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This time on Infection Landscapes we are going to cover one of the most significant infectious diseases to affect humans: tuberculosis. Tuberculosis is an ancient disease and is currently the world's second leading cause of death due to an infectious disease.
The Pathogen. Tuberculosis is caused by bacteria in the Mycobacteriaceae family. This family is comprised of many slow growing, acid-fast bacilli, most of which live in soil and water and help to degrade organic material. However, there are five species that are capable of causing tuberculosis in humans, and three of these are highly pathogenic. Mycobacterium tuberculosis, M. africanum, M. bovis are the three highly pathogenic agents capable of causing tuberculosis in humans. M. tuberculosis causes the vast majority of human tuberculosis worldwide.
M. canettii and M. microti are also capable of causing tuberculosis in humans but these are rare etiologic agents. This group of 5 closely related bacteria that cause tuberculosis in humans are referred to collectively as the Mycobacterium complex. Because of the primacy in human infection and the global burden of disease, this discussion will focus on infections with M tuberculosis.
Mycobacteria are thin rod-shaped bacteria and are approximately 4µm by 0.3 µm in size. These bacteria are strictly aerobic and have a high concentration of high molecular weight lipids in their cell wall. As a consequence, these organisms are hydrophobic and thus resistant to water-based bactericidal agents, as well as drying out, which is very important to the infectivity of M. tuberculosis.
Mycobacteria are very slow growing in culture, which can impede diagnosis for people with active tuberculosis. Mycobacteria require 4 to 6 weeks to grow on solid media, and 9 to 16 days using rapid liquid cultures.
The target cells for M. tuberculosis are macrophages in the alveoli deep in the the lungs.
The Disease. Infection with M. tuberculosis begins with latent infection that can progress to active disease. Latent tuberculosis infection (LTBI) is asymptomatic and does not constitute active disease. Most people with LTBI do not know they are infected. Following initial infection in most people, the immune system will contain and control the infection, but, typically does not eliminate the infection. Approximately 5% to 10% of individuals are not able to control the initial infection and will develop primary tuberculosis, while a large proportion of the the remaining 90% to 95% of individuals are left with LTBI. Among this large group of people, M. tuberculosis can remain dormant in macrophages and other cells for decades. The dormant myocbacteria will become active again in approximately 5% to 10% of those with LTBI as a result of various factors that can lead to reduced vigilance of the immune system. Active tuberculosis among this group is referred to as reactivation tuberculosis.
Clinical tuberculosis most often affects the lungs and respiratory tract. However, it can affect almost any organ system. Active tuberculosis can manifest as pulmonary or extrapulmonary disease irrespective of whether the individual is a primary or reactivation case. However, approximately 80% of clinically manifested tuberculosis is pulmonary among individuals with good immune function, while extrapulmonary tuberculosis can be seen more frequently in immunocompromised people. Pulmonary tuberculosis can be mild or severe and present with any of the following symptoms: coughing with or without blood in the sputum, fever, night sweats, chills, weight loss, anorexia, fatigue, and chest pain. Extrapulmonary disease can also present with fever, fatigue, night sweats, and wasting, but prominent symptoms will typically stem from the affected organ system. Extrapulmonary tuberculosis will commonly involve the pericardium, genitourinary tract, gastrointestinal tract, vertebrae of the spine and other bones of the skeleton, the meninges, adrenal glands, lymph nodes, eyes, and skin. The figure below depicts common symptoms of different tuberculosis classifications by anatomical site. It shows how some symptoms are common across different classifications while others are specific to a particular classification of tuberculosis.
Systemic tuberculosis occurs when M. tuberculosis is disseminated throughout the body by way of the blood or lymph, with small lesions appearing in most organ systems. Disseminated tuberculosis was originally called miliary tuberculosis because the lesions appeared as grains of millet. When it does occur, miliary tuberculosis is more common in children and in immunocompromised people.
The Epidemiology and the Landscape. Mycobacterium tuberculosis is spread primarily by airborne transmission. People with LTBI do not transmit infection to others. People with active pulmonary tuberculosis release very small droplets into the air when they cough, talk, or sing. As these droplets evaporate in the air, the remaining droplet nuclei are comprised of the solid components of the mucous and, potentially, M. tuberculosis, which is capable of infecting a new host. M. tuberculosis is only moderately infectious as transmission occurs in only 20% to 30% of individuals exposed to someone with active tuberculosis. However, this is an average estimate, whereas any specific infection will depend on effective contact between an infected case and susceptible persons, which varies greatly by factors such as the immunocompetence of the susceptible host, frequency and intimacy of contact between infected and susceptible individuals, severity of disease in the infected individual, and housing, working, and other social conditions.
M. tuberculosis can also be transmitted by way of the gut, genitourinary tract, and eye, or through compromised skin. Transmission via these extrapulmonary, non-airborne, routes is relatively rare, but is more common in areas of high endemicity. Nevertheless, airborne transmission is still the most frequent route of infection across the world. The graphic below (published in Chest. 2012;142(3):761-773. doi:10.1378/chest.12-0142) presents a nice summary of the transmission and natural history of M. tuberculosis.
Approximately one third of the population of the world is infected with M. tuberculosis. That sentence is worth a pause to consider its magnitude. While many of these are latent infections and thus do not represent active tuberculosis cases, they do represent an incredibly large pool of infection from which an extremely large number of active cases emerge on an annual basis. As a result, there are approximately 1.8 million deaths due to tuberculosis across the world each year. Globally, this is the second leading cause of death due to an infectious disease. The global distribution of tuberculosis incidence is depicted in the map below produced by the World Health Organization (WHO):
Of all WHO global regions, The Southeast Asia region has the largest absolute number of cases, while the Africa region has the highest incidence density. Together, the WHO Southeast Asia and Africa regions account for almost 70% of the world's active tuberculosis cases. In some areas of these regions 60% to 70% of the adult population is latently infected with M. tuberculosis.
The natural history of tuberculosis directly affects its propagation through a population. Stage 1: In a given population in a particular period of time, the pathogen's reservoir is comprised of all those people with LTBI. Stage 2: Each year some proportion of these individuals with LTBI develop reactivation tuberculosis. Stage 3: New infections occur when the individuals with active disease transmit M. tuberculosis to their susceptible contacts. An average of 10 contacts are infected before the infectious individual is treated with anti-tuberculosis medication and further transmission is arrested. Stage 4: Five to ten percent of the newly infected contacts (the secondary infections) will develop primary tuberculosis, and then will transmit new infections to their contacts (Stage 3). Most of the remaining newly infected retain LTBI and replenish the pathogen reservoir (Stage 1).
Perhaps the most important feature of the epidemiology of tuberculosis emerges at a critical point where the social and physical landscapes converge: the structure of population density. Overcrowding is a defining feature of areas of high tuberculosis endemicity. As described above, ongoing close contact between active cases and susceptible individuals is necessary to maintain endemicity in a population. Moreover, housing conditions characterized by a lack of quality materials and very dense construction are typically the same conditions that characterize poor ventilation in the home and extended close contact between members of the household as well as neighbors. This landscape epidemiology defines areas wherein M. tuberculosis can be easily transmitted and propagate through a population, even for an organism that is not necessarily highly transmissible.
It is also important to note that co-infection with the human immunodeficiency virus (HIV) is probably the most significant risk factor for developing active tuberculosis once infected with M. tuberculosis. The risk of reactivation tuberculosis ranges from 3% to 14% per year, and averages 10% per year, among individuals who had LTBI prior to their infection with HIV. Forty percent of new M. tuberculosis infections among individuals already infected with HIV will develop primary active tuberculosis (compared to 5% to 10% of new infections among those not infected with HIV). Tuberculosis is now the leading opportunistic infection associated with HIV infection in most areas of the developing world.
Treatment. Treating tuberculosis requires a long-term commitment. Specifically, at least 6 months of treatment are required because of the heterogeneous population of M. tuberculosis in an infected individual, which is comprised of active and dormant organisms. Medication that is effective against active mycobacteria may not be against latent mycobacteria and, thus, extended treatment ensures that the whole population of M. tuberculosis will eventually be exposed to the drug. However, undergoing treatment over a long time period also favors the emergence of drug-resistance gene mutations in the M. tuberculosis population. Thus, at least two effective drugs must be administered: this reduces the probability of developing drug-resistant bacilli. Adherence to treatment with the full regimen is essential for treatment success. Non-adherence can lead to treatment failure in the individual as well as the development of antibiotic resistant forms of M. tuberculosis. To effect complete resolution of infection in the individual and mitigate the spread of antibiotic resistance in the population, WHO recommends the short-course of directly observed therapy (DOTS) regimen, comprised of four drugs (typically isoniazid, rifampicin, pyrazinamide, and ethambutol) for two months, followed by two drugs (typically isoniazid and rifampicin) for four months. Directly observed therapy requires that a health care worker must monitor each tuberculosis patient closely and observe the patient take each dose of anti-tuberculosis medication.
Nevertheless, antibiotic resistance has been a difficult ongoing problem for many years and has now reached a point of crisis, whereby some strains of M. tuberculosis are resistant to at least two of the first-line, and most powerful, drugs (isoniazid and rifampicin). Disease caused by these strains is known as multi-drug resistant tuberculosis (MDR-TB). Worse still, other strains have developed even more extensive resistance as a result of the inadequate and under-resourced management of MDR-TB in many regions of the world. These strains are also resistant to isoniazid and rifampicin, as well as at least one of the quinolones and at least one of the second-line drugs kanamycin, capreomycin, or amikacin. Disease caused by these strains is known as extensively drug resistant tuberculosis (XDR-TB).
Control and Prevention. There are several critical factors that need to be implemented to realize an effective tuberculosis control and prevention program. First, rigorous case finding and treatment is obviously critical to save the individual as well as to stop transmission of infection to contacts. Case identification must combine microscopy and clinical symptoms, and treatment should be comprised of the short-course of directly observed therapy (DOTS). Second, exhaustive contact tracing for contacts of each active tuberculosis case should be carried out in the field so that new infections can be identified and treated before becoming active cases. Third, a good surveillance system is fundamental to the control of any infectious disease. An administrative system for recording cases and monitoring outcomes is necessary to estimate the occurrence of disease and identify temporal trends and spatial clusters. Furthermore, good surveillance instruments combined with molecular epidemiology are also necessary to monitor antibiotic resistance in M. tuberculosis. Fourth, an adequate supply of tuberculosis medications must be available to populations with endemic tuberculosis. This may seem obvious, and it is, but unfortunately the lack of a consistent supply of medication has hampered many control programs particularly in poor areas of the developing world. Fifth, there must be a government commitment to tuberculosis control. Significant resources and public health infrastructure and personnel are required to implement and sustain tuberculosis control programs, and sustainability is critical because control of this disease requires a long-term effort. As such, a strong commitment by government agencies, which can mobilize the necessary resources and infrastructure, is essential to regional control of tuberculosis.
This time on Infection Landscapes we are going to cover one of the most significant infectious diseases to affect humans: tuberculosis. Tuberculosis is an ancient disease and is currently the world's second leading cause of death due to an infectious disease.
The Pathogen. Tuberculosis is caused by bacteria in the Mycobacteriaceae family. This family is comprised of many slow growing, acid-fast bacilli, most of which live in soil and water and help to degrade organic material. However, there are five species that are capable of causing tuberculosis in humans, and three of these are highly pathogenic. Mycobacterium tuberculosis, M. africanum, M. bovis are the three highly pathogenic agents capable of causing tuberculosis in humans. M. tuberculosis causes the vast majority of human tuberculosis worldwide.
Mycobacterium tuberculosis
M. canettii and M. microti are also capable of causing tuberculosis in humans but these are rare etiologic agents. This group of 5 closely related bacteria that cause tuberculosis in humans are referred to collectively as the Mycobacterium complex. Because of the primacy in human infection and the global burden of disease, this discussion will focus on infections with M tuberculosis.
Mycobacteria are thin rod-shaped bacteria and are approximately 4µm by 0.3 µm in size. These bacteria are strictly aerobic and have a high concentration of high molecular weight lipids in their cell wall. As a consequence, these organisms are hydrophobic and thus resistant to water-based bactericidal agents, as well as drying out, which is very important to the infectivity of M. tuberculosis.
Mycobacteria are very slow growing in culture, which can impede diagnosis for people with active tuberculosis. Mycobacteria require 4 to 6 weeks to grow on solid media, and 9 to 16 days using rapid liquid cultures.
The target cells for M. tuberculosis are macrophages in the alveoli deep in the the lungs.
The Disease. Infection with M. tuberculosis begins with latent infection that can progress to active disease. Latent tuberculosis infection (LTBI) is asymptomatic and does not constitute active disease. Most people with LTBI do not know they are infected. Following initial infection in most people, the immune system will contain and control the infection, but, typically does not eliminate the infection. Approximately 5% to 10% of individuals are not able to control the initial infection and will develop primary tuberculosis, while a large proportion of the the remaining 90% to 95% of individuals are left with LTBI. Among this large group of people, M. tuberculosis can remain dormant in macrophages and other cells for decades. The dormant myocbacteria will become active again in approximately 5% to 10% of those with LTBI as a result of various factors that can lead to reduced vigilance of the immune system. Active tuberculosis among this group is referred to as reactivation tuberculosis.
Clinical tuberculosis most often affects the lungs and respiratory tract. However, it can affect almost any organ system. Active tuberculosis can manifest as pulmonary or extrapulmonary disease irrespective of whether the individual is a primary or reactivation case. However, approximately 80% of clinically manifested tuberculosis is pulmonary among individuals with good immune function, while extrapulmonary tuberculosis can be seen more frequently in immunocompromised people. Pulmonary tuberculosis can be mild or severe and present with any of the following symptoms: coughing with or without blood in the sputum, fever, night sweats, chills, weight loss, anorexia, fatigue, and chest pain. Extrapulmonary disease can also present with fever, fatigue, night sweats, and wasting, but prominent symptoms will typically stem from the affected organ system. Extrapulmonary tuberculosis will commonly involve the pericardium, genitourinary tract, gastrointestinal tract, vertebrae of the spine and other bones of the skeleton, the meninges, adrenal glands, lymph nodes, eyes, and skin. The figure below depicts common symptoms of different tuberculosis classifications by anatomical site. It shows how some symptoms are common across different classifications while others are specific to a particular classification of tuberculosis.
The Epidemiology and the Landscape. Mycobacterium tuberculosis is spread primarily by airborne transmission. People with LTBI do not transmit infection to others. People with active pulmonary tuberculosis release very small droplets into the air when they cough, talk, or sing. As these droplets evaporate in the air, the remaining droplet nuclei are comprised of the solid components of the mucous and, potentially, M. tuberculosis, which is capable of infecting a new host. M. tuberculosis is only moderately infectious as transmission occurs in only 20% to 30% of individuals exposed to someone with active tuberculosis. However, this is an average estimate, whereas any specific infection will depend on effective contact between an infected case and susceptible persons, which varies greatly by factors such as the immunocompetence of the susceptible host, frequency and intimacy of contact between infected and susceptible individuals, severity of disease in the infected individual, and housing, working, and other social conditions.
M. tuberculosis can also be transmitted by way of the gut, genitourinary tract, and eye, or through compromised skin. Transmission via these extrapulmonary, non-airborne, routes is relatively rare, but is more common in areas of high endemicity. Nevertheless, airborne transmission is still the most frequent route of infection across the world. The graphic below (published in Chest. 2012;142(3):761-773. doi:10.1378/chest.12-0142) presents a nice summary of the transmission and natural history of M. tuberculosis.
Approximately one third of the population of the world is infected with M. tuberculosis. That sentence is worth a pause to consider its magnitude. While many of these are latent infections and thus do not represent active tuberculosis cases, they do represent an incredibly large pool of infection from which an extremely large number of active cases emerge on an annual basis. As a result, there are approximately 1.8 million deaths due to tuberculosis across the world each year. Globally, this is the second leading cause of death due to an infectious disease. The global distribution of tuberculosis incidence is depicted in the map below produced by the World Health Organization (WHO):
Of all WHO global regions, The Southeast Asia region has the largest absolute number of cases, while the Africa region has the highest incidence density. Together, the WHO Southeast Asia and Africa regions account for almost 70% of the world's active tuberculosis cases. In some areas of these regions 60% to 70% of the adult population is latently infected with M. tuberculosis.
The natural history of tuberculosis directly affects its propagation through a population. Stage 1: In a given population in a particular period of time, the pathogen's reservoir is comprised of all those people with LTBI. Stage 2: Each year some proportion of these individuals with LTBI develop reactivation tuberculosis. Stage 3: New infections occur when the individuals with active disease transmit M. tuberculosis to their susceptible contacts. An average of 10 contacts are infected before the infectious individual is treated with anti-tuberculosis medication and further transmission is arrested. Stage 4: Five to ten percent of the newly infected contacts (the secondary infections) will develop primary tuberculosis, and then will transmit new infections to their contacts (Stage 3). Most of the remaining newly infected retain LTBI and replenish the pathogen reservoir (Stage 1).
Perhaps the most important feature of the epidemiology of tuberculosis emerges at a critical point where the social and physical landscapes converge: the structure of population density. Overcrowding is a defining feature of areas of high tuberculosis endemicity. As described above, ongoing close contact between active cases and susceptible individuals is necessary to maintain endemicity in a population. Moreover, housing conditions characterized by a lack of quality materials and very dense construction are typically the same conditions that characterize poor ventilation in the home and extended close contact between members of the household as well as neighbors. This landscape epidemiology defines areas wherein M. tuberculosis can be easily transmitted and propagate through a population, even for an organism that is not necessarily highly transmissible.
It is also important to note that co-infection with the human immunodeficiency virus (HIV) is probably the most significant risk factor for developing active tuberculosis once infected with M. tuberculosis. The risk of reactivation tuberculosis ranges from 3% to 14% per year, and averages 10% per year, among individuals who had LTBI prior to their infection with HIV. Forty percent of new M. tuberculosis infections among individuals already infected with HIV will develop primary active tuberculosis (compared to 5% to 10% of new infections among those not infected with HIV). Tuberculosis is now the leading opportunistic infection associated with HIV infection in most areas of the developing world.
Treatment. Treating tuberculosis requires a long-term commitment. Specifically, at least 6 months of treatment are required because of the heterogeneous population of M. tuberculosis in an infected individual, which is comprised of active and dormant organisms. Medication that is effective against active mycobacteria may not be against latent mycobacteria and, thus, extended treatment ensures that the whole population of M. tuberculosis will eventually be exposed to the drug. However, undergoing treatment over a long time period also favors the emergence of drug-resistance gene mutations in the M. tuberculosis population. Thus, at least two effective drugs must be administered: this reduces the probability of developing drug-resistant bacilli. Adherence to treatment with the full regimen is essential for treatment success. Non-adherence can lead to treatment failure in the individual as well as the development of antibiotic resistant forms of M. tuberculosis. To effect complete resolution of infection in the individual and mitigate the spread of antibiotic resistance in the population, WHO recommends the short-course of directly observed therapy (DOTS) regimen, comprised of four drugs (typically isoniazid, rifampicin, pyrazinamide, and ethambutol) for two months, followed by two drugs (typically isoniazid and rifampicin) for four months. Directly observed therapy requires that a health care worker must monitor each tuberculosis patient closely and observe the patient take each dose of anti-tuberculosis medication.