module 1 pneumology

*1Transmission and Pathogenesis of Tuberculosis

Module 1 Transmission and Pathogenesis of Tuberculosis

Module 1 Transmission and Pathogenesis of Tuberculosis*Module 1: Objectives

Briefly describe the history of tuberculosis (TB)

Explain how TB is spread (transmission)

Define drug-resistant TB

Explain the difference between latent TB infection (LTBI) and TB disease

Explain how LTBI and TB disease develop (pathogenesis)

Describe the classification system for TB


*History of TB


Module 1 Transmission and Pathogenesis of Tuberculosis*TB has affected humans for millennia

Historically known by a variety of names, including:ConsumptionWasting diseaseWhite plague

TB was a death sentence for manyHistory of TB (1)Vintage image circa 1919Image credit: National Library of Medicine


HISTORYBone lesions in mummified skeletons since 1,000 BCHippocrates - term phthisis meaning consumption Tuberculosis comes from tubercules (fr.)- describing the clinical lesionsMiddle Ages- White Plague having TB was the equivalent of a death sentence1882 24th March- the German pathologist Robert Koch identified the TB bacillus Mycobacterium tuberculosis1907 - Development of the first vaccine BCG 1944 Chemotherapy using the single antibiotic to treat active TB1950s Multiple drug chemotherapy


ROBERT KOCH 1882


Module 1 Transmission and Pathogenesis of Tuberculosis*Until mid-1800s, many believed TB was hereditary

1865 Jean Antoine-Villemin proved TB was contagious

1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosisImage credit: Janice Haney CarrHistory of TB (2)Scientific Discoveries in 1800s


Module 1 Transmission and Pathogenesis of Tuberculosis*Before TB antibiotics, many patients were sent to sanatoriums

Patients followed a regimen of bed rest, open air, and sunshine

TB patients who could not afford sanatoriums often died at homeHistory of TB (3)SanatoriumsSanatorium patients resting outside


Nobel Prizes for Medicine is awarded to those who have conferred the greatest benefit of mankind in the field of medicine 1882 dr. Robert Koch discovery of the TB bacillus1908 dr. Paul Ehrlich use of drugs to combat infection1939 dr. Gerhard Domagk discovery of first anti TB drug Prontosil1952 dr. Selman Waksman development of SM as a drug cure for TB


TB MEDICATIONp-aminosalicylic acid (1946),isoniazid (1952), pyrazinamide (1954), cycloserine (1955), ethambutol (1962) rifampicin (1963)


Module 1 Transmission and Pathogenesis of Tuberculosis*Breakthrough in the Fight Against TBAfter 1960, TB death rates began to drop dramatically

Each year, fewer people got TB

Many TB sanatoriums had closed by mid 1980s


Module 1 Transmission and Pathogenesis of Tuberculosis*TB ResurgenceIncrease in TB in mid 1980s

Contributing factors:Inadequate funding for TB control programsHIV epidemicIncreased immigration from countries where TB is commonSpread in homeless shelters and correctional facilitiesIncrease and spread of multidrug-resistant TB

March 16, 1992 Newsweek Magazine Cover


Module 1 Transmission and Pathogenesis of Tuberculosis*TB History Timeline


*TB Transmission


Module 1 Transmission and Pathogenesis of Tuberculosis*

Transmission is defined as the spread of an organism, such as M. tuberculosis, from one person to another.

TB Transmission (1)


Module 1 Transmission and Pathogenesis of Tuberculosis*M. tuberculosis causes most TB cases

Mycobacteria that cause TB:M. tuberculosis M. bovisM. africanumM. microtiM. canetti

Mycobacteria that do not cause TBM.avium complex, M.xenopi, M.Kansasi M. tuberculosisTB Transmission (2)Types of Mycobacteria


TB Transmission (3)Since TB is a disease of respiratory transmission, optimal conditions for transmission include: overcrowding poor personal hygiene poor public hygiene

Module 1 Transmission and Pathogenesis of Tuberculosis*TB is spread person to person through the air via droplet nuclei

M. tuberculosis may be expelled when an infectious person:CoughsSneezesSpeaks Sings

Transmission occurs when another person inhales droplet nucleiTB Transmission (4)


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Transmission (5)Dots in air represent droplet nuclei containingM. tuberculosis


Module 1 Transmission and Pathogenesis of Tuberculosis*Probability that TB will be transmitted depends on:Infectiousness of person with TB diseaseEnvironment in which exposure occurredLength of exposureVirulence (strength) of the tubercle bacilli

The best way to stop transmission is to:Isolate infectious personsProvide effective treatment to infectious persons as soon as possibleTB Transmission (6)


MYCOBACTERIUM TUBERCULOSISis the etiologic agent of tuberculosisin humans.is a fairly large nonmotile rod-shaped bacteriumis an obligate aerobe is a facultative intracellular parasite has a slow generation time


Mycobacterium tuberculosisserpentine cords not classified as either Gram-positive or Gram-negative

acid-fast bacteria resist de staining by acid-alcohol after being stained by certain aniline dyes

Mycobacterium tuberculosis. Acid-fast stain. CDC.


Mycobacterium tuberculosisImpermeability to stains and dyesResistance to many antibiotics Resistance to killing by acidic and alkaline compounds Resistance to osmotic lysis via complement depositionResistance to lethal oxidations and survival inside of macrophages


The cell wall structure of MtThere is no true outer membrane in M.TuberculosisThe cell wall complex contains peptidoglycan, arabinogalactan and mycolic acid and lipoarabinomannan. Over 60% of the mycobacterial cell wall is lipidMycolic acid 50% of the dry weight of the cell wallIt is strong hydrophobicConsidered an important determinant of virulence


Growth characteristics Very slow growth rate generation time of 20- 24 hrsGrow on simple carbon and inorganic nitrogen sources Rough, non-pigmented corded colonies, with a weak catalase activity and reduces nitrate

Types of media:Albumin in an agar base Lowenstein-JensenPotato and egg base media- MiddlebrockBroth based culture systems for improvement in speed and sensitivityBACTECMGITSepti Check AFBCAMLIC ( Continuosly Automated Mycobacterial Liquid Culture system)


Mycobacterium tuberculosisHas a particular predilection for the lungsHas special mechanisms for cell entry.Can grow intracellularlyInterferes with the toxic effects of reactive oxygen


VIRULENCE MECHANISMS AND FACTORS common for nearly all mycobacteriaMycolic acid glicolipids can elicit granuloma formationCatalase-peroxidase - resist the host cell oxidative response Sulfatides and trehalose dimycolate - trigger toxicity in animal models


Mycobacterium tuberculosisInhalation and deposition in the lungs of the bacillus leads to:Clearance of the organism orlatent infection orRapid progressive disease (primary disease)Active disease many years after the infection (reactivation disease)


*Drug-Resistant TB


Module 1 Transmission and Pathogenesis of Tuberculosis*Caused by M.tuberculosis organisms resistant to at least one TB treatment drug

Isoniazid (INH) (HIN)Rifampin (RIF)Pyrazinamide (PZA)Ethambutol (EMB)

Resistant means drugs can no longer kill the bacteriaDrug-Resistant TB (1)


Module 1 Transmission and Pathogenesis of Tuberculosis*Drug-Resistant TB (2)

Primary ResistanceCaused by person-to-person transmission of drug-resistant organismsSecondary ResistanceDevelops during TB treatment:

Patient was not given appropriate treatment regimen OR Patient did not follow treatment regimen as prescribed


Module 1 Transmission and Pathogenesis of Tuberculosis*Drug-Resistant TB (3)

Mono-resistantResistant to any one TB treatment drugPoly-resistantResistant to at least any 2 TB drugs (but not both isoniazid and rifampin)Multidrug resistant (MDR TB)Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugsExtensively drug resistant (XDR TB)Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)


*TB Pathogenesis


Module 1 Transmission and Pathogenesis of Tuberculosis*

Pathogenesis is defined as how an infection or disease develops in the body.TB Pathogenesis (1)


Module 1 Transmission and Pathogenesis of Tuberculosis*Occurs when tubercle bacilli are in the body, but the immune system is keeping them under control

Detected by the Mantoux tuberculin skin test (TST) or by blood tests such as interferon-gamma release assays (IGRAs) which include:

QuantiFERON-TB Gold test (QFT-G)QuantiFERON-TB Gold In-Tube (QFT-GIT)T-Spot.TB test (T-SPOT)

People with LTBI are NOT infectiousTB Pathogenesis (2)Latent TB Infection (LTBI)


Module 1 Transmission and Pathogenesis of Tuberculosis*Develops when immune system cannot keep tubercle bacilli under control

May develop very soon after infection or many years after infection

About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives

People with TB disease are often infectiousTB Pathogenesis (3)TB Disease


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Pathogenesis (4)Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to alveoli


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Pathogenesis (5)Tubercle bacilli multiply in alveoli, where infection begins


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Pathogenesis (6)A small number of tubercle bacilli enter bloodstream and spread throughout body


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Pathogenesis (7)LTBIWithin 2 to 8 weeks the immune system produces immune cells (macrophages, T lymphocytes, giant cells, epithelioid cells) that surround the tubercle bacilli

These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Pathogenesis (8)TB DiseaseIf the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease

This process can occur in different places in the body


Stages of TB pathogenesis (1)Droplet nuclei are inhaled and need to reach the alveolar space.7-21 days after initial infection mycobact tuberculosis multiplies within macrophages until the macrophages burst.Then:T cell activation and liberation of cytokines, including gamma interferonthe individual becomes tuberculin-positiveactivated macrophages may release lytic enzymes and cytokines tubercle formation begins


Stages of TB pathogenesis (2)This is known as the primary infection. The patient will heal and a scar will appear in the infected sites. There will also be a few viable bacilli/spores 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.

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.


Stages of TB pathogenesis (3) When a person's immune system is weak,Progressive destruction occurs: bacterial products, tumor necrosis factor, reactive oxygen intermediates and reactive nitrogen intermediates, contents of cytotoxic cells - caseous necrosisBacilli may spread hematogenously to produce disseminated TBBacilli may spread mechanically into lung airways!


Untreated80% will dieRecoverChronic disease repeated episodes of spontan healing by fibrotic changes around the lessionsReactivation disease persistent bacteria suddenly proliferate disease process is localized, lesion located at the lung apices, with less dissemination


Module 1 Transmission and Pathogenesis of Tuberculosis*LTBI vs. TB Disease

Latent TB Infection (LTBI)TB Disease (in the lungs)Inactive, contained tubercle bacilli in the bodyActive, multiplying tubercle bacilli in the body TST or blood test results usually positive TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not infectious Often infectious before treatment Not a case of TB A case of TB


*TB Pathogenesis

Progression from LTBI to TB Disease


Module 1 Transmission and Pathogenesis of Tuberculosis*Progression to TB Disease (1)Risk of developing TB disease is highest the first 2 years after infection

People with LTBI can be given treatment to prevent them from developing TB disease Detecting TB infection early and providing treatment helps prevent new cases of TB disease


Module 1 Transmission and Pathogenesis of Tuberculosis*Infection with HIV

Chest x-ray findings suggestive of previous TB

Substance abuse

Recent TB infection

Prolonged therapy with corticosteroids and other immunosuppressive therapy, such as prednisone and tumor necrosis factor-alpha [TNF-] antagonistsOrgan transplant

Silicosis

Diabetes mellitus

Severe kidney disease

Certain types of cancer

Certain intestinal conditions

Low body weight Some conditions increase probability of LTBI progressing to TB diseaseProgression to TB Disease (2)


Module 1 Transmission and Pathogenesis of Tuberculosis*Progression to TB Disease (3)People Exposed to TBNot TB InfectedLatent TB Infection (LTBI)Not InfectiousPositive TST or QFT-G test resultLatent TB InfectionMay go on to develop TB diseaseNot InfectiousNegative TST or QFT-G test resultNo TB InfectionFigure 1.5


Module 1 Transmission and Pathogenesis of Tuberculosis*In an HIV-infected person,TB can develop in one oftwo ways:

Person with LTBI becomes infected with HIV and then develops TB disease as the immune system is weakened

Person with HIV infection becomes infected with M. tuberculosis and then rapidly develops TB disease

Progression to TB Disease (4) TB and HIVImage credit: Mississippi State Department of Health


Module 1 Transmission and Pathogenesis of Tuberculosis*Progression to TB Disease (5)TB and HIVPeople who are infected with both M.tuberculosis and HIV are much more likely to develop TB disease

TB infection and NO risk factorsTB infection and HIV infection (pre-Highly Active Antiretroviral Treatment [HAART]) Risk is about 5% in the first 2 years after infection and about 10% over a lifetimeRisk is about 7% to 10% PER YEAR, a very high risk over a lifetime


*TB Pathogenesis

Sites of TB Disease


Module 1 Transmission and Pathogenesis of Tuberculosis*Sites of TB Disease (1)Bacilli may reach any part of the body, but common sites include:


Module 1 Transmission and Pathogenesis of Tuberculosis*Sites of TB Disease (2)

LocationFrequencyPulmonary TBLungsMost TB cases are pulmonaryExtrapulmonary TBPlaces other than lungs such as: Larynx Lymph nodes Pleura Brain Kidneys Bones and jointsFound more often in:

HIV-infected or other immunosuppressed persons

Young childrenMiliary TBCarried to all parts of body, through bloodstreamRare


*TB Pathogenesis

TB Classification System


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Classification System (1)Based on pathogenesis of TB

ClassTypeDescription0No TB exposureNot infected No history of TB exposureNegative result to a TST or IGRA 1TB exposureNo evidence of infection History of TB exposureNegative result to a TST (given at least 8-10 weeks after exposure) or IGRA2TB infection No TB diseasePositive result to a TST or IGRA Negative smears and cultures (if done)No clinical or x-ray evidence of activeTB disease


Module 1 Transmission and Pathogenesis of Tuberculosis*TB Classification System (2)Based on pathogenesis of TB

ClassTypeDescription3TB, clinically active Positive culture (if done) for M.tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease 4Previous TB disease (not clinically active) Medical history of TB diseaseAbnormal but stable x-ray findings Positive result to a TST or IGRA Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease 5TB suspected Signs and symptoms of TB disease, but evaluation not complete


Module 1 Transmission and Pathogenesis of Tuberculosis*Module 1: Case Study (1)

A 30-year-old man visits the health department for a TST because he is required to have one before starting his new job as a health care worker. He has an 18mm positive reaction to the TST. He has no symptoms of TB, and his chest x-ray findings are normal. (pg. 16)


Module 1 Transmission and Pathogenesis of Tuberculosis*Module 1: Case Study (2)Should this be considered a case of TB?

No. The man described above has TB infection. He has an 18mm positive reaction to TST, but no evidence of TB disease. Therefore, this is not a case of TB.

Should this man be considered infectious?

No, he should not be considered infectious. This man has LTBI, not TB disease. People with TB infection and no evidence of TB disease are not infectious.


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