Thursday, April 18, 2013

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.


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.


61 comments:

  1. One-third of the world population -- that's a huge proportion! Of that number (over 2 billion people), would it be correct to assume around 70-80% are latent cases? Also, for the estimated TB incidence rates, do those include latent infections or only active ones?

    How important is surveillance and treatment of latent TB infection? Considering the large number of cases and intensive treatment, it may be too costly and unwieldy overall to track down all cases, especially in the developed world (though many institutions in the US require a TB test, so that helps somewhat).

    Also, no mention is made of the TB vaccine in this article...? Admittedly its effectivity is not that high.

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    1. TB vaccine is only 60-80% effective in prevention for up to 10-15 years. It is not much useful outside endemic areas. Also you can’t booster it.

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    2. I was also wondering about surveillance - in large, crowded, population dense areas, it seems impossible to identify all the people that came in contact with someone who has TB. Just imagine trying to do that here in New York City - so many people use public transportation daily that it would create a real problem. Obviously this wouldn't be the case in developing countries but I wonder if there are variations state to state in procedures for dealing with/controlling outbreaks based on population density and use of public spaces and transportation.

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    3. Racquel BreretonJune 17, 2014 at 9:14 AM

      Multi-drug resistant TB is a growing concern and is highly attributed to poor adminstration of initial drug therapy, whether due to patient compliance or shortage of antibiotics.

      It's also interesting to note cases of extrapulmonary TB. I observed a diagnosis labeled "TB of the heart", which I initially thought was made in error. It wasn't until I did a google search that I found TB on the pericardium is possible but also very curable.

      Working in a laboratory, I have seen cases of TB isolated from multiple body sites, including the urinary tract, blood, and most commonly respiratory samples. It's interesting to note unusual cases of disseminated TB isolated from uncommon body systems.

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    4. Is part of the reason TB is able to become so drug-resistant because it is a fat-based bacteria, rather than a water based one?

      And I agree with everyone that surveillance would be difficult. I think in these times TB, though clearly an infectious disease dominant ing our world, is highly under-publicized. Also, with such long latency periods, it's hard to convince people they need to be proactive and take meds that are preventive of the reactive stage, because most people's mentality is, it's not broken yet so why fix it.

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    5. I think part of the reason why TB has become resistant is because many individuals do not finish their antibiotic medications as they are advised to do by their doctors. This would most likely contribute to antibiotic resistance.

      I also agree with you that TB is very hard to keep an active surveillance on because it is highly infectious and many who have it are unaware and able to spread it. Transportation has also contributed immensely to the spread of TB, which also makes it harder to tract down exposed individuals.

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    6. @ Racquel: I thought TB was found only in the pulmonary system, and am surprised to learn that TB could be located in other parts of the body. “TB of the heart” along with other site identification is quite a new phenomenon for me, and has opened my eyes to TB in other parts of the body. I wonder if a sample of unknown origin tested in the lab and found to have TB, can be identified by the body site from which it was extracted.

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    7. As others had previously mentioned about the importance of surveillance, I too believe that surveillance play a major role in tracking TB infection as well as information on treatment regimen in case of reinfection. Additionally, contact tracing and case management plays a huge role in maintaining a proper TB surveillance. Thus, having a robust system is necessary in tracing the index patient and interviewing their contacts for further investigations. Since majority of the new cases, particularly in NYC are amongst the foreign-born, it seems reasonable to link the immigration health status to the city’s TB registry.

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    8. Monsurat Odeneye:

      Surveillance of TB is definitely important to help monitor the disease on regional, global and national levels. TB Surveillance will allow health workers assess the disease burden and measure TB incidence. It will also help reveal high-risk populations especially in the case of a developing countries such as the people of Swaziland, South Africa with HIV infection, who are vulnerable to the disease. It also can help detect cases such as the outbreak of Multi-drug resistant. It is crucial to keep track of all individuals with TB and ensure it gets recorded in the TB register to allow health workers monitor and record the patient’s treatment until completion. Lastly, it can help determine possible transmission chains of TB cases and to identify clusters for investigations.

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  2. Tamara raises good questions. I would like to pursue further study on this. I would guess incidence rates would include only active cases, but I'm interested to know what the actual incidence would refer to.
    I'm also curious about the TB vaccine, and intend to do further study, maybe post briefly on findings. I believe that there are more virulent and drug resistant strains of TB in some places. I'd like to know more about who is affected by these, and how effectively the medical community at large has responded to them.

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  3. Drug therapy for TB is relatively long, for pulmonary TB 6 months and extrapulmonary, MDR-TB and XDR-TB varies 6-12 months. Patient compliance is a big problem especially with all the side effects. DOTS regimen helps quite a lot. Thankfully so far in US, we don’t see many cases of XDR TB but there was supposedly an outbreak of XDR TB in South Africa in 2006. It would be difficult to treat XDR-TB in litigious society like US.

    Another strain is TDR-TB, Totally drug resistant tuberculosis. Fortunately, very few cases of this strain are reported world over but it is a rising problem. Rates of TB have been dropping in US and now seen more in foreign-born population and minorities.

    Last year, one guy with XDR-TB travelled from US to several countries in Europe defying doctors and CDC. Does anyone remember the case; it was all over in media?

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    1. I didn't hear of the case where the man travelled through Europe, but I did hear of a case where an infected homeless man exposed a lot of people (can't remember the number) in NYC during his travels between mental & general hospitals, and jail. He didn't have any comorbidities, but was still infectious.

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    2. “Andrew Speaker” a personal injury lawyer from Atlanta was the case I was talking about.

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    3. Racquel BreretonJune 17, 2014 at 9:00 AM

      I do recall the case of the Nepalese man who was detained at the U.S. border carrying a strain of XDR-TB.

      http://online.wsj.com/news/articles/SB10001424127887323978104578332461533970412

      While he interacted with hundreds of people throughout his extensie travel, it is somewhat reassuring to note that infection requires prolonged exposure and is also determined by the susceptibility of the host.

      There was also a case of an healthcare worker infected with active TB who worked on a labor and delivery unit in a NYC hospital. The same concept applied. Measures were taken to assure no active TB infection was transmitted to patients, however it was not of dire concern considering infection requires ample and prolonged exposure.

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  4. I was also blown away by the sheer number of people who are infected with M. tuberculosis, as well as by the number of yearly deaths due to the infection. The enormous number of infected people makes sense when I saw that an average of 10 contacts are infected before an individual is treated. I'm wondering whether a population can become saturated with the infection at a given point, whether some people are more resistant to primary infection than others.

    Directly observed therapy appears to be a great way to minimize the risk of antibiotic-resistant strains of M. tuberculosis. Is DOT only employed for active tuberculosis, or also for patients who are carrying the latent organism? How does this play out in countries with an enormous prevalence of the disease?

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    1. I would think that DOT therapy would be near impossible in countries with high prevalence of the disease just due to the financial resources and manpower involved to track a large population with active tb. I'm also wondering what the lasting effect of a prolonged drug treatment with multiple types of antibiotics would be on the immune system and an individual's overall wellbeing. I would think that it would lower the immune response and reduce immunogenicity in general. With a weakened immune system due to long drug treatment, it would perhaps increase the risk of acquiring other types of infections as well.

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    2. I think that this is where the work of NGOs and community workers become important. In South Africa,for instance, caregivers employed by NGOs with private funding partner with communities and clinics and provide services to the community where government resources fall short. They actively participate in the care and tracking of TB patients and help to ensure medication adherence.

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    3. As far as the CDC's website on directly observed therapy (DOT) is concerned, both active and LTBI are recommended to get DOT. It makes sense since 5-10% of those dormant, LTBI becomes active every year for various reasons and not having DOT could likely be one of the factors.

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  5. In response to Ms. Allison -
    DOT is used for both latent and active tuberculosis. Mycobacterium is very slow growing bacteria and that makes it very important to maintain therapeutic level of antibiotics in body for prolonged period of time to achieve complete cure. Non-compliance with medication regimen not only leads to increased morbidity but also antibiotic resistance, as result MDR-TB and XDR-TB.
    Every DOT center or hospital has staff, which medicates patient every alternate day (3 times a week) for full duration of regimen. Patient swallows meds and/or gets shots on every visit, this ensures compliance. Occasionally, reliable patients can be given prescriptions to take at home daily.
    DOT therapy is international as recommended by WHO. I did rotation in DOT center in my medical school in India. In south Asia, they follow DOT regimen pretty much everywhere. I don’t know about Europe.

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    1. But then again, I just wonder how reliable DOT truly is? In other words, in areas that have poor infrastructure and limited resource but have high endemicity of TB, how effective can DOT truly be? I guess I'm just thinking along the lines of poor rural areas in which there maybe a small medical treatment clinic and a largely sick population. I think that DOT can be burdensome and impractical in areas that truly cannot allocate the resource to it. Not only that but if the strain on resources is too high, I feel that they are likely to miss many cases of TB because they cannot afford to follow and watch those with active TB who can pass on TB to those they have sustained contact with.

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  6. Treating TB requires consistent access and adherence to the drug regimen, and non-compliance not only prevents those who have TB from getting better, but contributes to MDR-TB. I remember reading about Paul Farmer and his work on TB and HIV-AIDS in developing nations. He implemented a system utilizing community healthcare workers, who go and deliver medications to patients in order to ensure the continued access and adherence necessary to treat these diseases. Additionally, he has done a lot of work towards treated MDR-TB, including using DOTS-plus, which has a provision for treating MDR-TB.

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    1. In response to the previous post:

      Based on WHO,about 3.6% of new TB patients in the world have multi-drug resistant strain in 2013. Treatment for MDR TB involves drug therapy over many months or years. Despite the longer course of treatment, the cure rate decreases from over 90 percent for nonresistant strains of TB to 50 percent or less for MDR TB. Therefore building an effective TB control and prevention program is necessary. Also the labor cost becomes expensive if community healthcare workers have to deliver medication to TB patients for years for their MDR TB treatment.

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  7. I found the sheer number of active TB cases to be striking; one third of the world is infected with TB. Although these are latent cases it still speaks loud about how quickly TB can spread in populations. I also found it striking that there are 1.8 million deaths due to TB. This highly pathogenic infection has the ability to lay dormant in macrophages for decades. I imagine that this level of dormancy makes it even more difficult to control TB. I wonder if the TB treatment is specific only to active TB or if it is appropriate for those with latent infections?

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    1. Janay, as discussed in class today, the ideal treatment for TB consists of several drugs administered at once to ensure that all the stages of the bacilli population are targeted and to help prevent mutation. I think that a big problem is that a large portion of individuals with latent infections have no idea that they are infected in the first place. With limited screening tools in certain areas, it can be very difficult to even find out who needs to be treated in the first place.

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    2. Although it is a problem that individuals with latent TB are not aware of their infection status, the fact that a person does not become infective until they show symptoms and the infection is not longer latent prevents the spread of TB from becoming even more extensive. Although it is still an extremely difficult task to do surveillance for a disease like TB in terms of identifying those in contact with each infected individual, it is frightening to imagine how impossible it would be if those with non-symptomatic infections were infectious.

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    3. I agree that it is not an easy task to find out all the infected individuals for treatment. But I also find that the current control measures for TB in U.S. do not effectively identify the vaccinated and LTBI individuals, as they are just grouped as having previous exposure to TB and given medications when found with positive PPD results. Non-compliance to the treatment is common from this population pool as they themselves are sometimes unclear about their status or even in denial of the infection. This would cause delay for treatment among the infected and the rapid spread of the disease in the susceptible population.

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    4. This was a very detailed account for TB. I have always been somewhat interested in the topic as both my great grandmother's parents died from TB, (her father before her birth, and her mother immediately after). I wasn't aware that TB could take so long to grow in cultures. Is it understood why there can be such a long latency period in individuals? Also, I was just wondering, (which I will look up on my own time), when was the ppd test introduced, and why did TB claim so many lives if it is generally so latent in the early 1900s. Was it because it was more prevalent at the time so deaths appear higher? Or was the strands that were present then different, or stronger. All of TBs symptoms are so mild I could see how one would assume it was nothing more than a common cold or flu. Also, the treatment period is so long. I have heard of medication usage for only 3 months in latent individuals. Does anyone know about such treatments, because 3 months is a big difference.

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    5. Britany,
      To try to answer a few of your questions:
      1) In response to the reason for the long latency, it appears that the body's immune response to M. tuberculosis is the formation of granulomas to fight off the infection. Granuloma can be more of a jail for bugs vs. a death sentence; they wall off the infection so that damage is contained, but they don’t necessarily eradicate it. Indeed, live bacilli have been isolated from granulomas, or tubercles, in the lungs of people with clinically inactive TB. The way I like to think of it is that the infection and immune response are in a sort of equilibrium. The bacteria can persevere in these granulomatous lesions for years, just waiting for this equilibrium to shift in its favor (a “jailbreak”, if you will).
      2) The PPD test was developed in the early 1900's.
      3) As for historical deaths in the early 1900's, the reasons I believe for the large number of TB deaths in that era are twofold. a: There really weren’t any real drugs to fight off TB in those times. a: Urban overcrowding, poor sanitation, and lack of real isolation protocols in those days added to the rampant spread of tuberculosis, and high death tole.
      4) Treatment for TB is complicated, but is divided into treatment for latent TB and active TB. Latent TB is non-infectious and is usually treated with isoniazid, rifampin, or rifapentine for generally for 6 to 9 months, depending on the regiment. Active TB is highly infectious and is generally treated with isoniazid, rifampin, ethambutol, and pyrazinamide for 6 to 9 months. Regiments vary depending on the drugs used, and specific needs of the given patient populations ( ie HIV/AID, pregnancy, etc).

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    6. Given the nonspecific symptoms of tuberculosis and the range of clinical presentation, it is difficult to diagnose without a lab culture. I actually read that tuberculosis is often mistaken for a malignancy due to the gradual progression of disease. I go to school in Miami, where we see several people from endemic countries. Surveillance is high here and even when developing a differential diagnosis, it always a good idea to keep TB in mind.

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    7. In response to Britany’s questions, I think Marco has done an excellent job in answering, but I would like to share my thoughts as well. I believe that the large number of deaths attributable to TB in the early 1900s was due to a higher incidence rate of TB at that time. Changes in the social and physical landscape were probably one of the factors contributing to the increase. Early 1990s should be the time that urbanization started to take place in the United States, and this probably led to an increase in population density, which could be the reason for why TB was transmitted much faster than before. I think that these bacteria have been existing for a long time, and it was the change in our environment that triggered their emergence. I do not think that the strands at that time were “stronger”; the ones that are present nowadays with antibiotic resistance are probably much “stronger”.

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    8. I agree with many of these points regarding transmission of TB due to nonspecific symptoms, overcrowding and poor sanitation. I also feel that unless you are a healthcare worker or change jobs annually you will most likely not be tested for TB. This may also contribute to the spread of latent TB and why the infection rate is so high. Being that the symptoms are nonspecific a person may not seek a physicians opinion until things are bad and the TB is active since many peole go years without seeing one.

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  8. In one of my epidemiology courses, a classmate mentioned hookah smoking and the threat of tuberculosis. After reading this post, I have a better understanding of TB transmission.The small droplets released by those with active infection may be deposited into the hookah pipes themselves. As mentioned, M. tuberculosis resists drying out; this may help its survival in hookah pipes. It may be a relatively rare occurrence since it's hard to imagine someone smoking while experiencing the symptoms of an active tuberculosis infection, but it is possible.

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    1. Nicole you brought a very interesting point, yes hookah smoking is becoming one of the modern ways of transmitting TB as hookah is very much smoked in North Africa, north east Africa and the middle east the incidence of tuberculosis has increased because of the pipe sharing and because of the myth that hookah smoking is safe and is prestigious look mask the danger of this new mode of transmission specially among the youth and its becoming prevalent in the US in places like Chicago, Virginia and New York (i recently so a hookah bar in Nostrand Ave) in the past it was known that TB is a disease of the low socioeconomic class, but because hookah is common among middle class and college students there might be an epidemiological shift.

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  9. I was surprised to see that tuberculosis is 20 - 30% infectious for those contacted with active Tuberculosis which shows why its so important for clinicians to practice proper isolation techniques. I was not surprised that southeast Asia has some of the highest rates of TB being that there are high levels of overcrowding in that region. I believe that active TB is mostly found in the apices of the lungs being that the bacteria is more likely to live in parts of the lung that are more oxygenated. Still deep in the Alveoli but not deep in the lung.

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    1. Couple things to note, David. First, latent infection if M. tuberculosis is not transmissible. Only individuals with active TB are infectious to others. Second, pulmonary TB can occur in any region of the lung, and extra-pulmonary TB can occur in any organ system in the body. Third, alveoli = deep lung.

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  10. One critical factor in the control and prevention of tuberculosis that the article mentions is contact tracing for contacts of active tuberculosis cases to prevent them becoming active cases. Is this carried out here in the US and to what extent? Considering the significant amount of resources needed and expense involved in treating tuberculosis,I am not sure that this is carried out and is even possible in developing countries. With lack of resources and funds,the priority may be just to treat cases only. Failure to trace contacts may be one reason tuberculosis becomes an epidemic in some developing countries.

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  12. Monsurat Odeneye: As an African who lived a decent amount of years there, African countries appear to experience the worst tuberculosis epidemic, especially since there is a high HIV epidemic there as well. Tuberculosis is a common coexisting condition in people who die from AIDS, and in Africa a major factor of concern is that testing, early diagnosis and treatment of tuberculosis is ill suited to the detection of the disease especially in HIV-infected patients. Many people remain ill and even contagious for a prolonged period before the disease is eventually detected, while thousands tend to die without ever receiving a diagnosis, and even if eventually treated they are likely to relapse.
    I believe poverty stricken areas in these developing countries are at higher risk, since a lot of tuberculosis patients do not have access to good health care. It would be good to see Africa’s health care system implement new strategy for early identification of people with tuberculosis and contain the disease better, which can help reduce the transmission and mortality rate of the disease in the country and even globally.

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    2. The first thing that we need to think about are factors that might contribute to tuberculosis in Africa. These factors are malnutrition, smoking cigarettes and pollution. If we send more food to Africa, stop importing cigarettes to Africa and reduce pollution in Africa through a proper handling of toxic materials, we would reduce the high prevalence of tuberculosis among people. These people became more susceptible to tuberculosis through these factors.

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    3. I don't think that any of those suggestions are really feasible though. Solving malnutrition cannot simply be fixed by increasing aid, you cannot just stop importing cigarettes to an entire continent, and god only knows what it would take to reduce pollution. While improving all three of the contributors you noted would certainly decrease TB rates (and probably dozens of other diseases) the focus needs to be on more sustainable responses.

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    4. Yes, I would have to agree that tackling the development of the disease through singular approaches to decrease malnutrition, smoking and pollution could decrease TB rates as well as improving social and physical landscapes such as creating better housing conditions they are not feasible objectives to obtain without multidisciplinary methods to alter behavior. While developments could help facilitate improvements of many physical and social health aspects in addition to decreasing TB, to be sustainable would require much time and financial effort. That is not to say those improvements should not be implemented, they should. They would compliment prevention and control framework learned in class such as government commitment, adequate supply and access to therapy along with compliance to treatment regime, continual surveillance and education of TB.

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  13. S.Wallace- The length of treatment is quite long regardless if one has active or latent TB. Also, one of the more serious potential side effects is having complications with your kidneys. With regard to developed countries, I think a lot more people with latent TB would pursue treatment (since it’s not mandated for example in the U.S.), if it was shorter in months, and in turn perhaps this would help contribute to keeping the number of people with latent TB down in the pathogen's reservoir (at least in developed countries).

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  14. Perhaps the most troubling aspect of Tuberculosis for me is the rapid proliferation and the natural history of this disease. It is troubling that one-third of the world’s population are infected with Tuberculosis (either primary or LTBI). Undoubtedly close proximity and overcrowding are main causes of the infectivity and prevalence in certain parts of the world. That said, I do think that more effective measures of quarantine must be taken to combat the natural history of TB. For example when five to ten percent of those who are newly infected develop primary TB and pass it onto their new contacts (i.e. stage 4 meets stage 3) a major problem is apparent. Given that this disease has been known for such a long time, I’d think that international public health efforts would’ve been stronger.

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    1. TB
      I think that quarantine can be useful in combating the natural history of the disease. However would the more realistic solution be to stress therapy compliance?Unfortunately this relies on the actual therapy being readily available to the infected individuals. This requires that there are policies in place in the local or state government that mandate having the drugs readily available at all times. Then comes the issue of so many people may not even know that they are infected. There are so many factors that influence the the endemicity of TB, that definitely include features of the pathogen itself, but is also so reliant on the social structures and features of a landscape like Dr. Walsh on this post. We need to do a much better job at combating this disease and I think we need to increase national awareness and public health interest in this disease.

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  15. I used to snicker a little at those people who wear masks while out in public, but when one considers that in New York we can possibly encounter people from every continent and nation everyday who may carry this disease the possibility of infection is astounding. Ponder for a moment that the trip from Manhattan to Downstate can take about one hour while contained in a poorly ventilated metal tube (AKA the subway), with people coughing, sneezing and touching everything. Between breathing in the germs and touching the poles and seats and possibly touching your eyes and face after, the chances of infection get greater by the minute. Now, add in the portion of the community that is immuno-compromised who also share the same space and it's a wonder we don't have a massive TB outbreak here.

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  16. TB is greatly influenced by the socio-economical factors of the population. As the post mentioned: "Overcrowding is a defining feature of areas of high tuberculosis endemicity". With all the strides in treatment and immunization (despite of drug resistance), it seems that the most effective way to combat the disease is to raise the quality of live. The WHO map clearly reflects the disease distribution along the lines of countries advancement in general.

    One point to add; The absence of any significant physical findings does not exclude active disease. In the high-risk patient, respiratory isolation and sputum sampling are essential. This information was drilled in my head long ago when I worked in Egypt and it's still valid today here in the US.

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  17. Prior to reading this article, I did know that tuberculosis is an ancient diseases, which has lead to millions of deaths worldwide. However, I did not know that it was actually the “world's second leading cause of death due to an infectious disease,” as stated in the article. It is scary to know that not everyone infected with TB bacteria becomes sick, thus, resulting in the two TB conditions discussed (latent tuberculosis infection and active tuberculosis). It is interesting to know even though transmission occurs in “only 20% to 30% of individuals exposed to someone with active tuberculosis,” in places like Southeast Asia and Africa regions 60% to 70% of the adult population is latently infected with M. tuberculosis. Another interesting point of this article is that the epidemiology of tuberculosis “emerges at a critical point where the social and physical landscapes converge: the structure of population density.” Thus places that are overcrowded, where ongoing close contact between active cases and susceptible individuals occurs, maintain endemicity. TB can be cured if a complete treatment is administered, with at least 6 months required due to the heterogeneous population of M. tuberculosis in an infected individual, which is comprised of active and dormant organisms. Control and prevention is essential, given the complicated nature of this infectious disease. These include: case identification, exhaustive contact tracing for contacts of each active tuberculosis case, good surveillance system and having an adequate supply of tuberculosis medication. People should follow such protocols of prevention in order to promote public health and protect others from infection.

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    1. Hi Karla, I think you bring up a really interesting point about TB: that a very small proportion of exposed people actually develop active disease, while the majority of the adult population in Asia and Africa are actually infected with it. According to this article, people don't even know if they're infected with latent TB, because they're asymptomatic! This, in addition to the severity of the disease in immuno-compromised people, is probably why every current and future hospital worker is screened for TB. Also, the biology of the disease (the fact that it stays latent in the majority of people it infects) contributes to the landscape of the disease:the fact that it's still endemic in certain areas of the world.

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  18. Considering that LTBI is an inapparent infection due to its asymptomatic features, it creates much difficulty to increase specificity when diagnosing the infection. It was interesting to see that it is a signature disease of urban poverty, passed easily in overcrowded and poorly ventilated spaces. Vaccines and antibiotics are crucial for medical progress in treatment and prevention. In order to diminish TB in the developing world accurate diagnostic exams are desperately needed. Despite that fact the TB can be cured, one must consider the difficulty for those infected to take several antibiotics nearly every day for six months, particularly in parts of the world without running water or refrigeration (which is far from easy). For improvements to be made, we must see investments from international aid organizations and from private companies. Efforts should be required to lower the cost of diagnosing tuberculosis.

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    1. The control and prevention section of this entry is nicely detailed. The suggestions provided are necessary to be implemented to have effective tuberculosis control and prevention. Particularly, it is essential to mention the importance of sufficient supply of tuberculosis medications in populations with endemic tuberculosis because medication is obvious for disease control but, the lack of medications in such area may be noticed less. Unfortunately, medication supply is not consistent in poor areas. I agree with you that international aid organizations and private companies should contribute to efforts towards diagnosing and preventing tuberculosis. I also agree with an earlier post; Alexia suggested that there should be more national awareness and public health interest in this disease. It would be nice to know if such proposals have been put into action, and if so, to what extent.

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  19. It is believed that the HIV epidemic has given new life to the TB epidemic as its rates are rising globally, according to an article published by Paul Nunn in Nature Reviews Immunology in October 2005. Given the staggering statistics discussed in this article such as “one third of the population of the world is infected with M. tuberculosis” and that “globally there are 1.8 million deaths annually due to TB” there seems to be a great need to bolster prevention and treatment programs addressing HIV in order to prevent the spread of TB.

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  21. Very informative post. TB is the leading opportunistic infection associated with HIV infection globally. It was interesting to learn that approximately forty percent of new M. tuberculosis infections among individuals who are HIV+ develop primary active tuberculosis. This percentage is a lot higher when compared to the 5 to 10 percent of new infections that become primary active TB among those who are HIV-.

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  22. This post on TB and the wide reach it has in the human population makes me think the disease is underestimated as a potential serious threat. The drug resistance that has developed and the prevalence of HIV/AIDS makes the disease very challenging to tackle and very deadly to many millions of people. I’ve read about the rapid development of the disease in the former Soviet Union where poverty and poor health hit the population hard in the early 1990s. Russia has the highest incarceration rate after the U.S. and conditions in the overcrowded prisons make inmates very vulnerable to both HIV and TB. It is such a set back given the huge efforts to control the disease in the twentieth century.
    In some earlier posts it is reported that the vaccine is not very effective. I’m interested in this because I have wondered why the PPT test is administered so often to so many people in this country and not the vaccine like in Europe—it seems not very efficient, but there is clearly more for me to learn here.

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  23. This has been a most informative post. The fact that TB thrives in densely populated areas is quite worrisome being from NYC. However, the map shows that the US is has one of the lowest prevalence rates for TB. Considering that the vaccine is not mandatory here that is quite interesting.
    I had Two questions while reading this post.
    1. 80% of those infected will not present with primary TB. The diagram titles "Natural History of TB" shows several arrows that display the "elimination of the bacteria" among those infected with LTBI. How does that happen?
    2.Is there a mechanism that triggers LTBI to go active and cause clinical TB?

    Thanks

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  24. It was very interesting to learn about the non-pulmonary signs and symptoms of active TB. While working as a paramedic, we were generally told to look out for bloody sputum in high risk populations as the main warning sign.
    In a global context, the higher rates of active TB in HIV positive persons seems like another way to frame and promote HIV/AIDS treatment and prevention efforts. Reduction in immunocompromise would have the added benefit of reducing the number of active TB cases and therefore the overall infection rate in areas with high HIV/AIDS prevalence.

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  25. When considering the control of TB, my initial thoughts went to vaccine. But with one-third of the world's population infected with both dormant and active TB, even if there was a vaccine, you would only have two-thirds of the population (approximately 67%) with immunity-- which would probably not be enough for herd immunity.

    Also, I would be interested to see whether research has considered if the antibiotic resistance genes are seen across the Mycobacterium subspecies, or if it is just in M. tuberculosis. If not, could comparative genomic studies of the different subspecies yield important information about what leads to the resistance in the M. tuberculosis suspecies?

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  26. Several drugs can cure TB, but only if they are taken for many months. However, MDR continues to proliferate as a resistant strain. Then, even when treated with the strongest drugs for two years, the resistant TB is fatal about 60 percent of the time.
    A while ago, I watched a documentary on MDR in Russian prisons. Dormant bacteria became active for malnourished prisoners and easily spread to their fellow inmates. Russian prisons are a major source of multi-drug-resistant TB. As tens of thousands of infected inmates re-enter society, TB spreads when they cough and sneeze. With frequent traveling, MDR is a big threat. To control MDR in Russian prisons, public health officials are supplying the costly second-line drugs. Prison health care workers are diligent in making sure that infected inmates take the entire course of the drugs, even if that means the prisoners have to remain in jail for up to two years past the start of their treatment. In Russia, it may be possible to contain prisoners past their sentence, but this definitely will not be supported in our American legal system, even if it means it would prevent others from infection.

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    1. Kesha, that's a really interesting example of being able to observe treatment of TB with a confined population of subjects. Obviously holding people against their will is not a suitable method for monitoring TB treatment in other parts of the world. Areas where TB is endemic are important places for resource allocation to the use of the DOTS procedure. Educating not only the public but also public officials about the importance of the WHO/CDC procedure is crucial to illustrating the message of the incredible burden of this disease in the world-- and most specifically in Southeast Asia and South/Central Africa.

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    2. Jamie, I definitely agree that the WHO should allocate resources for these public health efforts. It would be beneficial if there were a way to decrease the amount of overcrowding in these prisons where TB is running rampant, but I do not know how feasible that is. But if these public health prevention measures were put into place, these prisons may be able to save money on medical costs for the inmates as well.

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