a dormant state, as long as the person's immune system remains active and functions normally this person isn't bothered by the dormant bacillus. Dr.T.V.Rao MD 65
  • 66.
    Primary complex • Ghon’sfocus with Enlarged lymph nodes appear after 3- 8 weeks after infection. • Heals in 2 – 6 months calcified, • Some bacteria remain alive and produce latent infections. • Infection activated in Immunosuppressed conditions Eg. HIV infections and AIDS • Can produce Meningitis, Miliary tuberculosis, other disseminated Tuberculosis. Dr.T.V.Rao MD 66
  • 67.
    Reactivation of Tuberculosis •When a person's immune system is depressed., a secondary reactivation occurs. 85-90% of the cases seen which are of secondary reactivation type occurs in the lungs. Dr.T.V.Rao MD 67
  • 68.
    Koch’s Phenomenon • Tuberculosisinfected Guinea pig if injected with Living Tubercle bacilli • The site around the injection becomes necrotic. • Koch found the same reaction when injected with old Tuberculin ( heated and concentration of the tubercle bacilli ) • It has produced the same reaction • This is called as Koch’s Phenomenon. Dr.T.V.Rao MD 68
  • 69.
    Post Primary Tuberculosis •Mainly occurs due to Reactivation of Latent infection. • May also due to Exogenous reinfection • Differs from Primary Infection. • Leads to – Cavitation's of Lungs, Enlargement of Lymph nodes, Expectoration of Bacteria laden sputum Dissemination into Lungs and other extra pulmonary areas. Dr.T.V.Rao MD 69
  • 70.
    Majority of theTuberculosis are Pulmonary Dr.T.V.Rao MD 70
  • 71.
  • 72.
    Complication of Tuberculosis. 1.Meningitis. 2. Pleurisy, 3. Involvement of Kidney, 4. Spine ( Potts spine ) 5. Bone Joints, 6. Miliary tuberculosis Dr.T.V.Rao MD 72
  • 73.
    Symptoms and Singsof Tuberculosis Dr.T.V.Rao MD 73
  • 74.
    Clinical Illness withTuberculosis • Pulmonary Disease – Major manifestation with involvement of Lungs Hemoptysis, Chest pain Fever sweets Anorexia Cavity formation in Lungs Dr.T.V.Rao MD 74
  • 75.
  • 76.
    Extra pulmonary Tuberculosis •Bacteria on circulation leads to bacteremia leads to involvement of GUT, Genito urinary system, Meningitis Gastro Intestinal system, skin, Lymph nodes Bone marrow. Spinal infection Potts spine, Arthritis Dr.T.V.Rao MD 76
  • 77.
  • 78.
    Multidrug-resistant tuberculosis (MDR-TB) • Drugresistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Dr.T.V.Rao MD 78
  • 79.
    Definition of MDRTuberculosis • MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD). XDR-TB is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin). Dr.T.V.Rao MD 79
  • 80.
    MDR tuberculosis dangerousto Society too • Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals Dr.T.V.Rao MD 80
  • 81.
    X- MDR • Theterm ‘totally drug resistant’ has not been clearly defined for tuberculosis. XDR-TB severely reduces the options for treatment although they have not been studied in large cohorts. Treatment options for XDR-TB patients who have resistance to additional second-line anti- TB drugs are even more limited. Dr.T.V.Rao MD 81
  • 82.
    Epidemiology • An ancientdisease, called as white plague • 1/3 of the world population is infected • 2 billion infected • Each year 9 lakhs to 1 million are infected • Poor nations phase the burnt of the disease. • In developing world > 4o% of the population is effected • 15 million suffer the disease • 3 million are highly infective. Dr.T.V.Rao MD 82
  • 83.
  • 84.
    Types of specimens: -Sputum. -BAL. -Pleural effusions - Urine - Stool -CSF -Aspiration ( gastric – cold abscess) - Blood in case of haematogenous TB Dr.T.V.Rao MD 84
  • 85.
    85 Sputum Collection • Sputumspecimens are essential to confirm TB – Specimens should be from lung secretions, not saliva • Collect 3 specimens on 3 different days • Spontaneous morning sputum more desirable than induced specimens • Collect sputum before treatment is initiated
  • 86.
    86 Culture • Used toconfirm diagnosis of TB • Culture all specimens, even if smear is negative • Initial drug isolate should be used to determine drug susceptibility
  • 87.
    Laboratory Diagnosis 1- Sputumsmears stained by Z-N stain Three morning successive mucopurulent sputum samples are needed to diagnose pulmonary TB. Advantage: - cheap – rapid - Easy to perform - High predictive value > 90% - Specificity of 98% Disadvantages: - sputum ( need to contain 5000-10000 AFB/ ml.) - Young children, elderly & HIV infected persons may not produce cavities & sputum containing AFB. Dr.T.V.Rao MD 87
  • 88.
    2- Detecting AFBby fluorochrome stain using fluorescence microscopy: The smear may be stained by aura mine-O dye. In this method the TB bacilli are stained yellow against dark background & easily visualized using florescent microscope. Advantages: - More sensitive - Rapid Disadvantages: - Hazards of dye toxicity - more expensive - must be confirmed by Z-N stain Dr.T.V.Rao MD 88
  • 89.
    Quantitation of AFBin Sputum Smears • No of Bacilli No of Fields Report as • 0 300 Negative • 1-2 300 Doubtful • 1- 9 100 1+ • 1- 9 10 2+ • 1-9 1 3+ • 10 or >10 1 4+ Dr.T.V.Rao MD 89
  • 90.
    Lowenstein–Jensen medium • Whengrown on LJ medium, M. tuberculosis appears as brown, granular colonies (sometimes called "buff, rough and tough"). The media must be incubated for a significant length of time, usually four weeks, due to the slow doubling time of M. tuberculosis Dr.T.V.Rao MD 90
  • 91.
    3- Cultures onL J media Lowenstein –Jensen medium is an egg based media with addition of salts, 5 % glycerol, Malachite green. Advantages: - Specificity about 99 % - More sensitive (need lower no. of bacilli 10-100 / ml) - Can differentiate between TB complex & NTM using biochemical reactions - Sensitivity tests for antituberculous drugs ( St, INH, Rif., E) Disadvantages: Slowly growing ( up to 8 weeks ) Dr.T.V.Rao MD 91
  • 92.
    Detection and identificationof mycobacteria directly from clinical samples • Genotypic Methods : • 􀂄 PCR • 􀂄 LAMP • 􀂄 TMA / NAA • 􀂄 Ligase chain reaction • 􀂄 Phenotypic Methods : • 􀂄 FAST Plaque TB Dr.T.V.Rao MD 92
  • 93.
    • Essentially PCRis a way to make millions of identical copies of a specific DNA sequence , which may be a gene, or a part of a gene, or simply a stretch of nucleotides with a known DNA sequence, the function of which may be unknown Polymerase Chain Reaction (PCR) Dr.T.V.Rao MD 93
  • 94.
    • Interferon-γ assays measurecell- mediated immunity by quantifying IFN-γ released from sensitized T cells in whole blood/PBMCs incubated with TB antigens. Quantiferon-GOLD Dr.T.V.Rao MD 94
  • 95.
    Tuberculin Test Interpretation: * Apositive test indicates previous exposure and carriage of T.B. * A negative tuberculin test excludes infection in suspected persons * Tuberculin positive persons may develop reactivation type of T.B. * Tuberculin negative persons are at risk of gaining new infection * False positive reactions are mainly due to: - Infection with nontuberculous mycobacteria * Dr.T.V.Rao MD 95
  • 96.
    * False negativereactions may be due to: - • False negative reactions may be due to: • - Sever tuberculosis infection (Miliary T.B.) - Hodgkin’s disease • - Corticosteroid therapy - Malnutrition - AIDS • * Children below 5 years of age with no exposure history: • - Positive test must be regarded suspicious Dr.T.V.Rao MD 96
  • 97.
    Tuberculin Test ( MantouxTest ) • Test to be interpreted in relation to clinical evaluation. • Even the induration of 5 mm to be considered positive when tested on HIV patients. • Lacks specificity.
  • 98.
    Tuberculin Testing -Limitations • False positive reactions are mainly due to: • - Infection with nontuberculous mycobacteria • * False negative reactions may be due to: • - Sever tuberculosis infection (Miliary T.B.) - Hodgkin’s disease • - Corticosteroid therapy - Malnutrition - AIDS • * Children below 5 years of age with no exposure history: • - Positive test must be regarded suspicious Dr.T.V.Rao MD 98
  • 99.
    Recent Methods forDiagnosis I – BACTEC 460 ( rapid radiometric culture system ) specimens are cultured in a liquid medium (Middle brook7H9 broth base )containing C14 – labeled palmitic acid & PANTA antibiotic mixture. Growing mycobacteria utilize the acid, releasing radioactive CO2 which is measured as growth index (GI) in the BACTEC instrument. The daily increase in GI output is directly proportional to the rate & amount of growth in the medium. Dr.T.V.Rao MD 99
  • 100.
    III Polymerase ChainReaction (PCR) & Gene probe Nucleic acid probes & nucleic acid amplification tests in which polymerase enzymes are used to amplify ( make many copies of specific DNA or RNA sequences extracted from mycobacterial cells. Advantages: - Rapid procedure - High sensitivity (1-10 ( 3 – 4 hours) bacilli / ml sputum) Dr.T.V.Rao MD 100
  • 101.
    Tuberculosis and HIVinfection • HIV association has become a threat to the developed countries too • HIV association will lead to rapid spread of tuberculosis Dr.T.V.Rao MD 101
  • 102.
    HIV Considerations • HIVis the strongest risk factor for progression to active disease • HIV kills CD4+ T Helper cells which normally inhibit M. tuberculosis • HIV interferes with PPD skin test • Protease inhibitors interfere with rifampin Dr.T.V.Rao MD 102
  • 103.
    MDR tuberculosis • Multidrugresistant tuberculosis has become a global threat. • In 1993 WHO declared Tuberculosis a Global emergency • Animals shed the bacilli in Milk, human’s get infected after drinking the unsterilized Milk • Pasteurization has reduced the incidence of Bovine tuberculosis. Dr.T.V.Rao MD 103
  • 104.
    Second Line DrugTreatment (SLD’s) Less effective, more costly and more toxic, 50% cure rate • Four months intensive phase (5 drugs) – Kanamycin – Ethionamide – Pyrazinamide – Ofloxacin – Cycloserine or Ethambutol • 7X times p/w in hospital » Followed by
  • 105.
    Why Tuberculosis continuesto be Important • Someone in the world is newly infected with TB bacilli every second. • Overall, one-third of the world's population is currently infected with the TB bacillus. • 5-10% of people who are infected with TB bacilli (but who are not infected with HIV) become sick or infectious at some time during their life. People with HIV and TB infection are much more likely to develop TB. Dr.T.V.Rao MD 105
  • 106.
    March 24th World TBDay Dr.T.V.Rao MD 106
  • 107.
    Treatment Drugs used : 1-First line drugs : - Isoniazid - Rifampicin - Pyrazinamide - Ethambutol - Streptomycin 2- Second line drugs (more toxic and less effective): - Kanamycin - capreomycin - Cycloserin - ethionamide - ciprofloxacin - Ofloxacin * Noncompliance (failure to complete the course): Directly observed therapy (DOT) Health care workers observe the medication Dr.T.V.Rao MD 107
  • 108.
    Directly Observed Therapy– Short Course • DOTS (directly observed treatment, short- course), is the name given to the World Health Organization-recommended tuberculosis control strategy that combines components: • Case detection by sputum smear microscopy • Standardized treatment regimen directly observed by a healthcare worker or community health worker for at least the first two months Dr.T.V.Rao MD 108
  • 109.
    Immuno-prophylaxis • Intradermal injectionof live attenuated vaccine Bacille Calmette-Guerin (BCG). • The strain causes self limited lesion and induces hypersensitivity & immunity. • Coverts tuberculin negative person to positive reactor. • Immunity lasts for 10-15 years. Immunity 60- 80% • Some studies proved BCG is doubtful value in prevention of Tuberculosis Dr.T.V.Rao MD 109
  • 110.
    Bacillus Calmette-Guérin (BCG) •Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured (230 passages) in an artificial medium for 13 years, Dr.T.V.Rao MD 110
  • 111.
    BCG • Given atbirth without tuberculin testing • Protects against TB, the disease runs milder course in protected, prevents skeletal, meningeal & miliary forms. • Also found useful in leprosy, leukaemias and other malignancies by non-specific stimulation of RE system. Dr.T.V.Rao MD 111
  • 112.
    • Programme Createdby Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 112

Editor's Notes

  • #53 The most important mechanism by which infectious droplets are produced is coughing. However, any vigorous expiratory maneuver such as sneezing, singing, talking or even quiet breathing, can also produce infectious droplets. One of the ways in which treatment reduces infectiousness is to rapidly decrease cough. [Image Credit: Andrew Davidhazy, School of Photo Arts and Sciences/RIT. ]
  • #86 Appendix 12 - Fundamentals of TB Presentation
  • #87 Appendix 12 - Fundamentals of TB Presentation