1. Unit 3 – Overview of TB Disease
Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. Learning Objectives
At the end of this unit, participants will be able to:
Describe the causes of TB
Describe how TB is transmitted
Describe the difference between TB infection and TB disease
Identify high risk populations and high risk behaviours
Describe the pathogenesis of TB
Review objectives of the unit

3. What is Tuberculosis?
TB is an illness caused by one of four (4) types of bacteria:
Mycobacterium tuberculosis (M. tuberculosis)
Mycobacterium bovis (M. bovis)
Mycobacterium africanum (M. africanum)
Mycobacterium microti (M. microti)
The majority of TB cases are caused by Mycobacterium tuberculosis
M. tuberculosis complex consists of all four bacteria
Human TB is caused by MTB or rarely other organisms that all share several characteristics: they are acid fast, slow growing, aerobic (require oxygen) and can become dormant
Mycobacteria other than TB (MOTT) or non-tuberculous mycobacteria (NTM) can cause a positive smear at times but do not cause disease in humans as often as M. tuberculosis complex. The MOTT are found in the environment and can cause disease in a person whose immune system is suppressed but they are not transmitted person to person through the air like tuberculosis and are therefore not considered a public health risk
TB more common in than MOTT in Africa/Asia, but the opposite is true in Europe/N America. In addition to immunosuppression, lung damage (scarring, bronchiectasis) from prior infections (including TB) is a major risk factor for pulmonary MOTT. MOTT is “treatable” but is less often cured than is TB.

4. Characteristics of M. tuberculosis (1)
TB bacilli as seen under the microscope
Slightly curved, rod shaped bacilli
microns in diameter and microns in length
Acid fast - resists decolourisation with acid/alcohol
M.TB is not the only AFB+ micro-organism.
Acid fast is when the high lipid content of the cell wall of MTB resists decolourization with acid/alcohol
The differential diagnosis of AFB+ smeal include MOTT (Mycobacterial Other than Tuberculosis), such as MAC, and false positives due to stain contamination or the presence of dead organisms after treatment has begun.
Source: Kubica GP. Public Health Image Library [database on the Internet]. Atlanta, GA: Centers for Disease Control and Prevention; 1979 [site updated 2005 Mar 18, cited 2008 Jan 22]. Available from:
Source: Kubica GP, CDC, 1979

5. Characteristics of M. tuberculosis (2)
Thick lipid cell wall
Multiplies every hours
Can remain dormant for decades
Aerobic
Non-motile
Non-motile means it can not move around by itself; it needs a transport system
Aerobic means it likes an oxygen-rich environment
During primary infection, the germs go where the air goes, and any part of the lung can be affected. Upper lobe predominance in reactivation reflects the oxygen-rich environment of the upper lung zone airspaces, where the ventilation-to-perfusion ratio is greater than in lower zones. Upper lobe predominance does not occur by “spread” from elsewhere; the reactivating organisms were there from the time of primary infection.

6. Pathogenesis of TB Infection (implantation) Multiplication
Dissemination (spread to other parts of the body)
Cell-mediated immune response (healing)
Reactivation

7. Definitions Alveoli Macrophage Granuloma
The small air sac at the end of the airways in the lungs
Macrophage
A type of white blood cell that eats bacteria or foreign organisms, found in the alveoli of the lungs
Granuloma
Nodular inflammatory lesions that contain compactly grouped mononuclear phagocytes (macrophages)
Tuberculous granulomas are often caseating (necrotic at their center) and contain Langerhans giant cells
AFB can often be seen on staining
Note the difference in pathology of TB between normal immunity and immunosuppressed persons
Pathology in persons with normal immunity:
Granulomas
Giant cells
Caseous degeneration
Pathology in immunosuppressed persons
Poorly formed or no granulomas
No caseous degeneration
May be larger numbers of organisms

8. Infection (Implantation Stage)
HIV+ persons with TB infection have a very high risk of developing active TB disease
The implantation stage involves:
The TB bacteria is inhaled and travels through the airway to the alveoli of the lungs. When the TB bacteria reaches the alveolous, it is ingested by alveolar macrophages
However, the macrophage, before activation, cannot kill the TB bacteria. Once the TB bacteria is inside of the macrophage it multiplies
Organism prefers environment with high oxygen content
Lives within macrophages (intracellular pathogen)
Also grows outside cells in cavities and abscesses
The organism is primarily an intracellular pathogen, so we rely on our cell mediated immunity to control it. Antibodies play little or no role
Oxygen content of lungs: the upper lobes have comparatively lesser blood flow and ventilation which leads to an increase in alveolar oxygen pressure, and the disease tends to spread towards these regions from the post-primary seeding sites
Source: Centers for Disease Control and Prevention. Self-Study Modules on Tuberculosis, Atlanta, GA. Mod 1, Fig 1.4. Accessed from:
Source: CDC, 2001

9. Primary Infection A person with primary infection may have:
No symptoms
Limited symptoms
Progressive symptoms
When TB is first acquired, it causes primary infection
It may be asymptomatic and not recognised
It may cause symptoms but be self-limiting, healing without therapy
Rarely it may be symptomatic and progressive causing a serious disease
This primary disease may be limited to the lung and intrathoracic lymph nodes, or it may spread to other organs causing disseminated disease
Progressive Primary TB on chest x-ray is not necessarily in the upper lobes
Typical findings are hilar/paratracheal adenopathy, plueral effusion and/or a periperhal infiltrate in any lobe
A person with a calcified peripheral nodule and calcified adjacent hilar node is said to have a “Ghon complex”

10. How TB is Spread (1) Person-to-person
Through the air by a person with TB disease of the lungs
Less frequently transmitted by ingestion of Mycobacterium bovis found in unpasteurised milk products
Rarely transmitted by inhalation of aerosolized infected fluids (e.g., TB abscess)
For last bullet: It is important to recognize that it is not just the site or abscess but the aerosolizing of the germs within the site

11. How TB is Spread (2)
A person with infectious pulmonary TB (PTB) who coughs, sneezes, or speaks
Tiny particles of water (droplet nuclei) containing the TB bacteria enter the air and can remain suspended in the air for several hours
The bacteria can then be inhaled by others sharing the same air space
The moist breath that comes out through the mouth and nose contains tiny droplets of water. Once out of the mouth, the larger droplets fall to the ground and the moisture from the smaller droplets start to evaporate (dehydrate) leaving behind droplet nuclei which are very light and can stay suspended in the air for hours
Each droplet nuclei contains several TB bacilli (TB germs)
A person must inhale the air containing the droplet nuclei in order for transmission to occur
Although the bacteria can survive in the air for many hours, the bacteria can be killed by direct sunlight or cleared out of a room by opening the windows to let fresh air in’
Source: Centers for Disease Control and Prevention. Self-Study Modules on Tuberculosis, Atlanta, GA. Mod 1, Fig 1.2. Accessed from:
© ITECH, 2006
Source: CDC, 2001

12. Probability of Transmission
Environment in which exposure occurred
Infectiousness of person with TB
Immunologic status of exposed person
Duration of exposure
Virulence of the organism
The probability that TB will be transmitted from one person to another depends on four factors:
Environment
Chance of infection increases when with an infectious person in areas where the bacteria can easily survive such as: Indoors, in areas with poor ventilation, in areas with no sunlight
The bacteria can survive in the air for long periods of time but can be killed by sunlight or spread about by the wind.
Transmission is more likely to occur in a closed environment and less likely to occur outside where there is excellent ventilation
Infectiousness
Directly related to the number of TB bacteria that he or she expels into the air when he/she coughs, sneezes, etc. A person with TB disease who is coughing is putting more bacteria into the air than a person with TB disease who is simply breathing. An uninfected person who breathes in a lot of bacteria is more likely to become infected than someone who breathes in fewer bacteria.
A study by Kenyon, et al. showed that the risk of transmission of infected children increased with the degree of sputum smear positivity for acid-fast bacilli among female index cases – 10.8% if smear 0, 9.3% if smear 1+, 29.4% if smear 2+, 44% if smear 3+ (p<0.001)
Source: Kenyon T, Creek T, Laserson K, Makhoa M, Chimidza N, Mwasekaga M, Tappero J, Lockman S, Moeti T, Binkin N. Risk factors for transmission of Mycobacterium tuberculosis from HIV-infected tuberculosis patients, Botswana. Int J Tuberc Lung Dis. 2002; 6(10):
Immunologic status of exposed person
The stronger/healthier one’s immune system is, the less likely TB is to be transmitted
Duration of exposure
The longer an uninfected person is around someone with pulmonary TB disease the greater the chance that person will breathe in the bacteria. People who spend a lot of time around a person with TB disease, such as family members, roommates, friends, and coworkers, are at high risk of becoming infected with the TB bacteria.
Virulence of the organism
The ability of any agent of infection to produce disease. The virulence of a microorganism (such as a bacterium or virus) is a measure of the severity of the disease it is capable of causing.
Source: Medicinenet.com [Homepage on the Internet]. Definition of Virulence. c [reviewed 2001 Oct 20, cited 2008 Jan 23].

13. Spread of TB to Other Parts of the Body (Dissemination Stage)
Pulmonary
Lymph nodes
Pleural Effusion
Miliary
Kidney
Spine
Meningitis
The TB bacteria are inside the macrophage, they can travel through the lymphatic system to regional lymph nodes and through the bloodstream to more distant tissues and organs, including areas in which TB disease is most likely to develop: the apices of the lungs, the kidneys, the brain, and bone.
Those with HIV have higher risk of disseminated TB and extrapulmonary disease than those without HIV
Lymph nodes: mediastinal and abdominal lymph nodes are also common sites of HIV-associated TB
Source: Centers for Disease Control and Prevention. Self-Study Modules on Tuberculosis, Atlanta, GA. Mod 1, Fig 1.4. Accessed from:
Source: CDC, 2001
© ITECH, 2006

14. Healing Stage: Cell-Mediated Immune Response
Process of halting the multiplication of the TB bacilli and preventing further spread
This same response causes the skin test to be positive
For people with healthy immune systems, the body’s natural defenses will become activated
It can take from 2 to 10 weeks after infection before the body’s immune system recognises the threat and intervenes. This time period between when infection occurs and when the body’s immune system becomes activated is referred to as the window period
See Handout 3.1 for more information on this slide.
Source: © University of Alabama at Birmingham, Department of Pathology
© University of Alabama at
Birmingham,
Department of Pathology
Granuloma

15. Latent Infection
Period of time during which the person experiences no symptoms but is still infected with the bacteria
The bacteria lives inside macrophages or within a granuloma where the bacteria remains dormant
A person with latent TB infection cannot spread the bacteria to other people

16. Reactivation of TB (1) Dormant bacteria can become active again
Escape granuloma and enter the airway
The dormant TB bacteria inside of the granuloma can become active again later in a person’s life: this typically occurs when the immune system becomes weak allowing the TB bacteria to multiply out of the control of the immune system
During the reactivation stage, a person will generally experience symptoms and can spread the TB bacteria to others
Source: Centers for Disease Control and Prevention. Self-Study Modules on Tuberculosis, Atlanta, GA. Mod 1, Fig 1.4. Accessed from:
Source: CDC, 2001

17. Reactivation of TB (2)
Latent infection can reactivate, causing active TB disease
Reactivation occurs when the immune system weakens and the TB bacteria multiplies
TB bacteria and dead cells in the airway will cause a person to cough
Higher proportion of smear-negative PTB in PLWHA
During the reactivation stage, a person will generally experience symptoms and can spread the TB bacteria to others
This is the usual mechanism of development of active TB among adults. The disease may be pulmonary alone, extra-pulmonary alone, or both
“Most of the increasing TB burden in Botswana may be attributable to reactivation of latent infection.”
Source: Lockman S, Sheppard J, Braden C, Mwasekaga M, Woodley C, Kenyon T, Binkin N, Steinman M, Montsho F, Kesupile-Reed M, Hirschfeldt C, Notha M, Moeti T, Tappero J. Molecular and Conventional Epidemiology of Mycobacterium tuberculosis in Botswana: A Population-Based Prospective Study of 301 Pulmonary Tuberculosis Patients. Journal of Clinical Microbiology. March 2001; 39(3):
On account of the impact of HIV in decreasing the sensitivity of sputum smear-microscopy and the specificity of chest X-ray in the diagnosis of pulmonary TB in adults, it is important to follow recommended diagnostic guidelines (WHO 2003b) as closely as possible and to ensure good quality control of sputum smear-microscopy (Harries et al. 1998). NTPs should also consider the costs and benefits of expanding the use of fluorescence microscopy (Crampin et al. 2001; Kivihya-Ndugga et al. 2003) and the bleach (sodium hypochlorite) method to improve the AFB smear microscopy (Angeby et al. 2004)
Source: Maher D, Harries A, Getahun H. Tuberculosis and HIV interaction in Sub-Saharan Africa: impact on patients and programs; implication for policies. Tropical Medicine and International Health Aug; 10(8):
HIV is the most powerful known risk factor for reactivation of latent M. Tuberculosis infection to active disease

18. Question What is the difference between TB infection and disease?
Ask participants the question before reviewing the next slides.
Allow participants a few minutes to answer the question aloud.
Ensure that at the end of this step, participants are very comfortable with explaining the difference between infection and disease.

19. Infection
The bacteria lives inside a person without that person having any symptoms because the immune system is able to control the infection
Not all infected people develop TB disease
In HIV negative individuals, 10% lifetime risk of developing disease if TB infected
In HIV positive individuals, 10% ANNUAL risk of developing disease if TB infected

20. Disease
If the immune system cannot control the infection the bacteria multiply and cause disease
TB disease can develop soon after infection, many years after infection or it may never develop
What is one factor, besides HIV, that might increase the chance that TB infection progresses to disease?
Review slide
Ask participants to write down one risk factor, besides HIV, that might increase a person’s chance of infection progressing to TB disease
They can record this anywhere
It is important that you allow participants enough time to brainstorm and record something before moving on to the next slide, as the next two slides contain risk factors for progression from infection to disease
Participants will share their responses on the next slide

21. Risk Factors for Progression from TB Infection to TB Disease (1)
HIV/AIDS
Malnutrition
Recent TB infection
Extremes of age (children under 5 years of age and the very old)
Alcoholism and other substance abuse
Ask volunteers to share the responses they wrote down during the previous slide and say why they think it is a factor
Explain the greatest risk of active TB disease occurs in the first 2 years after infection
Review the slides and add factors that were not mentioned
Risk of reactivation is 10% over life-time for normal immune systems, risk of reactivation is 5-10% per year in the HIV infected population
Immune status – TB is more likely to progress from infection to disease in persons with a weak immune system. The very young (children under 5 years of age) and the very old have weak immune systems. Young children have weak immune systems because they are not yet fully developed. The elderly have weak immune systems because the immune system naturally weakens with age. Also, a person with HIV has a weak immune system and is at high risk for latent TB infection progressing to TB disease. It’s very important to identify TB infection in persons living with HIV as they have a 10% annual risk (50% lifetime risk) of their TB infection progressing to TB disease.
Many factors can increase the progression from latent TB infection to disease, although in the current time HIV/AIDS is the most frequent and most important
Lymphatic Malignancies – that cause decreased immunity and where the treatment is often immunosupressive
Immunosuppressive medications and treatments
Extremes of age – very old/very young

22. Risk Factors for Progression from TB Infection to TB Disease (2)
Silicosis of lung
Renal failure
Diabetes Mellitus
Lymphatic malignancies
Immunosuppressive medications and treatments including prolonged corticosteroid therapy
Gastrectomy
Gastrectomy - associated with high tuberculosis morbidity possibly due to other factors such as loss of weight
Renal failure - end stage renal failure patients often at risk of tuberculosis
The strength of a person’s immune system is also influenced by the food that a person eats. A person must eat enough and have a balanced diet to have a strong immune system. Someone who does not get enough vitamins in their diet or does not get enough food to eat has a weak immune system
Silicosis is permanent scarring of the lungs caused by inhaling silica (quartz) dust. Silica is the main constituent of sand, so exposure is common among metal miners, sandstone and granite cutters, foundry workers, and potters. Usually symptoms appear after years, and it is dependent upon the occupational exposure
Source: Merck Manuals Online Medical Library [database on the Internet]. Merck & Co., Inc. c2005 [cited 2008 Feb 4, content modified 2005 Nov]. Entry: Tuberculosis. Available from:
Source: Merck, 2005

23. Key Points (1)
Evidence of TB has been seen to be affecting humans for centuries
TB transmission occurs from persons with active pulmonary TB
TB droplets remain suspended in the air for hours
The bacteria can be killed by direct sunlight
Ventilation is important
Review the Key Points and summarise the unit

24. Key Points (2) When TB is first acquired, it causes primary infection
Persons with poor immunity, especially very young children and persons with AIDS, are more likely to have primary progressive disease
Latent infection-- period of time when person experiences no symptoms but is still infected with the bacteria