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

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

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.

Characteristics of M. tuberculosis (1) TB bacilli as seen under the microscope Slightly curved, rod shaped bacilli 0.2 - 0.5 microns in diameter and 2 - 4 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: http://phil.cdc.gov/phil/details.asp Source: Kubica GP, CDC, 1979

Characteristics of M. tuberculosis (2) Thick lipid cell wall Multiplies every 18 - 24 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.

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

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

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, 2001. Atlanta, GA. Mod 1, Fig 1.4. Accessed from: http://www.phppo.cdc.gov/phtn/tbmodules/modules1-5/m1/con6a.htm Source: CDC, 2001

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”

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

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, 2001. Atlanta, GA. Mod 1, Fig 1.2. Accessed from: http://www.phppo.cdc.gov/phtn/tbmodules/modules1-5/m1/con6a.htm © ITECH, 2006 Source: CDC, 2001

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):843-850. 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. c2001-2008 [reviewed 2001 Oct 20, cited 2008 Jan 23]. http://www.medterms.com/script/main/art.asp?articlekey=6911

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, 2001. Atlanta, GA. Mod 1, Fig 1.4. Accessed from: http://www.phppo.cdc.gov/phtn/tbmodules/modules1-5/m1/con6a.htm Source: CDC, 2001 © ITECH, 2006

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

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

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, 2001. Atlanta, GA. Mod 1, Fig 1.4. Accessed from: http://www.phppo.cdc.gov/phtn/tbmodules/modules1-5/m1/con6a.htm Source: CDC, 2001

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): 1042-1047. 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. 2005 Aug; 10(8):734-742. HIV is the most powerful known risk factor for reactivation of latent M. Tuberculosis infection to active disease

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.

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

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

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

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 10-20 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: http://www.merck.com/mmpe/sec14/ch179/ch179b.html Source: Merck, 2005

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

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