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Tuberculosis |
To TUBERCULOSIS COMPLEX: THE EVIL EMPIRE INTRODUCTION: TUBERCULOSIS TODAYIn 1984, the Public Health Service reported that the number of tuberculosis cases reported annually in 1953 had declined by 74 percent. It was widely believed that modern medicine had all but eradicated this potentially fatal disease. The wake-up call alerting the public to the resurgence of tuberculosis came between 1985 and 1993, when the number of cases reported in the United States began to increase steadily and dramatically. Today TB is back, and if proper measures are not taken to educate people about this preventable disease, infection rates will continue to rise at an alarming rate.
TUBERCULOSIS COMPLEX: THE EVIL EMPIRE(To the beginning.)The Adversaries Mycobacteria are Gram-positive, non-motile, pleomorphic rods, belonging to the family of Actinomycetales. The species in this genus show great diversity in many aspects.Most Mycobacteria have embraced the "good side of the force", with habitats in water and soil and abilities to degrade recalcitrant organic compounds such as vinyl chloride or phenanthrene and produce secondary metabolites such as steroids and optically active oxides of lower alkenes. However, a few have chosen the "dark side of the force"and have become intracellular pathogens of higher vertebrates inflicting great suffering and death in animals and humans. Mycobacterium tuberculosis belongs to this group. Mycobacterium tuberculosis along with M.bovis, M.africanum, and M.microti all cause the disease known as tuberculosis (TB) and are members of the tuberculosis complex.Each member of the TB complex is zoonotically pathogenic, however, M.tuberculosis is usually pathogenic for humans while M.bovis is usually pathogenic for animals. Tuberculosis Complex organisms share several clinically important biologic properties:
Method of Invasion (Transmission) Transmission of TB usually occurs by an airborne or aerosol route but
can also occur through the gastrointestinal tract. Coughing by humans or
animals with active TB produce droplet nuclei containing one to three
organisms. This TB-containing droplet nuclei can remain suspended in the
air for several hours. Infection will occur if inhalation results in the
organism(s) reaching the alveolus of the lungs. M.bovis transmission from
cattle to humans has occurred through drinking contaminated milk. Only
one-in-ten immunocompetent people infected with M.Tb will develop active
disease in their lifetime and therefore don t transmit the organism. In
contrast, nearly all cattle infected with M. bovis develop active disease
and can transmit the organism to other animals or humans. Among generally healthy persons, infection with TB is highly likely to
be clinically unapparent. As mentioned, the lifetime risk of developing
clinically evident TB after being infected is approximately 10%, however,
in specific subpopulations such as infants or persons with
immunodeficiency states, the proportion who develop clinical TB is much
higher. The most important factor that influences the clinical features of TB
is the site of involvement. In the United States before the epidemic of
infection with the human immunodeficiency virus (HIV), approximately85% of
newly diagnosed TB cases were limited to the lungs and remaining 15%
involved only nonpulmonary sites or both. The distribution of sites is
considerably different among persons with HIV infection. In a study of TB
patients with advanced HIV infection, 38% had only pulmonary involvement,
30% had only extrapulmonary involvement, and 32% had both. The
multiplicity of sites in HIV-infected persons is typical of what is seen
among persons who have a limited ability to contain infection with TB.
Included in this category are infants, the elderly, and persons with
primary or secondary immunodeficiency states resulting from coexisting
diseases or malnutrition. Method of Attack (Pathogenesis) The pathogenesis of tubercular infection and disease begins in most
cases with the inhalation of the tubercle bacilli. The usual inoculum is
no more than one to three organisms which are taken up by alveolar
macrophages and carried to regional lymph nodes. Spread may occur via the
lymphohematogenous route with dissemination to multiple organs. Most of
the disseminated lesions heal; although reactivation can cause miliary or
meningeal tuberculosis. From 2 to 8 weeks after infection, cell mediated
immunity (CMI) and hypersensitivity (DTH) develop leading to the
characteristic reactive tuberculin test and to the containment of
infection. Chemoattractants cause monocytes to enter the area and become
transformed into histiocytes forming granulomas. The bacilli may persist
within macrophages, but additional multiplication and spread are
prevented. Healing usually occurs with calcification. Caseous necrosis can
occur secondary to the immune response. Erosion into a bronchiole results
in cavity formation where bacilli can multiply and spread. Solid necrosis
can result from production of hydrolases from inflammatory cells causing
tissue liquefaction and crating a prime medium for replication, generating
up to 10 billion bacilli/ml. Those individuals who develop active disease either fail to contain the
primary infection or develop reactivation as a result of relative or
absolute immune suppression at a point remote from primary infection. This
is most likely to occur in immunocompetent adults within the first three
years after exposure. Factors related to progression of disease reflect a
weakened immune status and include intercurrent disease--particularly
diabetes mellitus, malignancies causing primary immunosuppression or
requiring toxic chemotherapy, or steroid-dependant diseases like asthma or
collagen vascular disease, poor nutritional status particularly related to
alcohol and drug abuse, smoking, the extremes of age, and HIV infection. TB WARS: MAN'S ANCIENT STRUGGLE(To the beginning.) TB's Assault on Humanity TB has had many aliases throughout history: The ancient Greeks called
it phthisis (to waste). The swollen glands of the neck
were called scrofula. It was called The Kings Evilin
medieval times because newly crowned kings of England and France were
believed to have powers to heal TB with their touch. TB of the skin was
known as lupus vulgaris. TB of the bone as Potts
disease with characteristic vertebral fusion and deformity of the
spine. The most familiar term for TB, at least to our grandparents and
great-grandparents was consumption, which means to
consume or wear away. Whatever mask it wore, TB was responsible for 20% of
deaths in London in the 1600s, over 30% of deaths in Paris in the 1800s
and today is a global emergency according to the world health
organization. M.bovis had been causing TB in the animal kingdom long before invading
humanity. However, after the domestication of cattle between 8000-4000 BC,
there is evidence of human infection by M.bovis likely through milk
ingestion. This coincides with archeological evidence of spinal TB (Potts
disease) 5000-1000 BC.M.bovis was the likely pathogen in human TB until
~1000 BC. After 1000 BC, widespread pulmonary TB emerged. In fact,
M.tuberculosis probably is an evolved, specialized form of M.bovis
developed among milk-drinking Indo-Europeans who then spread the disease
during their migration into western Europe and Eurasia.By the 1st
millennium BC, M.tb causing pulmonary TB had spread throughout the known
world. Earliest tangible record of pulmonary TB was between 668-626 BC.
The classic TB signs--cough, expectoration, hemoptysis, wasting of the
body, were well recognized. The earliest written evidence of pulmonary TB
was from the library of the Assyrian king Assurbanipal (668-626 BC): «The patient coughs frequently, his sputum is thick and sometimes contains blood. His breathing is like a flute. His skin is cold, but his feet are hot. He sweats greatly and his heart is much disturbed. When the disease is extremely grave, he suffers from diarrhea.» The Uncloaking of TB Exact pathological and anatomical descriptions of the disease began to appear in the seventeenth century. In his Opera Medica of 1679, Sylvius was the first to identify actual tubercles as a consistent and characteristic change in the lungs and other areas of consumptive patients. He also described their progression to abscesses and cavities. Manget described the pathological features of miliary tuberculosis in 1702. The earliest references to the infectious nature of the disease appear in seventeenth century Italian medical literature. An edict issued by the Republic of Lucca in 1699states that, "henceforth, human health should no longer be endangered by objects remaining after the death of a consumptive. The names of the deceased should be reported to the authorities, and measures undertaken for disinfection." In 1720, the English physician Benjamin Marten was the first to conjecture,in his publication, A New Theory of Consumption, that TB could be caused by "wonderfully minute living creatures", which, once they had gained a foothold in the body, could generate the lesions and symptoms of the disease. He stated, moreover, "It may be therefore very likely that by an habitual lying in the same bed with a consumptive patient, constantly eating and drinking with him, or by very frequently conversing so nearly as to draw in part of the breath he emits from the Lungs, a consumption may be caught by a sound person...I imagine that slightly conversing with consumptive patients is seldom or never sufficient to catch the disease." For the early eighteenth century, Dr. Marten's writings display a great degree of epidemiological insight. In contrast to this significant level of understanding about the etiology of consumption, which was already enabling prevention and a break in the chain of infection, those attempting to cure the disease were still groping in the dark. Then came the great breakthrough in uncloaking the causative agent of Tuberculosis.In 1865, the French military doctor Jean-Antoine Villemin single-handedly demonstrated that consumption could be passed from humans to cattle and from cattle to rabbits. On the basis of this revolutionary evidence, he postulated a specific microorganism as the cause of the disease, finally laying to rest the centuries old belief that consumption arose spontaneously in each affected organism. In 1882, Robert Koch discovered a staining technique that enabled him
to seeMycobacterium tuberculosis. What excited the world was not
so much the scientific brilliance of Koch's discovery, but the
accompanying certainty that now the fight against humanity's deadliest
enemy could really begin. A Few Famous people who died or suffered from Tuberculosis
Humanitys Counter-Assault on TB At the time of the discovery of the tubercle bacillus, 1/5 people developed TB during their lifetime. Also, at that time began the 1st great intervention strategy known as the sanatorium movement. The sanatorium system began in Europe in the 1850s, then was established in the US by Dr. Edward Livingston Trudeau in 1882. This was the beginning of a public health movement featuring community participation, emphasis on healthy life style (exercise and nutrition), and ordinances to improve sanitation and slum housing. Voluntary organizations to combat TB also formed during the sanitarium era including the National Tuberculosis Association in 1904, now the American Lung Association, the oldest voluntary health organization in the US. Advocacy for social reform, with emphasis on better housing and improved working conditions and nutrition were prevalent. The TB mortality rate began to steadily fall during this era presumably due to these societal improvements. The isolation of more than half of infectious patients in sanitariums or tuberculosis hospitals over time must have had some effect on the decline as well. The sanitarium era was a great social movement with both public sector and private sector commitment to halting tuberculosis. Direct intervention against TB included the pasteurization of milk to inhibit M.bovis as a cause of human TB and the introduction of the BCG vaccine - an avirulent strain of M.bovis that provides protection against M.tuberculosis challenge. This is currently the most widely used vaccine in the world. The US does not use BCG vaccine because studies show its efficacy against pulmonary TB in adults is 0-77% and there is a risk that BCG can cause TB in certain, especially immunocompromised, individuals. Active therapy began with the introduction of the artificial pneumothorax and surgical methods to reduce lung volume; M.tb grows best in a well oxygenated environment. The discovery of radiation by Von Roentgen in 1895 meant the progress and severity of a patients disease could be accurately followed. The end of the sanitarium era began with the discovery of the long awaited «magic bullets» of chemotherapy. In fact, the chemotherapy of infectious diseases, using sulfonamide and penicillins, had been underway for several years, but these molecules were ineffective against Mycobacterium tuberculosis. Since 1914, Selman A.Waksman had been systematically screening soil bacteria and fungi, and at the University of California in 1939 had discovered the marked inhibitory effect of certain fungi, especially actinomycetes, on bacterial growth. In 1940, he and his team were able to isolate an effective anti-TB antibiotic, actinomycin;however, this proved to be too toxic for use in humans or animals Success came in 1943. In test animals, streptomycin, purified from Streptomyces griseus, combined maximal inhibition of M. tuberculosis with relatively low toxicity. On November 20, 1944, the antibiotic was administered for the first time to a critically ill TB patient. The effect was almost immediately impressive. His advanced disease was visibly arrested, the bacteria disappeared from his sputum, and he made a rapid recovery. The new drug had side effects - especially on the inner ear - but the fact remained, M.tuberculosis was no longer a bacteriological exception, it could be assailed and beaten into retreat within the human body. A rapid succession of anti-TB drugs appeared in the following years. These were important because with streptomycin monotherapy, resistant mutants began to appear with a few months, endangering the success of antibiotic therapy. However, it was soon demonstrated that this problem could be overcome with the combination of two or three drugs. Following streptomycin, p-aminosalicylic acid (1949), isoniazid(1952), pyrazinamide (1954), cycloserine (1955), ethambutol (1962) and rifampin(rifampicin; 1963) were introduced as anti-TB agents. Aminoglycosides such ascapreomycin, viomycin, kanamycin and amikacin, and the newer quinolones (e.g.ofloxacin and ciprofloxacin) are only used in drug resistance situations. Combinations of a B-lactam antibiotic with a B-lactamase inhibitor enhance treatment effectiveness, but the newer drugs, including the macrolides, have not received much clinical testing. Two properties of anti-TB drugs are important: antibacterial activity,highest in
and their capacity to inhibit the development of resistance, the most effective drugs being
With the proper four drug regimen, there should be a rapid clinical improvement and a significant fall in the bacterial count. After a month, the patient should be afebrile, feel well and have regained weight. Coughing and sputum should have diminished and improvements will be visible on the X-rays. Although bacteria will still be present in the smears, they will become more and more difficult to culture. Improvements will be visible on the X-rays for three to four months. If the disease was initially severe, though, the end of treatment may not be reached for a year. During the 1950s, TB rates dropped in the US by 75% and TB hospitals were closing due to lack of patients. In 1987, the Advisory Council for the Elimination of TB put forth a plan to eliminate TB (1 case/1 million population) by the year 2010.A sigh of relief went up form the world--humanity won the war! The three thousand year struggle with TB was over!......Or was it? In 1985, for the first time in this century, the decline in the TB case rate stagnated and then began a slow steady increase that has persisted. Throughout the world, TB killed 3 million people last year; more than ever before! WHOs Dr. Joel Almeida said the current TB outbreak is a «fire raging out of control»in developing nations. If the current trend persists, 30 million people could die from TB in the next 10 years. TB is the leading killer of women. TB is the leading infectious killer of people living with HIV/AIDS 1/3 of HIV+ individuals become sick with TB. Someone is infected with TB every second. TB STRIKES BACK: THE DEADLY RESURGENCE(To the beginning.)TB's New Armor - Multidrug Resistance (MDR) The multiple drug regimen described earlier is very effective - >90% cure rate - IF taken for 6-8 months. Many patients especially in poorer countries or of low socioeconomic status in developed nations, stop taking them as soon as they start to feel better - which will happen after a few weeks - because of the inconvenience or to save money. TB then quietly mutates, regroups and comes back armored with drug resistance. 52% of isolates from relapsed cases are resistant to one or more drugs. Research indicates that it takes scientists 3 years to develop a new antibacterial drug, but it takes the bacteria only 3 months to develop a resistance to that drug. Preliminary data on rates of drug resistance in New York City showed that 19% of TB isolates were resistant to both INH and Rifampicin--the two most effective anti-TB drugs. According to WHO, 50 million people may be carrying drug resistant strains of tuberculosis.These drug-resistant strains have been described by Richard Bumgarner, deputy director of WHOs global TB program as an Ebola-like threat with wings. In this jet-age we live in, these strains are easily transported throughout the world. Anyone who breathes air is at risk from Wall street to the Great Wall of China. Chance of a random mutation conferring drug-resistance
"In a typical granuloma of a PPD+ individual, there are 102 - 104 bacilli." "In an active disease lesion, there are greater than 107 - 109 bacilli." "Cost of treating a TB case: $11 to $100" "Cost of treating an MDR-TB case: $150,000" TB Allies With HIV. Another troublesome development that has been linked to the increasing incidence of TB is the increasing incidence of HIV infection throughout the world and particularly in the United States. WHO estimates 1.7 billion (1/3 worlds population) is infected with TB. 10 million people in the world are infected with HIV. Of the 10 million HIV+ individuals, currently 4 million are co-infected with HIV and TB.TB is the leading cause of death in AIDS patients. In the US, the incidence of TB in AIDS patients has increased 500-fold. Chances are that only one out of ten immunocompetent people infected with M. tuberculosiswill fall sick in their lifetimes, but among those with HIV,one in ten per year will develop active TB, while one in two or three tuberculin test positive AIDS patients will develop active TB. Tuberculosis in HIV+ individuals is now listed by the Center for Disease Control (CDC) as a defining condition for AIDS. In HIV patients, TB progresses very rapidly. There is often delayed diagnosis due to skin test anergy and an atypical presentation. As mentioned, in immunocompetent individuals, 85% of TB is pulmonary. However, in AIDS patients, 38% is pulmonary, 30% extrapulmonary, and 32% both. TB and HIV form a deadly combination, each multiplying the impact of the other. When people are infected with both TB and HIV, TB is much more likely to become active because of the person's weakened immune system. As more TB cases become infectious, it means that larger numbers of people carry and spread TB to healthy populations.WHO estimates that by the end of the century, HIV infection will annually produce at least 1.4 million active cases of TB that otherwise would not have occurred. TB is already the leading cause of death among people who are HIV-positive, accounting for almost one third of fatalities worldwide and about 40% in Africa. Preliminary studies show that it is the leading opportunistic disease in 50-70 % of AIDS patients in parts of Asia, where the HIV virus is spreading more rapidly than anywhere else in the world. To worsen matters, WHO estimates that as many as two-thirds of all HIV-positive people who seek treatment are being misdiagnosed or treated improperly for TB, the most common error being the failure by health workers to ensure that patients actually take their anti-TB medicine. The HIV/TB alliance is bad, but it gets worse. Now the alliance is HIV and multiple-drug-resistant (MDR) TB. Molecular epidemiology has revealed several outbreaks among AIDS patients of an MDR strain of TB (strain) that is at LEAST resistant to INH, rifampicin, streptomycin, ethambutol, ethionamide, and kanamycin (6 drug resistance). The strain spreads rapidly among hospitalized AIDS patients and also health care workers and visitors. There is a 72-89% fatality rate with a very short interval from diagnosis of death (4-16 weeks). Development of MDR-TB
Bovine TBs Stealth Maneuver As M.tb strikes back directly at humanity, M.bovis has subtly positioned itself to strike through animal agriculture. Bovine-TB has been controlled in the US and other developed countries simply by slaughter of any animal that is positive for the tuberculin skin test. In developing nations, this may not be socially or economically feasible. In any case, the wildlife population will always ensurea reservoir of M. bovis is available to spread to other animals--and to humans. Recently, there have been many outbreaks of M.bovis caused tuberculosis in humans especially HIV+ patients. Most have occured in countries where M.bovis is endemic in the animal agriculture population. Multi-drug resistant strains of M. bovisare now appearing as well. The significance of this TB threat from M. bovis has not beentaken as seriously as the threat from M.tb. However, the scientific and medical community must not ignore the potential of an M. bovis TB epidemic. RETURN OF THE BASICS: HUMANITYS COUNTER-OFFENSIVE(To the beginning.)The DOTS System - Directly Observed Treatment The perception of TB's eradication had created a complacency that allowed the current resurgence of TB. However, there is still hope. We can fight back if we revive the anti-TB determination and dedication that our great grandparents and grandparents had during the sanitarium era. DOTS is an aggressive TB counterattack sponsored by WHO that helps governments establish TB programs with evaluation and monitoring systems to make health care workers more accountable for making sure patients take all their medicines.Relapses of TB usually occur within six months of the end of treatment, and in most cases are due to poor patient compliance. Patient compliance must be monitored throughout treatment; this is done at the National Tuberculosis Center throughdirectly observed therapyThe Key to the success of this program is to watch as patients swallow their medicine during the full 6 month regimen:
DOTS has been tested in New York, Tanzania, Indonesia, Peru, and China with good results. According to a report published in the March 10 issue of the Archives of Internal Medicine, the Program resulted in a 52% decrease in patients with MDR-TB in New York between 1991 and 1994. Research and Development Tuberculosis Complex Mycobacteria are difficult organisms to study and much more basic research needs to be done. The genome of Mtb is being sequenced and should be finished soon. A host gene (NRAMP) that determines susceptibility and resistance has been found in humans and the corresponding locus (Bcg) has been found in cattle and mice. A new anti-TB drug has been developed called rifampentene which reportedly can be taken by TB patients weekly instead of daily as with the other anti-TB drugs. It still needs FDA approval. Exciting developments are happening in vaccine research. Recombinant
live or attenuated vaccines designed to stimulate the immune systems T -
helper 1 response and thus augment the immune control of TB are being
developed. Brief Summary of Immune Response to TB Cell - mediated immune response vs. Humoral immune response
Public Commitment -- All for One and One for
All! Chemotherapy and other anti-TB regimens still require complete commitment by the public to control TB; money for care, education and research are needed. TB thrives on misery. It is rampant among prisons, homeless shelters, nursing homes for the elderly, AIDS victims, and immigrants from poor nations. As during the sanitarium era, a commitment to improving socioeconomic conditions can greatly reduce TB mortality. You may be amused to know that tuberculosis was once a romantic disease, associated with creative genius! Alexander Dumas wrote:
"It was the fashion to suffer from the lungs; everybody was consumptive, poets especially; it was good form to spit blood after each emothion that was at all sensational, and to die before reaching the age of thirty" Eugene O Neill wrote in a message to patients with tuberculosis:
"But let me add a warning: do not get snobbish. I remember I used to sort of despise the untutored, ignorant folk who did not have or had not had TB. I looked down upon such unfortunates as an inexperienced, inferior lot, who after all, couldn't know much about life or anything else. They simply didn't belong, thought I with a superior sniff -- until one day a friend, an eminent TB specialist, sensing my attitude, maliciously told me that truth -- that autopsies reveal the democratic fact that nearly everyone has had it! Which leaves us only one point of superiority to brag about: We know it and the rest of them don t." Dubos and Dubos wrote in The White Plague: Tuberculosis, Man and Society, 1987:
"Elucidation of the mechanisms of tuberculosis disease will long continue to require analysis by the methods of medical sciences. And the case of the stricken tuberculosis patient calls upon all the resources of medical practice. But the complete control of tuberculosis in society goes beyond medicine in its limited sense. It is a problem in social technology." Machiavelli wrote:
"It happens then as it does to physicians in the treatment of Consumption, which in the commencement is easy to cure and difficult to understand; but when it has neither been discovered in due time nor treated upon a proper principle, it becomes easy to understand and difficult to cure. The same thing happens in state affairs; by foreseeing them at a distance, which is only done by men of talents, the evils which might arise from them are soon cured; but when, from want of foresight, they are suffered to increase to such a height that they are perceptible to everyone, there is no longer any remedy." TB is not a romantic disease, nor should it be tolerated. Despite the fact that we have had the means to destroy TB, our ignorance and complacency have assured TB a continued role in human destiny. The specter of TB will always enslave us until we have the will to be free. |
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