In the year 2000, tuberculosis was responsible for 2 million deaths worldwide thus making it the 'world's leading cause of death from a single infectious disease' (2). Recent figures have revealed an increased occurrence of tuberculosis in many developed countries, primarily attributed to increased prevalence of AIDS, usage of immunosuppressive drugs as well as migration and poorer socioeconomic standards. Consequently, in the year 2000, the incidence of TB reached 9 million cases primarily reflecting the increased prevalence of AIDS (2).
Tuberculosis (TB) is a highly transmittable illness caused by the bacterium mycobacterium tuberculosis, primarily affecting the lungs (pulmonary), but may involve other areas of the body (extrapulmonary). As a result of tuberculosis, Potts disease may develop causing the vertebra to become soft and collapse, often leading to excessive curvature in the saggital plane (Kyphosis) (3). In some cases, there is excessive curvature in a lateral direction, a condition known as Scoliosis.
TB is an airborne infectious disease spreading when infected individuals cough, spit or sneeze. Classically sufferers will have a chronic cough with 'blood-tinged sputum', weight loss and fever.' (14) It is possible to diagnose TB through identifying the Mycobacterium tuberculosis organism in a given clinical sample. This method may be used in combination with X-Ray or scan imaging as well as a 'tuberculin-skin test'.
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This condition is typically treated with multiple antibiotic courses prescribed over long periods. Unfortunately, effective treatment is difficult as the chemical composition of the mycobacterial cell wall is very complex and not very well understood hindering drug entry. A growing problem today is antibiotic resistance associated with multi-drug resistant TB (MDR-TB). MDR-TB is TB that is resistant to the two most powerful first-line anti-TB drugs, isoniazid (INH) and rifampicin (RMP). This develops when an interruption to the course of treatment occurs or when drug levels are found to be insufficient in the body. MDR-TB is as easily transmitted as drug-sensitive TB and via the same ways. To prevent the risk of infection a vaccination is available, usually with a 'Bacillus Calmette-Guérin vaccine' (14).
Tuberculosis has featured very strongly in many diverse areas and cultures throughout history. The focus of this study is to establish the history of the disease during the period of the ancient Egyptians, and to determine a distinctive correlation between ancient and present day prevalence of the disease. Additionally, resistance is considered with special reference to TB as an opportunistic infection associated with HIV. Hence overall, the control of the disease from the time of its discovery to date is discussed as well as its resurgence over the recent years.
Foundations Of Mycobacterium Tuberculosis: Ancient Egypt
Geographically, ancient Egypt was wedged between the Mediterranean Sea to the north and Elephantine region to the south, with its eastern and western boundaries in the high desert on either side of the narrow strip of Nile valley and low desert either side of the River Nile. Ancient Egypt was divided into Upper and Lower Egypt with upper Egypt consisting of the long, narrow strip of land located south of the lower Egyptian Delta consisting of the Nile River, the floodplain, the low desert, and the surrounding high desert. (4) and lower (northern) region of the Nile River's delta made by the river as it empties into the Mediterranean Sea. A map of ancient Egypt is shown below:
(Source: The Quest For Immortality - Treasures Of Ancient Egypt (5))
Dynastically, Ancient Egyptian saw throughout its history 30 different reigns, each being a specific time period during which rulers belonged to the same family. (6) Groups of dynasties constitute a period, during which different dynasties ruled separate areas of the country at the same time. Appendix 1 demonstrates a brief timeline of the different dynasties and periods throughout the history of the Ancient Egyptians.
Ancient Egypt played host a great deal of historical evidence via advancements in literature recording in the form of papyrus, tomb portraits and present day anatomical examination of preserved mummies. During the late predynastic period (3100-2950 BC), hieroglyphic writing was employed to document medical activities, thus leading to the creation of some of the oldest medical literatures known to man (7). Specific references are made to tuberculosis in the Ebers Papyrus (1534 BC) (8), with 2 cases exhibiting the clinical features of the illness:
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"If you examine a man with a cystic node in his neck, you will find it like
the thymus gland because of its palpation and its white discharge ...
He has enlargement of the cystic node in his neck" (9)
Evidence as to the attitudes to those suffering from the disease is very sketchy due to the clinical nature of the information, rather than information regarding attitudes to those afflicted by the disease. These medical papyri mainly document the clinical features of the disease, as well as its existence, however fail to shed light concerning the extent to which the disease was ubiquitous among the ancient Egyptians. In order to do this and for a better understanding, archaeological evidence in the form of tomb portraits must be analysed to give an idea as to the extent of the disease.
The evidence for the existence of TB during ancient times thus comes from tomb portraits. Portraits of the deceased are considered to be accurate owing to need for realistic representation in order to convey the deceased in a manner that they wish to remain for eternity; their image at their death (10). It must also be considered that having physical deformity as a result of tuberculosis did not hinder chances of religious or civil progression.(7) Ankah-My-Was was illustrated in the Mastaba tomb of 2900BC as having tuberculosis in the thoracic region of the upper spine. The illustration depicted the sternum as abnormally protruding with the upper spine abnormally convex in a dorsal manner. Meanwhile the arm was in a midline position between the dorsum and ventral of the thorax. This suggests beyond any doubt that the person had tuberculosis affecting the upper thoracic spine (7).
(Source: 'Tuberculosis In Ancient Egypt' (7))
During the middle kingdom (2210 BC) at the tomb at Beni Hasan, another ancient Egyptian illustration showed a male character as having a hunchback, with evident kyphosis of the upper thoracic spine, leading to the depicted hunchbacked appearance. However, as the sternocostal region is not present on the representation, it is very difficult for modern day archaeologists to determine consequentially whether the individual suffered from tuberculosis. (7) During the new kingdom, at the tomb of Ipy at Thebes during the 19th dynasty (1330 BC) an image of a man exhibiting obvious features of kyphosis was demonstrated as well as a protruding sternocostal region, strongly indicating that this person suffered from tuberculosis. (7)
(Source: Tuberculosis In Ancient Egypt) (11)
These images are portrayed over 15 successive dynasties throughout ancient Egyptian history indicating that the disease was present for well over 1570 years thus demonstrating the infectious and persistent nature of the disease (12). The tomb portraits offer considerable evidence, once again signifying the existence of tuberculosis among the ancient Egyptians. Nevertheless this fails to provide empirical evidence that the physical deformities of those depicted in the images were as a direct result of tuberculosis or another condition. Hence in order to consequentially prove that tuberculosis was present among the ancient Egyptians, molecular examination and examination of preserved mummies is required.
Advantageously, the religious nature of the ancient Egyptians meant the bodies of the deceased were mummified, providing useful evidence for present day anatomists in determining whether the individual had suffered from tuberculosis during their lifetime. Extensive excavation undertaken at a burial site made during the early dynastic period (3400 BC) revealed four bodies believed to have suffered from tuberculosis. The first body to be exposed and examined was the remains of an adult male whose 8-10th thoracic vertebra had fused together. Furthermore, upon detailed analysis of the body, it seemed that the 9th thoracic vertebral body had exhibited significant erosion, effectively leading to the collapsing of the 8th vertebra onto the 10th vertebra. This internal destruction presumably resulted in significant kyphosis of the upper thoracic spine. Additionally, three other bodies were discovered at the same burial site, all of which were found to have suffered from tuberculosis. Recent pathological examinations have shown to support a statement made by Elliot Smith and Derry. The speculation imposed by Elliot Smith and Derry that "it is more probable than not that they are examples of the destruction wrought by the tubercle bacillus" (7) was indeed in place as the examination verified the infection found in all four bodies was the bacterium mycobacterium tuberculosis.
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The middle kingdom era followed shortly after the early dynasty revealing a burial ground with substantial specimens of mummies with Potts disease. This was demonstrated from one such mummy of an adult male where the 2nd, 3rd, and 4th vertebra in the lumbar region of the vertebral column had all fused together, indicating significant kyphosis of the thoracolumbar region. This is clear evidence for mycobacterium tuberculosis infection. At the same site of the middle kingdom era, another adult male was identified demonstrating the idea of how widespread the infection by the bacterium had become. The middle kingdom era was important for archaeologists and anatomists alike, as it provided a link between earlier dynasties of the old kingdom to subsequent dynasties of the new kingdom (7)
To date, the most convincing evidence available to support the presence of tuberculosis amongst the population of ancient Egypt is in fact the burial sites that date back to the 21st priesthood of Amun. A high dignitary by the name of Nesperehan exhibited obvious signs of Potts disease with significant kyphosis in the thoracic vertebral region. (7) Once more, the spinal deformity is apparent in the illustrations during the named period, a sign clearly indicative of the attitude towards sufferers of the disease as one not of negativity, facilitating both civil and religious advancement. The reason for this may actually be due the belief of the ancients that the physical deformity was not brought about by a disease. It must be stated however, that to empirically prove the presence of tuberculosis among the ancient Egyptians, molecular analysis of preserved vertebrae is required.
In a given sample of seven skeletal vertebrae located in Necropolis by Abydos during the predynastic period through early dynastic period (3500-2650 BC) (13), a single vertebral column exhibited obvious signs suggestive of tuberculosis, with two exhibiting alterations to the vertebral column, consequently unsuggestive of infection by the disease. Hence in this sample one case was found to have significant erosion of the vertebral body, and when molecularly analysed was pathologically proven to have been infected by mycobacterium tuberculosis. Additionally, a non specific case was also found to be pathologically infected by mycobacterium tuberculosis. As a result, this study yielded a 28% infection rate among the predynastic sample, a significant rate indicating a common occurrence of tuberculosis among the ancient Egyptians. However, it is to be emphasized that to empirically prove the existence of tuberculosis throughout the history of Ancient Egypt, vertebral remnants from the Middle and New kingdoms must be analysed to establish whether the disease was in fact present during those time periods.
Further studies and excavation of burial sites of the middle kingdom (2100-1500 BC) in Necropolis, West Thebes yielded a sample of 37 vertebrae for molecular analysis, three of which exhibited spondylitis typical of tuberculosis, two of which were molecularly proven to have been infected by mycobacterium tuberculosis. In this sample, ten individuals showed non-specific alterations within the vertebral bodies, where in particular, one individual was shown to have suffered the disease. At the same time, 12.5% of seemingly normal individuals were molecularly found to suffer from the disease, tuberculosis. Though this sample gave a significantly lower rate of infection than the previous dynasty, 16%, it was still a statistically significant value.
During the New Kingdom (1550-500 BC), 39 vertebral bodies were found in the Necropolis of Thebes West. These bodies were suitable for examination to aid the presence of tuberculosis among the era. The sample of 39 selected vertebrae yielded varying results where 5 were found to exhibit physical alterations, clearly indicating the presence of tuberculosis. Three of the five samples with these alterations were molecularly analysed and demonstrated clear signs typically present in any TB sufferer. Meanwhile, 12 vertebras from the same sample showed non-specific physical alterations, of which two were later identified as having suffered from the bacterium infection during their lifetime. The 22 remaining cases regarded as non-altered were also examined, giving one case of TB.
Henceforth deducing from all the molecular analysis the existence of tuberculosis and the time period of its presence amongst ancient Egyptians is acceptable. And so owing to the nature of tuberculosis as transmittable and persistent, it can be inferred that tuberculosis was highly prevalent amid the ancient Egyptians.
Tuberculosis: Advancement In Past 100 Years
Evidence collected between 1913 through 2006 stated "The prevalence of T.B. in Great Britain has declined dramatically over the last 100 years..." The availability of antibacterial drugs and vaccinations allowed the number of TB suffering individuals to significantly decrease, reaching its trough in 1987 with the biggest decline. Additionally, and possibly more importantly, the improved lifestyle of the modern world and social provisions are a major contribution to the near abolishing of TB:
"A principal determinant of mortality from tuberculosis is nutrition. Mortality from T.B. increases considerably as one passes from the economically
prosperous to the poor districts of any area"
Mycobacterium tuberculosis is the causative bacterium in the infectious disease, tuberculosis. This was identified Robert Koch (1843-1910) who is a pioneer in the field of tuberculosis. Besides the isolation of the bacterium and its identification, Koch also found tuberculin which was later to be used as part of the diagnostic testing for the disease in individuals. Wilhelm Conrad von Rontagen (1885) developed the X-rays that could measure the vertebral effect of infection. These two methods are usually used in conjunction with each other to diagnose a patient.
The turning point for this disease at which it became more under control was during the 1930's where initially sanatorium treatment was acknowledged as a having poor long term results. At first it, Christian Saugmann in 1908 introduced a procedure of collapse therapy involving artificial pneumothorax, used in conjunction with the sanatorium. However, later works of Bayaii in 1933 developed this idea farther, augmenting the results of treatment as well as improving the life overall life expectancy.
Graph 1 of Appendix 1 shows the incidence rates of tuberculosis in the UK, depicting a clearly marked severe decline over the past 100 years. Primarily, this reflects development of the BCG vaccination, one of the prevention methods of the disease. This significant fall in affected individuals may be attributed to the development of the anti-TB drugs, including streptomycin (1949) and rifampin (1963), both of which proved to be highly successful in preventing antibacterial resistance whilst exhibiting powerful antibacterial effects. Freidman and Hinshaw developed streptomycin, alongside Pfuetze, proving to be an effective specific anti-TB drug rendering treated patients with normal lives henceforth. This suggested that most cases identified as TB sufferers could be treated using the above stated drugs, as well as others. Due to recurrent infections, more potent drugs such as Cycloserine and Viomycin were developed which correspond to a decreased mortality rate of infections by mycobacterium tuberculosis.
Antituberculosis drugs such as sulphonamides, penicillin and others were first introduced throughout World War II, and later developed targeting mainly and attacking the mycobacterium tuberculosis. Waksman, of the 1940's isolated Actinomycin, which in 1943 allowed low toxicity yet high inhibition of the bacterium resulting in astonishingly pleasing outcomes leaving patients with a successful combat against the disease.
Recently, the problem of drug resistance has increased, primarily reflecting the corresponding increase in number of TB sufferers, a rise illustrated in a table of data collected from 1987 to 2006 (appendix 1, table 1). This rise may also be reflected by the increasing proportion of the population suffering from HIV/AIDS and receiving antiretrovirals and other TB therapies. The evidence from appendix 1 is clear in its implication of the rise in cases of TB since 1987. This upswing of incidence is caused by a significant contributing factor that is the development of transport methods thus resulting in an imported TB from different countries worldwide.
Also, the ensuing rise in incidence rates of TB since 1987 are perhaps correlated to the rise in individuals affected by the Human Immunodeficiency Virus (HIV) with the subsequent treatments using immunosuppressant drugs. This is because such drugs tend to decline the body's ability to defend itself naturally and so increasing susceptibility to TB.
Arguably the most important factor associated with an increase in the incidence of tuberculosis in the UK since 1987 reflects global multidrug resistance. As mentioned earlier in this study, it is a challenging problem resulting in a narrower range of drugs able to be used in the treatment of tuberculosis. Some cases illustrate some instances where drug resistance has become so substantial rendering drug therapy useless in their treatment.
Past And Present: Comparing Present Day and Ancient Egypt
From analysis of the ancient evidence available in the forms of tomb portraits, anatomical examination of mummified individuals, medical papyri and molecular analysis, the existence of tuberculosis amongst the ancient Egyptians is for certain. As was understood from the analysis, TB endured for a period longer than 1750 years, highly suggestive of the prevalence of the disease amongst ancient Egyptians, especially given its highly transmittable nature.
Recent advancements in the antituberculosis drugs available, and the vaccines that now exist have meant there is a significantly lower rate of modern day infection in comparison to 100 years ago. For these reasons it can so be inferred that prevalence of TB amongst the ancient Egyptian population was much greater than what it is in this present day. This can be hypothesized due to their unawareness and lack of knowledge in drugs, therapies and also vaccines. Nevertheless, evidence supporting the extent of disease prevalence in the ancient times remains sketchy, simply reasoned by the lack of written evidence to support this hypothesis. Even though many studies may have been able to molecularly prove the exitance of tuberculosis among the ancient Egyptians, the samples obtained are too small to be representative for the entire ancient population, and so no definite conclusions can be drawn.
Assessments performed on trends in antituberculosis drug resistance periodically would and will help inform on the progress and performance of the currently prescribed medication and its affectivity. Assessing the performance of national tuberculosis control programmes over time will inform of the necessary adjustments required to improve the control of the disease. The Global Project has already completed a third round of surveys and surveillance in 2002, combining the data from all three rounds to provide information on 109 countries or geographical settings worldwide. These areas represent almost 40% of notified smear-positive pulmonary cases of tuberculosis.
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The HIV/TB dual infection
Tuberculosis is the most common co-infection in individuals infected with HIV-1 (15). The causes of TB tend to occur intermittently and seldom is there any epidemiological correlation between incidences of infection. However in the more recent years it has become evident that the rising outbreaks of TB are caused by the resistance of the organism to multiple antituberculosis drugs. Most of the reported occurrences are found primarily involving persons infected with HIV-1 who are thought to have been exposed to strains throughout medical facilities. Of the nearly 15 million cases of HIV/TB infection worldwide, over two thirds of the cases were reported to exist in Sub-Saharan Africa. Though this is an alarmingly large ratio, this dual infection may be conjectured to continue expansion with increased interaction between the pathogens due to the spreading of HIV-1 in areas such as South-east Asia and other parts of the world.
The Human Immunodeficiency Virus (HIV) is an incurable type of retrovirus that eventually leads to the failure of the immune system causing Acquired Immunodeficiency Syndrome (AIDS). The individual may die as a result of contracting an Opportunistic Infection (OPI) during their time of infection by HIV. Unlike TB, HIV spreads via contact with blood, breast milk, vaginal fluid or semen where the virus is found to be present as free virus particles or within infected immune cells. In the more recent years, blood products for things such as blood transfusion have had less infectious rate due to blood screening, enabling the improvement of the control of the virus spread in the 'developed countries' (16).
The World Health Organization (WHO) in 2005 reported this 'pandemic infection' to affect 0.6% of the world's total population (16) with AIDS having killed over 25 million individuals since it was first discovered in 1981 up until 2006. Though this virus to date cannot be cured, it can be controlled and individuals can survive longer increasing their life expectancy with the use of antiretroviral treatment. The problem presented here is the availability of such drugs to treat the infected individuals especially with a third of reported cases found to reside in Sub-Saharan Africa, where poverty and development are major issues.
HIV is an infection of the T helper cells of the immune system; in particular, it is typified by the significantly low CD4+ T cell count. This count is decreased via three mechanisms involved in the life cycle of the retrovirus; direct killing of the infected cells at the first stage, followed by apoptosis of these cells, ending the cycle with the killing of the CD4+ T cells by CD8 cytotoxic lymphocytes (16). As the CD4+ cells decline in number, the body begins to lose its cell mediated immunity which is essential in fighting infections. This henceforth makes the body more susceptible to any OPIs.
During the replication process of the HIV-1 infection an OPI may be developed leading to AIDS. TB as an OPI may occur at any stage of the HIV-1 infection and is evidently correlated to the virus' mortality rates. In MDR-TB, the infection is believed to occur through antimicrobial agent-resistant organisms. Another possibility for the resistance is inadequate therapy leading to the selection of the drug-resistant strain throughout drug therapy.
Several studies that took place in the pre-HIV era demonstrated that drug resistance in TB comes about in two ways; throughout treating an individual, the drugs may be inadequate in conception, hence a resistant mutant emerges. This drug-resistant strain originally from drug-sensitive tuberculosis, is naturally selected for survival of the mycobacterium, and may well be transmitted to other uninfected persons ensuing primary drug resistance.
It was only recently discovered that, during HIV-1 replication, it is induced by mycobacterium tuberculosis from HIV-1 infected individuals, where mononuclear cells from these individuals are found more susceptible to contraction of infection (18). Particularly favoured by the virus, the mycobacterium environment is ideal for replication. A considerable amount of research has gone towards studying the impact of TB on the HIV-1 viral load, where one cross sectional study conducted by 'Toossi, Z et al' on the 'Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients' found 'circulating HIV-1 load was significantly higher in patients with the HIV/TB dual infection in comparison to individuals without the dual infection but matching CD4 count' (17). This same group conducted another longitudinal study on the HIV-1 patients who later went on to develop TB showed a significant rise in viral load at or around the time of diagnosis' (17).
In HIV-1 infection dually with TB, progressive primary TB is seen alongside the reactivation of the initial mycobacterium tuberculosis infection. The latter can bear a resemblance in early HIV-1 TB making it more favourable and responsive as a target to preventive treatment. As a further outlook for future ideas in preventive therapy, it may be considered that chemoprevention of TB given to individuals suffering from HIV-1 with higher CD4+ T cell counts is of greater reward. The reason for this lies in the effect of TB on the viral load in those patients that cause it to increase significantly. The abortion of TB via this method at this stage is beneficial however chemoprophylaxis may not be feasible to all infected patients, especially considering countries where HIV-1 and TB are found prevalent (19).
What can be done?
An employment of further research in this field would benefit medical advancement and patients alike in combating this disease and possible outbreaks of resistance. NICE (national institute for clinical excellence) in 2006 issued documented interventional guidelines hoping to improve rates of individuals completing treatment and in turn achieving 85% success; a standard set by CMO action plan and WHO. All of those suspected of an infection or seemingly at a high risk, including immigrants, prisoners, and the homeless will have greater screening and subsequent treatment of the disease. NICE has put forward a recommendation to strengthen surveillance systems acting as a method of control, as well as informing the groups considered at risk of infection. Also recommended by NICE to measure the on-going disease transmission, the strain typing scheme must be improved. It has been considered with great importance to decrease tuberculosis levels internationally.
Whilst the numbers of individuals infected with tuberculosis is on the increase, numerous methods have been implemented on an international scale to prevent a global epidemic. With the world population increasing at an exponential rate, and immigration rates high, can the government cope with increased pressure with limited resources, or will the UK be subjected to 'the white plague'?