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1 1 1 #41.7E137)AD7*:3)F4:G,)%3-*31)#::-H*7! " # $ % & ' ( #! % " The aim of the TB Basics module is to provide activists with fundamental information about tuberculosis in order to strengthen advocacy and scientific literacy around TB and TB/HIV. We hope that activists will use this information to inform their advocacy and to develop community education materials and sessions on TB. The facilitator notes and slide set are teaching tools that can be used as is or modified to suit your needs and audience. We estimate that it will take about two hours to complete this module using the attached slide set. Time estimates have been included in each section of the module for your reference but will vary based on the facilitator s comfort with the material and the participants understanding of the material. Please use the time allotments as a planning guide rather than a rule. The module is broken up into sections that can be taught as separate units or in one workshop. The information in the facilitator notes is organized into five main categories: Fundamental information provides further explanation of the information on the slides and slide notes, and is what we consider to be need to know information. Teaching points/exercises are optional and are meant to provide an opportunity to reinforce information and/or stimulate discussion. Summary/review revisits key points of each section and provide an opportunity for clarification or further explanation. Definitions provide explanation of commonly used and/or key terms. These terms are italicized in the main text. Nice-to-know information is not considered necessary or fundamental to understanding basics concepts of this module but is nice-to-know. Please be careful before citing this information in a workshop, as participants who are new to tuberculosis may get overwhelmed by too much information. These facilitator notes are meant to be used as a guide for and explanation to the slide set. However, facilitators should feel free to develop their own slide sets or teaching tools using the notes and/or modifying the slides depending on their needs.!)&*+,-./)+-*01)2).30)415*16)781)9:--:6*3;<) =%&'>?)!<)#@)@AB!(B The goal of this module is to provide participants with a foundation to understand the key concepts of TB disease. At the end of this module participants will 1. be familiar with the history of TB 2. be familiar with fundamental scientific concepts about Mycobaterium tuberculosis (MTB) 3. be able to explain how TB is transmitted 4. be able to explain the difference between latent TB infection and active TB disease 5. understand the immune response to TB 6. be familiar with some specific challenges to TB control in the context of TB/HIV coinfection 7. be able to identify some of the most pressing issues for TB advocates!)&*+,-./)+-*01)c).30)415*16)781)7:,*d+):3)781)+-*01)

2 2 2 SECTION 1 History of TB (slides 3-5; 5 minutes)!)&*+,-./)+-*01)i If the importance of a disease for mankind is measured by the number of fatalities it causes, then tuberculosis must be considered much more important than those most feared infectious diseases.!)&*+,-./)+-*01)j In this same talk, Koch outlined what became known as, Koch s Postulates, a set of criteria to determine if a microbe is the cause of a disease. At the time Koch was writing this piece, the idea that germs - tiny life forms too small to see - were the cause of many diseases was controversial. This idea, called germ theory, was contrary to then widely held beliefs that miasmas or bad spirits were the cause of most disease. This quote is from a lecture entitled The Etiology of TB, which was first presented at a meeting of the Physiological Society of Berlin in March 24, 1882 during which Dr. Robert Koch, one of the most influential early microbiologists, announced the discovery of MTB as the cause of TB. Koch was the first person to isolate the TB bacterium and detail its properties. It is also interesting that Koch began this important talk with an effort to convince his audience that TB should be counted among the most important infectious diseases. TEACHING POINT ASK THE PARTICIPANTS TO DISCUSS WHETHER THEY THINK THIS QUOTE IS STILL RELEVANT TODAY. NOTE TO FACILITATOR: GIVEN THE FACT THAT ONE-THIRD OF THE WORLD S POPULATION IS INFECTED WITH MTB AND IT IS THE LEADING KILLER OF PEOPLE WITH HIV, IT IS REASONABLE TO THINK THAT THIS QUOTE STILL HOLDS TRUE TODAY.!)&*+,-./)+-*01)K TB has been found in the mummified bodies of ancient Egyptians and Andean Indians, demonstrating that it has been infecting humans for thousands of years. However, it was not until 1882 that Koch was able to isolate MTB as the cause of TB. The disease was historically referred to as consumption during the late 1800 s and early 1900 s. B ' = = A $ L fact that it has been infecting humans for thousands of years from mummies in Egypt and ancient Andean Indians in South America. $? M!? N ) O '? B #! % " B Q: How long has TB been infecting humans? A: Thousands of years. Q: Who discovered TB? A: Robert Koch. N o t e t o f a c i l i t a t o r : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s, r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n t i f y.

3 3 3 SECTION 2 Fundamental Concepts (slides 6-11; 20 minutes)!)&*+,-./)+-*01)p The scientific name for the pathogen that causes tuberculosis is Mycobacterium tuberculosis (also referred to as MTB for short). When viewed with a microscope, it has a long rodlike shape and a thick, waxy-looking coat.!)&*+,-./)+-*01)q!"#$%&#'()*+,-'+%()#+.$/*/, also referred to as MTB, is a rod-shaped bacteria characterized by a thick waxy coating, it is the bacteria that causes the disease tuberculosis. 0&'1$2(3/-are any disease-causing substances or agents, such as bacteria, viruses, and other microbes. TIP: Depending on the comfort level of your audience with this informaton, it may be a good idea to use less technical language and refer to pathogens as germ, critter, or bug. The word pathogens comes from patho meaning disease, and gen refers to creation (like Genesis the creation story in the Bible). Bacteria are different from other microbes because they lack a membrane-bound nucleus. The term for this is prokaryotic. Algea and fungi are eukaryotic microbes, meaning they have a nucleus that is protected by a membrane. 4&#'()*& are single-celled microorganisms that are found virtually everywhere on earth. Tuberculosis may be referred to by a number of names or acronyms in conversation and in writings, including: TB, Mycobacterium tuberculosis, M. tuberculosis, MTB, M. tb, M.TB, TB bacterium/bacteria (bacterium is singular and bacteria is plural) or TB bacillus/bacilli (bacillus is singular and bacilli is plural). The prefix myco- can mean fungi (as in mycology, the study of mushrooms and other fungi), or waxy. In the case of MTB, it refers to the waxy coating of the cell wall. The term bacilli refers to the rod shape. Other bacterial shapes are cocci (round), spirochete (cork-screw), and pleomorphic (having a mixed shape). TB is a type of mycobacteria (myco means waxy in Latin). The TB bacterium are named for both its appearance (myco) and the disease it causes (tuberculosis).!)&*+,-./)+-*01)r There are over 70 types of mycobacteria -not all of them are harmful. However MTB is the most common in humans and the most harmful. Many nonharmful bacteria live in and on our bodies. In fact, there are around 10 times as many bacterial cells in a person s body than human cells. The skin, the mouth, and the reproductive and digestive tracts all contain large numbers of normal, healthy bacteria. Humans have trillions of bacteria in our gut that help us digest food and synthesize vitamins and hormones.!)&*+,-./)+-*01)s MTB s thick waxy cell wall is made primarily of mycolic acids and fat molecules called lipids. The makeup of the cell wall is important for two reasons. First, it allows the bacteria to live outside the body for a relatively long period of time, making it more capable of passing from one person to another because the protective structure allows the germ to spread through the air. Second, it makes the bacteria difficult to stain and look at under a microscope. The nature of the cell s waxy wall requires specific staining dyes after being washed in acidic solutions; therefore it is referred to as an acid-fast bacillus. This special kind of staining process is called acid-fast testing, and strips the bacterium of much of its cell wall through the acidic wash, making it more receptive to traditional staining techniques.!)&*+,-./)+-*01)2t MTB reproduces very slowly compared to other bacteria through a process known as binary fission. On average it will reproduce every hours, in contrast to many other bacteria that replicate in a matter of minutes, or an hour or so at most. This makes diagnosis of TB more difficult as it takes longer to detect TB in the body and to grow it in the laboratory. Because MTB has all the necessary genetic material to reproduce it does not require a host like HIV. TB and HIV are two of the most important infectious diseases in the world today. While they overlap in many important ways, they are also quite

4 4 4 different. TB is a large and complex bacteria that has been infecting humans since early civilization. HIV however is a tiny, relatively simple virus that has been infecting humans for less than a century. The downside for TB mutation in humans is that when they occur, they are more likely to become fixed and stable over time as compared to HIV.!)&*+,-./)+-*01)22 Critical differences between TB and HIV Unlike TB, most bacteria can be stained with a simple technique called gram staining, which exposes the cell wall to a couple of dyes that will either be absorbed by the cell wall (gram positive) or not absorbed (gram negative). DNA, a fatty cell wall, and many proteins. because it has a proofreading mechanism that regulates its mutations. and has ~4,000 genes. in a process called binary fission. for thousands of years. RNA with just a few proteins and a glycolipid (sugar-fat-protein) envelope. hence copies often contain changes or mutations. and has nine genes. machinery to replicate. years. In summary, TB is a large and complex bacteria that has been infecting humans for thousands of years while HIV is a tiny, relatively simple virus that has been infecting humans for less than a century. B ' = = A $ L<!"#$%&'())"*# is the process by which most bacteria reproduce. The bacterial DNA is replicated (an exact copy is made) inside the cell, and each of the two strands of DNA attaches itself to one end of the inner cell wall. The cell then divides, leaving two daughter cells. In most cases the daughter cells are genetically identical to the parent cell and to each other. The exception to this is when changes arise due to spontaneous (random) mutations. Most mutations harm the organism, either rendering it nonviable (unable to reproduce) or less capable of sustaining itself (compared to nonmutated forms). However, sometimes this process can lead to the changes that benefit the organism- for example making it less susceptible to antibiotics. This is the same process that drives all evolution, from simple one-celled organisms to complex plants and animals. slow rate of reproduction. It allows the TB bacteria to survive inside and outside of the body. It makes it difficult to stain so that it can be detected under a microscope. binary fission. thousands of years while HIV is a tiny, simple virus, relative to TB, that has been infecting humans for less than a century. $?M!?N< Q: What is the shape of the TB bacilli? A: Rod-shaped. Q: What does myco- mean? A: It means waxy in Latin and refers to the TB cell wall. Q: How does the waxy wall help MTB to survive? A: It allows MTB to survive outside of the body.

5 5 5 TB has been found in the mummified bodies of ancient Egyptians and Andean Indians, demonstrating that it has been infecting humans for thousands of years. There is strong evidence that HIV has been infecting humans for about 70 years. The origins of HIV have been traced to a species of nonhuman primate called pantroglodyte troglodyte-a type of chimpanzee native to equatorial Africa. Researchers found that a strain of Simian Immunodeficiency Virus (SIV) infecting these chimps is the likely source of all HIV-1 in humans, based on genetic similarities. By comparing the genes of this strain of SIV to HIV and comparing those differences to the rate at which HIV is known to mutate (change), it is estimated that the virus jumped from chimps to humans sometime in the first half of the 20th century. While it is not known exactly how the virus jumped from chimps to humans, most think it happened when a SIV-infected chimp was butchered by a human. Q: What does acid-fast bacilli refer to? A: The acidic wash that is used to strip away the TB cell wall so that it can be stained and viewed under a microscope. Q: How often does TB reproduce? A: It splits every hours through binary fission Q: Name two differences between HIV and TB A: See list on page 4 for reference. N o t e t o f a c i l i t a t o r s : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s, r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n t i f y.

6 6 6 SECTION 3 TB Transmission (slides 12 14; 15 minutes)!"&*+,-./)+-*01)2c TEACHING POINTS: 1. ASK PARTICIPANTS TO EXPLAIN HOW TB IS SPREAD. A. TB IS SPREAD THROUGH INHALING TB BACILLI. 2. IF APPROPRIATE, ASK PARTICIPANTS TO DISCUSS HOW TB IS NOT TRANSMITTED. A. VIA BLOOD, SPERM, VAGINAL FLUIDS, FOOD OR LIQUIDS, EATING UTENSILS, DUST, DIRT, OR VEHICLE FUMES.!)&*+,-./)+-*01)2I 56+'+, is the mucus or phlegm that is coughed up from the lungs that is often examined for the presence of TB bacilli. 7.8($.* are small air sacs in the lung. They are the site where most oxygen is brought into-and carbon dioxide is removed from-the lungs in a process that is known as gas exchange. TB is transmitted through the air from exposure to bacilli in the saliva of infected persons and sputum coughed up from their lungs. Once inhaled, the droplets can push their way into the lungs, settling in tiny air sacs known as alveoli. TB loves oxygen. So it often initially takes root in the oxygen-filled regions of the lungs. To get inside the lungs, TB typically travels through the nose and mouth. A single cough can generate more than 9,000 bacteria. A sneeze can produce triple that amount and propel the germs up to 10 feet away. Not all persons exposed to TB become infected! There are a number of factors that increase or mitigate the likelihood of transmission. EXCERCISE: ASK THE PARTICIPANTS TO LIST SOME OF THE FACTORS THAT MAY INCREASE OR DECREASE THE PROBABILITY OF INFECTION?!"&*+,-./)+-*01)2J Factors that may increase or decrease the risk of infection (this list is not exhaustive): Factors related to the person with TB (index case): whether their sputum is sputum smear positive (smear positive indicates a high level of MTB in their sputum); have a cough; are adhering to their TB medication regimen (after 2-3 weeks on treatment, persons with drug-susceptible TB are considered no longer infectious). Factors related to the person being exposed to TB (contact): Proximity and frequency of contact (how close one is to an infected person); age of contact (young children and older adults may be at increased risk for transmission). Environmental factors: ventilation; size of room or space; duration of exposure; sunlight or ultraviolet (UV) light (which kills TB bacteria). B ' = = A $ L< Via blood, sperm, vaginal fluids, food or liquids, eating utensils, dust, dirt, or vehicle fumes. through the nose or mouth:

7 7 7 $?M!?N< Q: What are three ways that TB is not passed from person to person? A: See list on page 5 for answers Q: Name two factors that can impact the risk of infection. A: See list on page 6 for answers Q: Can TB be passed from person-to-person through casual or close contact? A: Yes N o t e t o f a c i l i t a t o r s : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n t i f y.

8 8 8 SECTION 4 Who s Who in the Immune Response: Roles and Responsibilities (slides 15-19; 30 minutes)!"&*+,-./)+-*01)2k EXERCISE: ASK THE PARTICIPANTS WHAT OUR BEST DEFENSE IS AGAINST INFECTION AND DISEASE? A. THE IMMUNE SYSTEM. THIS IS YOUR BEST DEFENSE SYSTEM AGAINST ANY PATHOGEN (OR CRITTER, GERM, OR BUG). ASK PARTICIPANTS TO LIST SOME PARTS OF THE IMMUNE SYSTEM. A. SKIN, NAILS, HAIR, EYE LASHES, LYMPH NODES, CD4 CELLS, BONE MARROW, TONSILS, THYMUS, ETC. (PLEASE NOTE THAT THIS LIST IS NOT EXHAUSTIVE.)!)&*+,-./)+-*01)2P When TB gets into a person s body, the immune system will try and get rid of it. Some of the important players in the body s immune response to TB (and HIV) are: 73*'2(3-6)(/(3'*32-#(../ are the immune system s first responders. They patrol the body looking for cells and other materials that are foreign (and potentially harmful) to the body. ANTIGEN PRESENTING CELLS (macrophages cells) patrol the body looking for germs. and dendritic!&#)$61&2(/ are a type of antigen-presenting cell, they are large (macro) cells that engulf (phage meaning to eat ) invading organisms and bring them to the coordinating cell of the immune system, the CD4 T cell. CD4 T CELLS act as coordinator of the immune response instructing other ells to attack specific invading germs. CD8 T CELLS are involved in cell to cell killing, when ordered by CD4 T cells they seeks out and destroy cells that have been infected by a specific germ. 9(3:)*'*#-#(../ are also a type of antigenpresenting cell, and have long, stringlike projections from their cell bodies called dendrites. These dendrites act like the strings on a mop, grabbing a hold of invading organisms to transport them to the CD4 T cell. ) B CELL B CELLS are immune cells that when instructed by the CD4 T cells make antibodies. ANTIBODIES are sticky proteins that attach to germs marking them for destruction by the immune system or hampering their ability to reproduce. Antibodies are specific to the germ (bacteria, virus, or other harmful toxins).!)&*+,-./)+-*01)2q The immune system sends out an army of immune cells to look for anything that is not supposed to be there. The first wave of patrol cells are dendritic cells and macrophages. These cells are known as antigen-presenting cells, and guard against foreign invaders entering the body. Antigen-presenting cells can be thought of as the advance scouts of the immune system, as they alert the body to foreign invaders (pathogens or germs). MACROPHAGE DENDRITIC CELL

9 9 9 Dendritic cells use long tentacles, called dendrites, to grab TB bacilli while macrophages engulf TB. Dendritic cells can be likened to string mops, with the dendrites being like the strings on the mop. Macrophages are large cells that eat microbes. Macro means large and phage means eat.!)&*+,-./)+-*01)2r) Both of these cells transport TB to the lymph nodes, which act as the communication and meeting center for the immune system. In the lymph nodes, the antigen-presenting cells chop up the TB bacilli and present it to the CD4 T cell (also known as the CD4 cell, T4 cell, T4 helper cell, or less accurately as helper T cell, or T cell) which coordinates the immune response. CD4 T cells are the coordinator cells of the immune system and are responsible for sending out instructions to other immune system cells telling them how to respond to a challenge. Th2 Th1 ;",61-3$:(/ are small, bean shaped structures and are the work centers of the immune system. They act as filters-trapping bacteria, viruses, and other pathogens-and as meeting places for immune system cells. <9=->-#(../ act as coordinators of the immune response instructing other cells (like B cells and CD8 T cells) to attack specific invading pathogens. Some alternative ways of explaining the role of the CD4 T cell are as the conductor of the immune system orchestra or the general of the immune system army or the boss of the immune system workplace or the brains of the immune system. B B B B cytokines Antibody Response (or Humoral)! B Cells! Antibodies! Attacks germs outside of cell (e.g. germs in blood) CD4 T cell cytokines Cellular Response! CD8 T cells! Cell to cell killing! Attacks germs inside of cells (e.g. infected cells) CD8 T cells T8 T8 T8 T4 T4 T4 Thymus <"'$?*3(/ are proteins produced by certain immune cells that act as chemical messengers between cells. They can stimulate or inhibit the growth and activity of various immune cells in response to a specific pathogen or disease. CD4 T cells use specific cytokines to direct CD8 T cells and B cells. <9@->-#(../ are immune system cells involved in cell-to-cell killing. When instructed by a CD4 T cell, they seek out and destroy cells that have been infected by a specific pathogen. They are sometimes called CTLs or cytotoxic T Lymphocytes, which translates to immune system cells that are toxic to other cells. 4-<(../ are white blood cells that when instructed by CD4 T cells make antibodies. 73'*%$:*(/ are sticky proteins that attach to freefloating pathogens (those not inside a cell), marking them for destruction and hampering their ability to reproduce and attach to tissues and cells. CD4 T cells are so called because their cell membranes contain (or express) large amounts of a protein known as CD4. The CD stands for cluster differentiation-a system for classifying certain proteins.!"&*+,-./)+-*01)2s The immune responses to pathogens can be divided into two broad categories: Th1 (cellular immunity) or Th2 (humoral or antibody response). The Th1 or cellular response involves the CD4 T cell using cytokines, or cellular messages (imagine SMS or text messages between cells), to direct the CD8 T cell to recognize and eliminate infected cells. CD8 T cells are also called cytotoxic T cells (CTLs). This means they are cells that are toxic to other cells; in other words, they are cells that kill other infected cells. In the Th2 or antibody (humoral) response, the CD4 T cell directs B cells to make antibodies which are proteins that stick to free floating pathogens preventing them from infecting new cells and marking them for destruction. Unfortunately, antibodies are largely ineffective against TB. TIP: It is helpful to come up with nonscientific ways to explain some of these concepts. For instance, another way to describe the two immune responses is:! "! Cellular (or Th1) immune response: A robber (pathogen) breaks into a house, so the police chief (CD4 T cell) tells the police officer (CD8 T cell) to find the house where the robber is (infected cell) and set the house on fire so that the robber is killed and the house is destroyed, thereby stopping the robbery (or killing the infected cell).! "! Antibody (or humoral or Th2) immune response: A robber (pathogen) is walking on the street looking for a house to rob (a cell to infect) and the

10 1010 police officer (B cell) comes up to him and puts stickers (antibodies) all over his body that say robber. Now the robber is unable to break into a house because he has stickers all over his hands AND he will be noticed and picked up by the police before he can break into a house (or killed by patrolling immune cells) because they can see that he is a robber. EXERCISE ALLOW 10 MINUTES FOR GROUP WORK AND 5 MINUTES PER GROUP FOR PRESENTATION: DEPENDING ON THE SIZE OF THE GROUP, BREAK PARTICIPANTS INTO GROUPS OF NO MORE THAN EIGHT, AND ASK EACH OF THE GROUPS TO DEVELOP A WAY TO TEACH OTHERS ABOUT THE IMMUNE RESPONSE. PARTICIPANTS CAN ACT IT OUT, DRAW IT, WRITE A SONG-WHATEVER THEY WANT. IT SHOULD INCLUDE THE ROLES OF ANTIGEN-PRESENTING CELLS BOTH DENDRITIC CELLS AND MACROPHAGES, CD4 T CELLS, CD8 T CELLS AND B CELLS. DEPENDING ON THE TIME AVAILABLE AND ON THE SIZE OF THE GROUP, YOU MAY ASSIGN ONLY ONE TYPE OF IMMUNE RESPONSE PER GROUP. GIVE THE GROUPS 10 MINUTES TO DEVELOP THEIR PRESENTATION, AND THEN BRING THE GROUP BACK TOGETHER TO PRESENT. The immune system has a mixed record in responding to TB infection. Many healthy people will eliminate or at least control TB infection for life, keeping it from ever making them sick. Some will not. People with compromised or deteriorating immune systems from HIV infection, malnutrition, old age, or other factors, or children with developing immune systems, are less able to keep the infection in check. As previously mentioned, the antibody (or humoral or Th2) response to TB seems largely ineffective. B ' = = A $ L) A generic immune response behaves something like this: dendritic cell. cell, which is the coordinator cell of the immune system. Some infections will illicit one type of response or the other, but most will initiate both. type of T cell, called a CD8 T cell, to find and destroy any cells that are infected by the pathogen. signals another type of white blood cell, called a B cell, to produce antibodies (sticky proteins) to bind to the pathogen so that it is unable to infect cells and is marked for destruction. The antibody immune response is ineffective in combating TB. $?M!?N< Q: Describe a basic immune response. What role do the following cells play in the response: CD4 cells, CD8 cells, B cells, antigen-presenting cells? A: See explanations on page 9. Q: What are other names for cellular and humoral immunity? Please explain what happens in each response. A: Cellular: Th1, and humoral: Th2 or antibody. See explanations on page 9 to guide explanation of the each of these responses.

11 1111 Q: What is an antibody? A: A sticky protein produced by B cells that binds to a pathogen so that it cannot infect a cell and mark it for destruction by other cells. Q: Extra credit: What is a cytokine? A: A cellular chemical messenger. N o t e t o f a c i l i t a t o r : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n t i f y.

12 1212 SECTION 5 Immune Response: Latent TB Infection (LTBI) versus Active TB Disease (slides 20-30; 30 minutes)!"&*+,-./)+-*01)ct A)&3+.$,&/ are immunologic prisons made of TBspecific CD4 and CD8 T cells that enclose and trap tubercles, keeping them from causing symptoms or being passed on to other people. >+%()#.(/ are TB bacilli contained within a hard shell. Tubercles are the result of TB s ability to short circuit a normal immune system process called phagocytosis the macrophage engulfs and destroys an invading organism. By shutting off the macrophage s ability to break it down, the bacteria is left inside the macrophage, protected from the immune system. When TB is encased in a tubercle it changes what it eats and how much oxygen it needs. It also greatly slows down the speed at which it reproduces. These changes allow it to survive for long periods of time- in some cases an entire human lifespan- inside the body Many people incorrectly use the terms TB infection and TB disease interchangeably. This mistake is both common and understandable, but needs to be cleared up.!"&*+,-./)+-*01)c2 EXERCISE: ASK THE GROUP TO DESCRIBE THE DIFFERENCE BETWEEN LATENT TB INFECTION AND ACTIVE TB DISEASE.!"&*+,-./)+-*01)CC Latent TB infection (LTBI) refers to the period of time when the immune system has been successful in containing the TB bacilli and preventing disease. Active TB disease refers to the time when TB breaks out of latency and causes disease. In some cases, persons may progress to active disease right after being infected with TB. In these cases, the immune system fails to contain TB in granulomas (see below for further explanation) and is referred to as progressive primary TB disease.!"&*+,-./)+-*01)ci Numbered Parts of the Diagram STEPS OF A PHAGOSOME INGESTING A PATHOGEN 1. Pathogens 2. Phagosomes 3. Lysosomes 4. Waste material 5. Cytoplasm 6. Cell membrane During latent TB infection, TB bacilii are captured and encased by macrophages in a structure called a tubercle. The tubercles are in turn walled off by other macrophages and white blood cells in a structure called a granuloma. When in a latent state, TB changes its diet by requiring little to no oxygen, and divides less often to survive inside the granuloma. It is important to note that a person who is latently infected with TB is not contagious and does not experience any symptoms of TB. One of most important reasons that TB is so widespread is because it has developed ways of hijacking our body s normal immune response. a. Ingestion of the pathogen through a process called phagocytosis, followed by an internal pocket called a phagosome being formed b. Normally, the phagosome fuses with another pocket called a lysosome (which contains substances capable of breaking down or lysing the pathogen) to create a phagolysosome. In a normal immune response, the pathogen is broken down in preparation for disposal in the phagolysosome. A cytokine called interferon gamma (IFN-gamma) activates macrophages in a way that promotes lysosome/phagosome fusion and the creation of the phagolysosome. Importantly, TB has the ability to block this process in order to survive in the macrophage s phagosome and prevent its transport by cellular mechanisms to the lysosome for degradation and disposal. c. Waste material is expelled!"&*+,-./)+-*01)cj

13 1313 When TB enters the body, TB-specific CD4 and CD8 T cells move into the lung to contain TB bacilli and eliminate infected cells. This is done to contain the infection and keep it from spreading. In the next step, these immune cells try to release cytokines (cellular chemical messengers) to activate macrophages in a way that normally direct them to break down and dispose of TB. This process known as phagocytosis. (Remember, that phage means eat ; and cyto means cell ). TB has evolved so that it can block cytokines (those chemical messengers). So instead of being eliminated from the body, the TB microbe is encased in the hard shell known as the tubercle. The tubercle protects and hides TB.!"&*+,-./)+-*01)CK The tubercles are contained by TB-specific CD4 and CD8 T cells in an immunological prison called a granuloma that can keep TB from causing disease and spreading it to other people. This can be thought of as both good and bad. It is good in the sense that granulomas can effectively contain TB in such a way that it may never make someone sick, or be transmitted to another person. It is bad in the sense that this process hides the infection from the immune system, allowing the bacteria to survive possibly becoming active at a later time and making a person sick. By changing its diet when in latency and requiring very little oxygen to survive, TB can remain dormant or reproduce at very low levels for an entire lifetime. This ability to change from the active form that uses large amounts of oxygen to a far less active state where very little oxygen is needed is one of the key features of TB. If it were unable to make this switch, the TB would die off inside of the granuloma, because it would be starved of the oxygen it would need to survive. Researchers are trying to figure out how TB is able to survive in this latent form. Understanding this process better might lead to ways of stopping it or figuring out ways to keep it from being able to activate to cause disease. TEACHING POINT: ASK PARTICIPANTS TO EXPLAIN THE DIFFERENCE BETWEEN A TUBERCLE AND A GRANULOMA.!"&*+,-./)+-*01)CP In a matter of weeks after the initial exposure, TB is usually contained by the immune system. Most (about 90%) of the newly generated TB-specific CD4 and CD8 T cells are no longer needed and they automatically die off in a process called apoptosis (cell suicide). This is a normal part of a healthy immune response. TEACHING POINT ASK PARTICIPANTS WHY THEY THINK MOST OF THESE CELLS MUST DIE. ANSWER: THESE CELLS MUST UNDERGO APOPTOSIS BECAUSE THE BODY DOES NOT NEED THEM ANYMORE, AND KEEPING THEM ALIVE WILL TAKE TOO MUCH ENERGY.!"&*+,-./)+-*01)CQ Apoptosis Memory cells Memory immune response

14 1414 The remaining TB-specific CD4 and CD8 T cells become memory cells that continue to patrol for TB and are capable of responding rapidly if they encounter TB again. Immunologic memory enables our immune systems to respond to future challenges so quickly that infection cannot be established in the body at all. This is what we call immunity. It is also how vaccines work. It is important to note that these cells are specific to the pathogen that they were first exposed to. In this case, these CD8 T cells generated in response to TB will only be able to fight TB for the rest of their lives.!"&*+,-./)+-*01)cr In HIV-negative persons, the body s immune system usually keeps TB infection under control. In fact, people with latent TB infection never exhibit symptoms, and only 1 in 10 cases progress to active TB. On the other hand, HIV-positive persons with LTBI have an annual risk of about 10% of developing TB disease. In other words, they have a 1 in 10 chance, every year of their lives, of progressing to active disease. What is the difference between someone having a 10% lifetime risk of developing TB disease (for HIV-negative people) compared to a 10% annual risk for people with HIV? A 10% lifetime risk means that 1 in 10 HIV-negative people with LTBI will develop TB disease over the course of their entire lives. So if you have a group of 100 HIV-negative people with LTBI, 10 of these individuals will develop active TB disease at some point in their lives, meaning that 90 will never get sick with or be able to transmit TB. Most of those who develop TB disease will do so within the first two years after infection. However, people with HIV have about a 10% risk of developing TB disease each year. So, imagine a group of 100 HIV-positive people who have LTBI. After the first year, 10 of them will likely develop TB disease. Leaving 90 HIVpositive persons latently infected with TB. In the second year, 9 of these 90 people (or 10%) will likely develop TB disease, meaning a total of 19 out of the original 100 HIV-positive persons latently infected with TB progressed to active TB disease. After the third year another 8 (or 10% of the remaining 80 latently infected) people would be expected to progress to TB disease, meaning that 27 out of 100 have developed TB disease in three years. The math is a bit challenging, but after 10 years, 64 of the 100 people with HIV who were latently infected with TB would be expected to progress from LTBI to TB disease. START WITH DURING YEAR 1 DURING YEAR 2 DURING YEAR HIV-positive people with LTBI 90 HIV-positive people will stay latently infected 81 HIV-positive people will stay latently infected 73 HIV-positive people will stay latently infected And so on. Total who develop active TB disease during the year 10 (or 10% of 100) will develop active TB disease 9 (or 10% of 90) will develop active TB disease 8 (or 10% of 81) will develop active TB disease Total with active TB disease N o t e t o t h e f a c i l i t a t o r : t h e s e s t a t i s t i c s a r e b a s e d o n pre-haart data.

15 1515 <&8*'*(/ are enlarged air spaces in the lung caused by tubercles breaking out of granulomas. Cavity!"&*+,-./)+-*01)CS Latent TB infection can progress to active disease when the body becomes weak from disease, malnutrition, immune suppression, or even old age. In most people with a healthy immune system, this may never happen-the TB will stay latent, trapped inside of the granulomas. If the immune system is compromised, the immunologic prison of the granulomas no longer successfully contains the tubercles and they begin to multiply and break out of the granulomas damaging the lung tissue and creating cavities. UG-E:3.4/)#@ refers to TB disease of the lungs.?v74.,g-e:3.4/)#@ refers to TB disease outside of the lungs.!"&*+,-./)+-*01)it Active TB disease may manifest in the lungs (pulmonary TB) and/or in other parts of the body (extrapulmonary TB). Pulmonary TB is the most common form of TB disease. As a result, many people mistakenly believe that TB is a disease of the lungs only. Typically, pulmonary TB expels pus into the lungs, which a patient may cough up in spit or sputum. In fact, the most common way doctors diagnose TB is to look for the bacteria in sputum using a microscope. Extrapulmonary TB (EPTB) is normally rare, but occurs in up to 40% of TB cases among people with HIV. B ' = = A $ L< Latent TB infection refers to the time when a person is infected with the MTB bacteria, but the infection is contained by the immune system, and the person is not sick or contagious. Active TB disease refers to the time when a person s TB infection breaks through the immune system s control and causes symptoms of disease and that person may be contagious. In fact, HIV-negative persons have only a 10% chance that they will develop active TB over the course of their lifetime, while people with HIV have a 10% chance of developing active TB disease each year. An HIV-positive person bears an increased risk of progressing to TB disease, particularly as immune function decreases. Likewise, factors such as young and old age, malnutrition, and other disease may increase an individual s risk of disease progression to active TB disease. $?M!?N< Q: What is the difference between latent TB infection and active TB disease? A: Latent TB infection refers to the time when a person is infected with the mycobacterium tuberculosis bacteria, but the infection is contained by the immune system, and the person is not sick or contagious. Active TB disease refers to the time when a person s TB infection breaks through the immune system s control and causes symptoms of disease and that person may be contagious. Q: Is someone who is latently infected with TB at risk for transmitting TB to another? A: No. Q: What is the risk for a latently TB infected HIV-negative person developing active TB disease as compared to an HIV-positive person? A: An HIV-negative person s risk is about 10% over his or her lifetime and an HIV-positive person s risk is about 10% per year. N o t e t o t h e f a c i l i t a t o r : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n f i t y.

16 1616 SECTION 6 Challenges to TB Control in TB/HIV Coinfection (slides 31-33; 10 minutes)!"&*+,-./)+-*01)i2 Extrapulmonary TB (EPTB) Active TB disease often manifests in the lungs (pulmonary TB) but can also be found in other parts of the body (extrapulmonary TB). Pulmonary TB is the most common form of TB disease. Extrapulmonary TB (EPTB) is normally rare but occurs in up to 40% of TB cases among people with HIV and rarely involves only a single organ. TB s ability to cause disease in so many parts of the body helps to illustrate how challenging it is. Extrapulmonary TB may attack one specific organ or multiple of areas of the body. Because of this, many medical providers miss diagnosing EPTB because of the many possible symptoms of this disease. TEACHING POINT: ASK PARTICIPANTS TO NAME AREAS OF THE BODY WHERE THEY THINK TB CAN CAUSE DISEASE.!"&*+,-./)+-*01)IC) EPTB can be found in various parts of the body: common form of EPTB. common form of EPTB in people with HIV. (pericardium).!"&*+,-./)+-*01)ii Smear-negative TB (for more on this see TB/HIV Impact and TB Diagnostics modules) The most common test used to diagnose TB is sputum-smear microscopy. Patients suspected of having TB provide a sputum sample (coughed up from the lungs), which is washed in an acidic solution in order to retain specific staining dyes so that the TB bacilli can be seen under a microscope (see section 2). Smear test results may be reported as acid fast bacilli-positive (AFB+) or acid fast bacilli-negative (AFB-), or more commonly known as smear positive or smear negative. People with HIV have fewer TB bacteria in their sputum, due to fewer CD4 and CD8 T cells, which in healthy bodies expel TB into the sputum. As CD4 T cells are lost due to and compromised by HIV infection, CD8 T cells lose the directional support they need to do their job of killing TB-infected cells because they are no longer being told to kill TB-infected cells. TB is expelled into the sputum when TB-infected cells are killed. Therefore, the chance of smear-negative TB increases because fewer TB bacilli are released in the sputum. This means that TB is not being released into the sputum, so despite the fact that someone may have TB in his or her system it is not

17 1717 detected using sputum-smear microscopy. Up to 61% of people coinfected with HIV and TB generate smear-negative tests in other words, an incorrect diagnosis. B ' = = A $ L< People with HIV are more likely to have extrapulmonary and smear-negative TB because of their impaired immune function. As a result, they are at risk for being misdiagnosed as not having TB. $?M!?N Q: What is the difference between pulmonary and extrapulmonary TB? A: Pulmonary TB refers to TB in the lungs, and extrapulmonary refers to TB outside of the lungs. Q: Name two types of extrapulmonary TB. A: See list on page 14. Q: Why are HIV-positive people at increased risk for smear-negative TB? A: Because they are less likely to have functioning CD4 and CD8 cells that kill the TB-infected cells thereby expeling TB into the sputum. N o t e t o f a c i l i t a t o r : I f p a r t i c i p a n t s h a d d i f f i c u l t y w i t h t h e s e q u e s t i o n s r e t u r n t o t h e s l i d e s t o r e i n f o r c e p o i n t s t h e y d i d n o t i d e n t i f y.

18 1818 SECTION 7 Advocacy Issues (slide 34; 5 minutes)!"&*+,-./)+-*01)ij Because new cases of TB occur most often in HIV-positive persons in most high burden settings, there is tremendous overlap between the HIV and TB epidemics. While the international community has begun making important progress in expanding worldwide access to life saving HIV treatments, much of this progress is threatened by the lack of attention to HIV/TB coinfection. Until TB is more effectively addressed within the context of HIV, efforts to combat HIV internationally will be less effective. There are lessons to be learned from the HIV advocacy movement. HIV activists have shown that concerted advocacy can shape an effective response to public health challenges. HIV advocacy has also shown that a good scientific understanding of the disease is crucial in both developing and implementing advocacy priorities. One of the most pressing issues for TB advocates in relation to basic science is the urgent need for better understanding of TB, as this is essential for newer and better prevention and infection control strategies, vaccines, diagnostics, and treatments. Unfortunately, the Global Plan to Stop Tuberculosis: ( did not originally account for basic science in its research priorities. However, the research component of the Plan is going through a revision, and basic science will be included in the research priorities. Additionally, the governments of countries bearing a high TB burden need to increase their investment in basic science research and programs. And given the challenges facing people with HIV in TB control, national AIDS control programs need to include TB control in their program activities. =%&'>?)$?M!?N<!"&*+,-./)+-*01)IK 1. How long has TB been infecting humans? 2. When was TB first isolated, and by whom? 3. Name two differences between TB and HIV. 4. Why are people with HIV at higher risk for TB? 5. What is the difference in risk for developing active TB disease for a person with HIV versus a person who does not have HIV? 6. What is binary fission? 7. What does AFB refer to? 8. How is TB transmitted? Name one factor that may impact TB transmission. 9. What are antigen-presenting cells? 10. What role do CD4 T cells play in the immune response? 11. What is the difference between latent TB infection and active TB disease? 12. Why are people with HIV more likely to have smear-negative TB? N o t e t o f a c i l i t a t o r : P l e a s e n o t e t h a t t h i s i s n o t a n e x h a u s t i v e l i s t o f r e v i e w q u e s i t o n s a s i t o n l y t o u c h e s o n s o m e o f t h e i n f o r m a t i o n d i s c u s s e d i n t h i s m o d u l e, t h i s i s m e a n t t o b e a g u i d e a n d f a c i l i t a t o r s a r e e n c o u r a g e d t o d e v e l o p t h e i r o w n r e v i e w q u e s t i o n s.