Tuberculosis is caused by infection with Mycobacterium tuberculosis bacteria, which most often affects the lungs. It spreads through the air when people who have active TB in their lungs cough, sneeze, speak, or sing. Only those with active lung infection are infectious. Most exposed people will develop latent TB infection without symptoms, but around 10% will develop active TB disease, especially if their immune system is weakened.

2. Dr. Ashraf El Adawy
Consultant Chest Physician
TB TEAM EXPERT – WHO
Mansoura-Egypt
Basic concepts of Tuberculosis

3. What is Tuberculosis
Tuberculosis (TB) is an infectious granulomatous disease caused by Mycobacterium tuberculosis human type or rarely M. bovis.
TB disease most often affects the lungs, but can occur anywhere in the body.

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TB Transmission

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M. tuberculosis causes most TB cases .
Mycobacteria that cause TB:
–M. tuberculosis
–M. bovis
–M. africanum
–M. microti
–M. canetti
Mycobacteria that do not cause TB
–e.g., M. avium complex
M. tuberculosis
Types of Mycobacteria

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TB is spread person to person through the air via droplet nuclei
M. tuberculosis may be expelled when an infectious person:
–Coughs
–Sneezes
–Speaks
–Sings
Transmission occurs when another person inhales droplet nuclei

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Dots in air represent droplet nuclei containing
M. tuberculosis

8. Number of Droplets produced by DifferentAerosol Producing Maneuvers Number of droplets 01000020000300004000050000CoughingTalkingSingingLoudon RG, et al. Am Rev Respir Dis 1968;98:297-300

9. Characteristics of an infectious patient
Patient must be able to produce airborne infectious droplets.
It requires some 5,000 bacilli in 1 ml. of sputum to yield positive a smear, and 10,000 to identify a smear as positive with a 95% probability.
Patients with a positive smear are by far more infectious than those with a negative one and positive culture.
Probability of becoming infected varies depending on the distance between source and receptor.

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Probability that TB will be transmitted depends on: Infectiousness of person with TB disease Environment in which exposure occurred Length of exposure Virulence (strength) of the tubercle bacilli
Not Everyone Exposed Becomes Infected

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Infectiousness - 1
Patients should be considered infectious if they:
–Are undergoing cough-inducing procedures
–Have sputum smears positive for acid-fast bacilli (AFB) and:
Are not receiving treatment
Have just started treatment, or
Have a poor clinical or bacterial response to treatment
–Have cavitary disease
Extrapulmonary TB patients are not infectious

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Infectiousness - 2
Patients are not considered infectious if they meet all these criteria:
–Received adequate treatment for 2-3 weeks
–Favorable clinical response to treatment
–3 consecutive negative sputum smears results from sputum collected on different days

13. Extra-pulmonary cases are almost not infectious, unless they have pulmonary tuberculosis as well.
Individuals with latent tuberculosis infection are not infectious, as they do not have replicating bacteria and cannot transmit the organism.
Direct sunlight quickly kills tuberculosis bacilli, but they can survive in the dark for several hours.
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14. Factors Affecting Pathogenicity
Active Infection
-Only individuals with an active infection can transmit the disease Transmission
-Aerosolized droplets need to be <10μm in order to evade the ciliated epithelium of the lung to establish infection in the terminal alveoli Growth & Structure
-Only require a very few number of bacteria to establish an infection (1-10 bacteria)
M. Tuberculosis in sputum (stained in red)

15.  Tuberculosis is usually spread from person-to- person through the air by droplet nuclei that are produced when a person with pulmonary or laryngeal tuberculosis coughs, sneezes or sings.
Droplet nuclei may also be produced by aerosol- producing investigations such as sputum induction, bronchoscopy and through manipulation of lesions or processing of tissue or secretions in the laboratory.
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16. The larger droplets containing higher numbers of bacteria do not serve as effective vehicles for TB transmission as they do not remain airborne for long periods.
If they are inhaled, they do not reach the alveoli because they deposit in the upper airways where they are trapped in the mucous blanket, carried by muco-ciliary action to the oropharynx and swallowed or expectorated.
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17. Micro-droplets, 1 to 5 μm in diameter containing 1-5 bacilli, are highly infectious.
They can remain suspended in air for long periods of time. These droplets are small enough to reach the alveolar spaces within the lungs, where the organisms replicate.
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18. Exposure Time
-Most infected individuals expel relatively few bacilli, transmission of TB usually occurs only after prolonged exposure to someone with active TB.
-On average, 50% of people are likely to become infected with TB if they spend 8hrs/day for six months or 24hrs/day for two months working or living with someone with active TB.

19. Health of Individuals
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-Active TB typically occur in individuals whose immune systems have been weakened by age, disease, improper nutrition or use of immunosuppresive drugs.

20. The susceptible individual
Compromised immune system
HIV
Diabetic
Steroid therapy
Chemotherapy (cancer)
Children <5years
Poor nutrition

21. The environment
Presence of someone with active TB disease who is not on effective therapy ( undiagnosed, untreated, non-compliant, unrecognized drug resistance)
Exposure of susceptible individuals to an infectious person in small enclosed settings
Inadequate ventilation that results in insufficient dilution or removal of infectious droplet nuclei
Re-circulation of air containing infectious droplet nuclei

22. TB Transmission
4 steps in TB pathogenesis:
1. Exposure
2. Infection
3. Disease
4. Death

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10% of infected persons will develop TB disease at some point in their lives
– 5% within 1-2 years
– 5% at some point in their lives

24. TB Infection

25. Source of Infection:
The source of infection can be either:
Human: Mycobacterium Tuberculosis
Animal: Mycobacterium Bovis
Human infection with M bovis has decreased significantly as a result of the pasteurization of milk and effective tuberculosis control amongst cattle.

26. Tuberculosis can affect most organs in the body, but the lung is the main organ affected.
If left untreated, each person with smear-positive pulmonary TB will infect, on average, between 10 and 15 persons in each year.
Those who will be infected with TB will not necessarily get the disease. The immune system “walls off” the TB bacilli, which can lie dormant for years.
On average, 10 percent of the infected individuals develop the disease during their lifetime.
When someone’s immune system is weakened, chances of developing TB are increased.

27. ExposureInfectioustuberculosisNon-infectioustuberculosisDeathRiskfactorsRiskfactorsRiskfactorsRiskfactorsA Model for the Epidemiology of TuberculosisRieder HL. Infection 1995;23:1-4Subclinicalinfection

28. Steps in the pathogenesis of TB
Exposure
Sub-clinical Infection
Non-Infectious
Infectious
Death

29. Natural history of tuberculosis in a newly infected (adult) contact (infection is not necessarily disease)
CONTACT
NO INFECTION
INFECTION
NO DISEASE
DISEASE
EARLY DISEASE
LATE DISEASE
Cell-mediated
immunity
(5%)
(5%)
(90%)

30. DIAGNOSIS:
CONTACT
NO INFECTION
NO DISEASE
DISEASE
EARLY DISEASE
LATE DISEASE
(5%)
(5%)
(90%)
INFECTION
cell-mediated
immunity
PPD positive

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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 infectious
Latent TB Infection (LTBI)

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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 infectious
TB Disease

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TB Disease
• Occurs when immune system cannot keep bacilli contained
•Bacilli begin to multiply rapidly
• Person develops TB symptoms

35. Natural history of untreated TB
Without treatment, after 5 years.
50% of pulmonary TB patients will be dead.
25% will be healthy (self-cured by strong immune defense).
25% will remain ill with chronic, infectious TB.

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LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli in the body
Active, 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

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LTBI vs. TB Disease
LTBI
TB Disease
Tubercle bacilli in the body
TST or QFT-Gold® result usually positive
Chest x-ray usually normal
Chest x-ray usually abnormal
Sputum smears and cultures negative
Symptoms smears and cultures 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

38. BCG immunization gives variable protection against the progression of TB from infection to disease.
The main benefit of BCG is the protection against the development of the serious forms of TB in children in the first two years of life, such as TB meningitis and miliary TB.
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39. Note…
-Infection does not mean disease!
-Infection can lead to active disease or dormant state of pathogen
-Primary infection is usually asymptomatic and a positive tuberculin skin test 4-6 weeks after infection is the only evidence of infection.
-Active disease develops differently (Healthy individuals VS. Immunocomprimised individuals)

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TB Pathogenesis
Progression from LTBI to TB Disease

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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-α] antagonists
Organ 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 disease

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Progression to TB Disease
People Exposed to TB
Not TB Infected Latent TB Infection (LTBI) Not Infectious
Positive TST or QFT-G test result
Latent TB Infection May go on to develop TB disease
Not Infectious
Negative TST or QFT-G test result
No TB Infection
Figure 1.5

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In an HIV-infected person,TB can develop in one of two ways:
1.Person with LTBI becomes infected with HIV and then develops TB disease as the immune system is weakened
2.Person with HIV infection becomes infected with M. tuberculosis and then rapidly develops TB disease
TB and HIV

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People who are infected with both M. tuberculosis and HIV are much more likely to develop TB disease
TB infection and NO risk factors
TB 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 lifetime
Risk is about 7% to 10% PER YEAR, a very high risk over a lifetime

45. Latent TB Infection (LTBI) Tubercle bacilli in the body Usually positive skin test Not infectious No symptoms Normal chest X-ray Sputum smears and cultures are negative Not a “case” of TB

46. Tuberculin skin Test (TST)
When a healthy person is infected for the first time with the tubercle bacilli, the body will develop a specific immune response. This immune reaction (cell-mediated immunity) can be assessed by TST.
Tuberculin is an antigen produced from dead tubercle bacilli, purified protein derivative PPD of. In the Mantoux test, 0.1 ml of tuberculin is injected intradermally.

47. Most people infected by M. tuberculosis or vaccinated by BCG will react to TST and develop an induration at the site of injection.
The diameter of this induration is measured after 48 to 72 hours.
Results are recorded in millimeters.
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Tuberculin skin Test (TST)

48. Tuberculin Skin Testing

49. A positive TST is of no diagnostic value for adult TB, but in a non-BCG-vaccinated individual it indicates infection by Mycobacterium, without proof of tuberculosis disease..
A negative TST is a fairly good indication that there is no TB infection.

50. Interpretation of the Tuberculin skin Test:
According the used cut off point in Egypt
The TST will be considered positive if the induration diameter is 15 mm or more within the 5 years after BCG vaccination.
The TST will be considered positive if the diameter of the indurated area is 10 mm or more when there is no history o f BCG vaccination regardless the age or after 5 years of vaccination.
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51. According the used cut off point in Egypt
If the investigated patient is known to be immune- compromised, the TST will be considered positive if the induration diameter is 5 mm or more at any age.
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Interpretation of the Tuberculin skin Test:

52. Limitations of TST
TST will be positive in cases with either infection or active disease, so it cannot differentiate between both conditions.
TST also cannot differentiate infection with M tuberculosis from other mycobacteria.
After BCG vaccination, it is not possible to distinguish between a tuberculin skin test reaction caused by virulent mycobacterial infection or by vaccination itself.
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53. False negative Reactions to Tuberculin:
1. Factors related to the person being tested:
Infection:-
A.Viral (HIV, measles, chicken pox).
B.Bacterial (typhoid fever, brucellosis, typhus, leprosy pertussis, overwhelming TB).
C.Live virus vaccinations (measles, mumps, polio).
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54. False negative Reactions to Tuberculin:
1. Factors related to the person being tested:
Metabolic derangements (chronic renal failure).
Nutritional factors (severe protein depletion).
Disease affecting lymphoid organs (Hodgkin’s disease, lymphoma, sarcoidosis)
Age (newly born).
Recent or overwhelming infection with M. tuberculosis.
 Stress (surgery, burns…etc).
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55. 2. Factors related to the tuberculin used:
• Improper storage (physical denaturation: exposure to light and heat).
• Improper dilutions.
• Chemical denaturation.
• Contamination.
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False negative Reactions to Tuberculin:

56. 3. Factors related to the method of administration:
• Injection of too little antigen. ,
• Delayed administration after drawing into syringe.
• Injection too deep
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False negative Reactions to Tuberculin:

57. 4. Factors related to reading the test and recording results:
• Inexperienced reading.
• Error in reading
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False negative Reactions to Tuberculin:

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TB Pathogenesis
Sites of TB Disease

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Bacilli may reach any part of the body, but common sites include:
BrainLymph nodePleuraLungSpineKidneyBoneLarynx

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Sites of TB Disease
Location
Frequency
Pulmonary TB
Lungs
Most TB cases are pulmonary
Extrapulmonary TB
Places other than lungs such as:
• Larynx
• Lymph nodes
• Pleura
• Brain
• Kidneys
• Bones and joints
Found more often in:
• HIV-infected or
other
immunosuppressed
persons
• Young children
Miliary TB
Carried to all parts of body, through bloodstream
Rare

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Question
What percentage of people with LTBI (but not HIV infection) usually develop TB disease?
About 10% of all people with LTBI will develop disease at some point
–About 5% of recently infected will develop TB disease in first year or two after infection
–Additional 5% will develop disease later in life
Remaining 90% will stay infected, but free of disease, for the rest of their lives

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What part of the body is the most common
site for TB disease?
Lungs are the most common site
What are some other sites?
- Larynx
- Lymph nodes
- Pleura (membrane around the lungs)
- Brain
- Kidneys
- Bones and joints
Question

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Case Study
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.

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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.