Thursday, April 14, 2011

All you ever wanted to know about tuberculosis but were afraid to ask!

My TB paper for microbiology...


            Consumption, or what is more commonly known as tuberculosis (TB), first showed itself in humans about 8 thousand to 10 thousand years ago. Some theorist believe that TB did not originate in humans, but that animals were the primary carriers before it spread. The initial spread of TB came from cows, and the fact that early humans used to live in close quarters with their animals made the transmission of this disease easy between species (10). New research suggests that TB first came from humans (4). When not much was known about TB, there was very little hope for surviving it once infected, people simply did not have the means or resources to cope, diagnose, and treat such a horrific disease.

            During the 1700s, TB was responsible for one-fifth of deaths in the US as well as one-third of deaths in Europe. This was a disease the world soon realized did not distinguish between social class or age. TB was considered an epidemic, sweeping across the United States killing over 2 million people a year. Throughout the centuries there were spikes in lulls in the amount of lives that were claimed by TB. Sometime between the late 1950's and the early 1980s the number of TB cases started to go down. Between the mid 1980's and the early 1990s the epidemic rose again, the cause of this is contributed to HIV, and the immune deficiency problems that coincided with it (Daniel). Today, there are 160 million new infections of TB every year, but thanks to modern medical technology, not everyone with the disease will die from it (10).

            A person who has been infected with TB will exhibit coughing; sometimes coughing up bloody septum, fevers, nights sweats, and severe weight loss. Since this is a disease that primarily associates itself in the lungs, the person will also experience horrible chest pain (4). These symptoms are so non-specific it is often hard to be certain whether a patient has TB without doing further testing. If the infection is outside the lungs (extra pulmonary), other symptoms will occur, such as meningitis if it's in the nervous system. TB can also spread to the blood stream, bones, and lymphatics, intestinal tract, almost every body system (7).

            Tuberculosis is caused by the aerobic bacterium Mycobacterium tuberculosis, which is a non-spore forming acid-fast bacilli. Once inside the body this bacterium has quite the defense against the body's immune system. The cell wall of M. tuberculosis contains an antigen that is immunogenic, which helps fight off macrophages, immune cells which kill foreign invaders. The cell wall also contains an extremely resistant lipid barrier which does not allow some antibiotics to penetrate it. This hearty cell wall is one of the things that makes TB so successful at infecting people (7).

            The primary target that TB will infect will be the lungs. Generally, TB will get inhaled, once inside the body it will either be expelled via nose hairs, or by mucus secreted by goblet cells lining the respiratory tract. If the bacteria make it past these defenses it travels through the respiratory tract down the trachea through the bronchioles, then it will settle down into the deepest part of the lungs, called the alveoli. It is here that it will begin to fight off the macrophages and the bacteria will begin to multiply into a full on infection. If the body's immune system is able to keep the infection in check, which essentially keeps the infection from spreading, then the patient will have what is called latent TB (4).   The first stage of TB is called Primary TB. This is when the individual usually has no signs or symptoms of the disease, but will sometimes have a positive reaction to a tuberculin test.

            TB spreads through the air. Any infected person who coughs, laughs, sneezes, or talks, will expel tiny droplets of nuclei (tiny particles that contain TB). These nuclei can remain in the air of any area that does not have proper ventilation or exposure to UV light. These nuclei cannot survive exposure to UV lights, and the ventilation will cause them to be swept away. Any person who is infected with TB has the potential to infect another person. This risk for infection becomes higher if the person is in a small space with a lot of other people. It was not always known that this disease was infectious (10).

Isolation, Diagnostic Testing, Identification

             In order to identify and diagnose tuberculosis several tests have to be done.  First, there will be a chest radiograph to see if there is any inflammation, pus, or scaring in the lungs. If this x-ray comes back abnormal (tissue shows up white) then the next step would be to make a smear of the patient's sputum. This sample should be collected every day for three days. This test does not give the definitive answer of TB, but it does test to see if acid-fast bacilli are present. If the staining indicates positive acid-fast, more than likely this is tuberculosis. Acid fast stains are positive if after the staining procedure the bacilli are a red color, which would be a different color than the rest of the media on the slide. 

            A culture of the septum will also need to be made and tested.  If TB bacteria grows from the samples, sensitivity testing is done on the bacteria. These tests will show which medicines will kill the bacteria. An antibiotic sensitivity (or susceptibility) test is done to help choose the antibiotic that will be most effective against the specific strains of bacteria infecting an individual person. Results of sensitivity tests can take between 1 and 6 weeks because TB-causing bacteria grow very slowly. This culture is the test that will give the definitive answer of yes or no to whether a person is infected with TB (7).

            Since TB takes such a long time to isolate and culture, there have been new tests made that guarantee faster results, not only are these results faster but they are just as accurate. This test, called polymerase chain reaction or PCR, will detect bacterial DNA. The results of this test take much less time and can be available in just a little over two hours. Some other tests that can be done to detect TB include skin tests as well as blood tests, however unlike the PCR and the culture tests mentioned above, the skin and blood tests cannot give a definitive answer as to whether or not a person is infected, more so these test work better at detecting latent tuberculosis (7).


Throughout early history as testing and diagnosis were limited. TB was diagnosed only in its later phases after the signs and symptoms were very evident and quite painful. As a result most early treatments focused on the relief of the symptoms not on preventative or even curative treatments. Many early procedures had little or no effect on the course of the disease. Inhalation of vapors, sucking of cracked ice, and the use of opiates for quieting the cough and pains of intestinal tuberculosis maintained a lasting popularity. It was clinical experience that revealed the therapeutic effects of healthy living, good food, and rest on TB.  But it took the resources of physiological, pathological, bacteriological, and chemical sciences to bring about the more effective forms of treatment such as pulmonary collapse, surgery, and the use of antimicrobial drugs (3).  Prior to the advent of anti-tuberculous medications, iatrogenic pneumothoraces were intentionally given to tuberculosis patients in an effort to collapse a lobe, or entire lung around a cavitating lesion. This was known as "resting the lung".

            The Bacille Calmette-Guérin or BCG vaccine is an attenuated, weakened strain ofMycobacterium bovis.  In 1908, two French scientists from the Louis Pasteur Institute, Calmette and Guerin, cultured a virulent tubercle bacillus from the udder of a tuberculent cow.  In 1921, they first used the vaccine they'd created on infants in Paris. The first use of the vaccine was an oral dose mixed with milk; it remained avirulent. The BCG vaccine may be administered several ways; orally, intramuscularly, subcutaneously, intracutaneously, via multiple puncture, and by scarification.  BCG vaccine was often given intracutaneously as it was the easiest to administer.  Determining accurate dosing was simpler, and it enabled the vaccination of a large number of patients in a short period of time.  Some complications of the BCG vaccine are: a slow healing ulceration at the injection site (sometimes referred to as Koch's phenomenon), an ulcer of the regional lymph nodes, a positive reaction to the purified protein derivative (PPD), skin complications such as keloid scars, blistering, and abscesses. When an individual experiences a positive TB reaction to the tuberculin test after having taken the BCG vaccine, it is difficult to determine if the reaction is due to exposure to TB, a reaction to the BCG vaccine, or if the individual actually having TB.

                       In 1940 Selman Walksman developed methods for growing soil microbes and screening them for their antibiotic properties. Walksman's graduate student, Albert Schatz discovered that a mold, Streptomyces griseus, was an antagonist and limited the survival of the TB bacteria in both soil and in sewage. In 1943 the inhibitory substance streptomycin was isolated from the cultures.   Streptomycin inhibited the growth of tubercle bacilli in both the body and in test tubes. By 1945, it was in clinical use for treatment of TB (12).  In 1949 streptomycin resistant TB bacilli were treated with para-amino salicylic acid (PAS), and in 1952 isoniazid became the mainstay in the treatment of drug resistant TB. Isoniazid also blocks the synthesis of mycoliac acids, which are the main constituent of the waxy wall ofM. tuberculosis. Streptomycin and other drugs did not eradicate TB, but they did effectively eliminate sanitaria (12).  Patients no longer needed to be sequestered from society in isolation, as these therapies relieved the most obvious symptoms and provided hope for an eventual cure.

In 1963, rifampin was introduced as a treatment. To minimize the emergence of drug resistance, patients are treated with a drug cocktail, called MDT (multiple-drug therapy).  The most commonly used treatment regimen is isoniazid, rifampin, and pyrazinamide.  More than 85 percent of patients who receive both isoniazid and rifampin have negative sputum cultures within two months after the initiation of treatment (12).  The emergence of multidrug-resistant strains of M. tuberculosis are often due to the initiation of treatment followed by a lapse after a few weeks, allowing larger numbers of mutant bacteria to survive. These mutants overcome and resist the drugs.  In the late 1980's, it became clear that a substantial number of patients weren't completing treatment.  To address this, the Center for Disease Control and Prevention recommended that direct observational therapy (DOT) by a trained health care worker be considered for all patients (12). Susceptibility to TB is dramatically enhanced in HIV-infected persons, and the spread of AIDS has been paralleled by resurgence in TB cases (12).  It is the number one killer of HIV infected persons. 

The search for an ideal vaccine that combines both the prophylactic and therapeutic approaches without confusing the TB skin test continues.  It is estimated that the development of a broadly effective, long-term protective vaccine may take another 20 to 50 years. Scientists at the Sequella Global Tuberculosis foundation are working on a replacement BCG vaccine, as well as preventative and therapeutic vaccines for TB (10).  The National Institute of Allergy and Infectious Diseases are also in early clinical trials for safety on vaccines also.  It is difficult because pharmaceutical companies have shown little interest in the development of a TB vaccine. 

            It is not just vaccinations that need to develop and improve.  The tests that are currently in use for TB are more than a century old and are not very accurate.  If a patient only has a few TB bacteria in a sputum smear, the laboratory technician may miss it.  Tuberculin skin tests may be misinterpreted, especially in a patient that has HIV.  Chest x-rays often won't show early TB and never show latent TB infection. Dr. Fred Kramer and Dr. David Alland are using the science of molecular beacons to test for TB.  The molecular beacons that are cultured with TB bacteria, light up if they bind to regions in the TB bacteria that are sensitive to rifampin. TB that is resistant to rifampin is very often resistant to isoniazid, so this test will help a physician to know which type of TB a patient has, the regular TB that can be treated with standard first-line drugs (rifampin, isoniazid, pyrazinamide, and ethambutol) or the multi-drug resistant TB that requires more toxic second-line drugs. This type of testing is also faster, more effective, and cheaper than current testing.


TB is still the leading cause of death from a curable infectious disease. In many resource-poor countries, especially those blighted with HIV, TB is on the rise with one person infected every second worldwide (12).  Today TB is a largely forgotten disease in the United States, having been replaced by cancer, AIDS, and cardiovascular diseases in the public awareness (12). Public opinion polls show that people in the United States do not perceive TB as a threat. This is due in part to the demographic of the disease, as the majority of those affected with TB live in the margins of society and the disease is once again in decline. Although multidrug resistant TB is a very serious problem, with a potential to worsen in the future, it represents a small and decreasing number of cases in the United States (13). 

With the possibility of a new vaccine still decades away, the epidemic still rages on.  One-third of the world's population is infected with TB.  Each year, another 8.4 million people become ill with TB.  Two to 3 million of them die, while one latently infects up to 20 people creating a time bomb of future disease.  In 1991, multi-drug resistant TB was present in 13 states of the US. While New York City successfully ran a campaign to control multi-drug resistant TB, things got worse nationwide.  By 1996, 42 states were reporting multi-drug resistant TB.  The World Health Organization reported in 1999 that TB is rampant in the former Soviet Union, China, the Ivory Coast in Africa, the Dominican Republic, Iran, and in India (10).  Only recently have public health experts come to realize that policy makers with political power  must be made to understand that preventing and curing TB is vitally important, not only for world health but for their own national prosperity as well. When policy makers understand this, we can then get the doctors, scientists, and public health officials to agree on the best way to control TB in their respective nations.

Unfortunately TB doesn't stay home. Since it spreads through the air via respiration, it travels with people.  Travel has never been easier or faster.  No place on Earth is much more than 24 hours away from another.  Until we can truly understand this, and why we should care about the epidemics in lands that seem remote and far away to us, TB will continue to be a growing threat. As more multi-drug resistant strains develop, treatment is becoming longer, costlier, and harder to complete.  When wealthier, more industrialized countries like the US don't provide the funding and education for TB research and testing, they are only putting their citizens at risk. 



1.) Alaska Department of Health in cooperation with Alaska Tuberculosis Association. 1955. Dear Lucy

2.) Daniel, T. M. 2000. Pioneers in Medicine and Their Impact on Tuberculosis. University of Rochester Press, Rochester, NY

3.) Dubos, R. and J. Dubos. 1952. The White Plague: Tuberculosis, Man and Society. Little, Brown, and Company, Boston, MA

4.) Feldberg, G. D. 1995. Disease and Class: Tuberculosis and the Shaping of Modern North American Society. Rutgers University Press, New Brunswick, NJ

5.) Furlow, B. 2010. Tuberculosis: A Review and Update. Radiol. Technol. 82:33-56.

6.) Hadden, E. L. 2007. MA Thesis. The Bacillus Calmette-Guerin Tuberculosis Vaccine Experiment on Southeast Alaskan Natives: An Experientment Without Informed Consent

7.) Knechel, N. A. 2009. Tuberculosis: pathophysiology, clinical features, and diagnosis. Crit. Care Nurse. 29:34-43.


8.) Mamunes, G. 2008 "So has a Daisy Vanished": Emily Dickinson and Tuberculosis. McFarland & Company, NC

9.) Ott, K. 1996. Fevered Lives: Tuberculosis in American Culture Since 1870. Harvard University Press, Cambridge, MA

10.) Reichman, L.B. and J. Hopkins Tanne.2002. Timebomb:The Global Epidemic of Multi-Drug-Resistant Tuberculosis. McGraw-Hill, New York, NY

11.) Rothman, S. M. 1994. Living in the Shadow of Death. BasicBooks, NewYork, NY

12.) Sherman, I. W. 2007. Twelve Diseases That Changed Our World. ASM Press, Washington, D.C.

13.) United States. Institute of Medicine. 2000. Ending Neglect: The Elimination of Tuberculosis in the United States. Geiter, L., ed. National Academy Press, Washington D.C.

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