tuberculosis ( tb ) is a contagious , infectious disease , due to mycobacterium tuberculosis ( mt ) , which usually lasts throughout the life course and determines the formation of tubercles in different parts of the body .
mt has very ancient origins : it has survived over 70,000 years and it currently infects nearly 2 billion people worldwide ; with around 10.4 million new cases of tb each year , almost one third of the world 's population are carriers of the tb bacillus and are at risk for developing active disease .
tb has always been associated with a high mortality rate over the centuries , and also nowadays , it is estimated to be responsible for 1.4 million tb deaths , among infectious diseases after human immunodeficiency virus ( hiv ) .
due to its infectious nature , complex immunological response , chronic progression and the need for long - term treatment , tb has always been a major health burden ; in more recent years , the appearance of multi - drug resistant forms and the current tb - hiv epidemic , associated with its severe social implications , treating and preventing tb have represented a permanent challenge over the course of human history [ 4 , 5 ] .
it has been hypothesized that the genus mycobacterium originated more than 150 million years ago .
mycobacterium ulcerans , causing infections since ancient times , requires specific environmental conditions as reflected nowadays in its distribution worldwide .
three million years ago , an early progenitor of mt might have infected early hominids in east africa   and 20.000 - 15.000 years ago , for the first time , the common ancestor of modern strains of mt might have appeared [ 8 , 9 ] .
egyptian mummies , dating back to 2400 bc , reveal skeletal deformities typical of tuberculosis ; characteristic pott 's lesions are reported and similar abnormalities are clearly illustrated in early egyptian art [ 10 , 11 ] .
the first written documents describing tb , dating back to 3300 and 2300 years ago , were found in india and in china respectively [ 12 , 13 ] .
the ancient hebrew word schachepheth is used in the biblical books of deuteronomy and leviticus in order to describe tb ; in the same period , in the andean region , archeological evidence of early tb , including pott 's deformities , was provided by peruvian mummies , suggesting that the disease was present even before the colonization of the first european pioneers in south america [ 15 - 18 ] . in the ancient greece tb
hippocrates described phtisis as a fatal disease especially for young adults , accurately defining its symptoms and the characteristic tubercular lung lesions .
excellent discoveries of the early scientists who studied tb were made in the same period : in greece , isocrates was the first author supposing that tb was an infectious disease , while aristotle suggested the contagious nature of " king 's evil " in pigs and oxes . in roman times ,
tb is mentioned by celso , aretaeus of cappadocia and caelius aurelianus , but it is not recognized as sharing the same etiology of extrapulmonary manifestations such as scrofula , pott 's disease and tb lupus . according to the greek clarissimus galen , who became personal physician of the roman emperor marcus aurelius in 174 ad , the symptoms of tb include fever , sweating , coughing and blood stained sputum ; he recommended fresh air , milk and sea voyages as successful treatments for the disease [ 20 - 22 ] .
after the decline of the roman empire , tb was widespread in europe in the viii and xix centuries , as witnessed by several archaeological findings .
the byzantine doctors aetius of amida , alexander of tralles and paul of aegina described the pulmonary and glandular forms of tb , while in the arabic empire , avicenna supposed the contagious nature of tb .
in the middle ages , scrofula , a disease affecting cervical lymph nodes , was described as a new clinical form of tb .
the illness was known in england and france as " king 's evil " , and it was widely believed that persons affected could heal after a royal touch . in the 12 century , william of malmesbury reported complementary treatments including visits at royal tombs , the kings ' touch or the use of a coin - talisman .
the practice of the king 's touch established by english and french kings continued for several years .
queen anne was the last english monarch to use this practice ( 1712 ) , george i put an end to it in 1714 , while in france it continued up to 1825 . in the middle ages , moreover , the french surgeon guy de
chauliac ( 1363 ) for the first time proposed a healing intervention for the cure of the " king 's evil " .
guy de chauliac was also strongly in favour of the removal of scrofulous gland with an engraving , as recommended by paul of aegina , who advised the surgical removal of the diseased gland , taking care not to harm vessels or nerves of which the neck region is rich .
as far as concerns the contagious nature of tb , a clear definition was first given by girolamo fracastoro in the sixteenth century .
the exact pathological and anatomical description of the disease was illustrated in 1679 by francis sylvius , in his work opera medica , in which he describes tubercles , their progression to abscesses , cavities and empyema in the lungs and in other sites of consumptive patients .
short afterwards , in italian health law , in particular in an edict issued by the republic of lucca in 1699 , there is the first official reference to the infectious nature of the disease . in 1735
the health board of the republic ordered the compulsory notification and isolation of consumptives , forbidding their admission in public hospitals , and establishing specific places for their treatment .
in 1720 , for the first time , the infectious origin of tb was conjectured by the english physician benjamin marten , in his publication " a new theory of consumption " . for the early eighteenth century
both terms consumption and phthisis were used in the 17 and 18 centuries , until in the mid-19 century johann lukas schnlein coined the term " tuberculosis " . in the 18 century in western europe , tb had become epidemic with a mortality rate as high as 900 deaths per 100,000 inhabitants per year , more elevated among young people . for this reason ,
tb was also called " the robber of youth " . during the industrial revolution , the diffusion of particularly problematic social conditions , such as extremely deprived work settings , poorly ventilated and overcrowded housing , primitive sanitation , malnutrition and other risk factors ,
up to a third of english tradesmen and employees died of tb , whereas the same proportion decreased to a sixth in the upper class .
the extreme anemic pallor of people affected by tb was at the origin of the new term " white plague " , coined during the 18 century [ 20 , 35 ] .
one hundred years later , tb was defined as " captain of all these men of death " because of its epidemic proportions in europe and north america , determining one in four deaths . at the beginning of the 19 century
, there was a large scientific debate about different theories concerning the etiopathological origin of phthisis , arguing whether it might be considered : an infectious disease  as generally considered in southern europe  an hereditary one  as stated in northern europe  or a form of cancer .
on the other hand , the discussion was about scrofula , tubercles , and phthisis as separate disease entities or manifestations of the same illness . in 1793 , the caseous necrosis , " cheese - like " , phthisic abscesses were named " tubercles " by the scottish pathologist matthew baille . in 1810 , the french physician gaspard - laurent bayle of vernet described the disseminated " miliary " tb in his work recerches sur la phthisie pulmonaire , recognizing tb not only as a disease affecting the lung , but a generalized one , clinically defined by coughing , difficulty in breathing , fever and purulent expectoration [ 37 , 38 ] . in 1819 ,
the french theophile laennac identified the presence of consolidation , pleurisy and pulmonary cavitation as pathognomonic signs of pulmonary or extrapulmonary tb .
tuberculosis most commonly affects the respiratory tract , but it could also infect gastrointestinal , bones , joints , nervous systems , lymph nodes , genitourinary tract and skin with inflammatory infiltration , caseation , necrosis , abscesses , fibrosis , formation of tubercles and calcification [ 39 , 40 ] .
he described their first appearance in the lungs , in their " miliary " ( " millet seed - like " ) form , their progressing to larger tubercles containing " cheese - like " ( " caseous " ) material , their breakdown into pus , and eventually forming cavities and empyema .
extra - pulmonary phthisic tubercles were recognized in the intestines , liver , meninges and other organs , as also described by sir percivall pott , a british surgeon that in 1779 defined as " pott 's disease " the vertebral collapse and spinal cord paralysis caused by tb infection [ 33 , 36 , 37 , 41 , 42 ] . in 1843 , the german physician philipp friedrich hermann klencke succeeded in the experimental reproduction of human and bovine forms of tb , causing generalized tb in rabbits , through a successful inoculation of material from a miliary tubercle into their liver and lungs . in 1849 lebert , publishing his work traite pratique des maladies scrofuleuses et tuberculeuses , suggested that the " king 's evil " was a childhood disease that might cause suppuration and ulceration of different body 's sites such as skin , ears , eyes , joints , bones , with a different pathogenesis from tb .
the first successful remedy against tb was the introduction of the sanatorium cure , described for the first time in 1854 in the doctoral dissertation " tuberculosis is a curable disease " by hermann brehmer , a botany student suffering himself from tb , who reported his healing after a travel to the himalayan mountains .
afterwards brehmer founded an institution in gorbersdorf , a mountain town situated in a fir forest , in order to cure patients with continuous fresh air and good nutrition .
the subsequent sanatoria were built with the same setup and permitted to cure a lot of tb patients in the next decades .
the infectious nature of tb was demonstrated in 1865 by jean - antoine villemin , a french military surgeon at the army medical school .
he formulated his hypothesis observing that tb was more frequent among soldiers who stationed for long times in barracks than among those in the field .
he also highlighted how healthy army recruits coming from the countryside often became consumptive some months after the beginning of their service .
villemin 's experiments consisted in inoculating a rabbit with " a small amount of purulent liquid from a tuberculous cavity " removed at autopsy from an individual died of tb .
as described in villemin 's work cause et nature de la tuberculose : son inoculation de l'homme au lapin , the inoculated animal remained alive and no disease signs were discovered , but at autopsy , three months later , extensive tb was evident .
villemin suggested that phthisis could be similar to glanders , an infectious disease in horses [ 20 , 34 , 36 , 37 , 47 ] .
preuves rationelles et exprimentales de sa spcificit et de son inoculabilit , dated 1868 , in which he stated the presence of tblike illnesses in different animals .
the author also noticed that more crowded urban areas had a higher prevalence of tb and that some parts of the world , like new zealand and australia , seemed to have not known tb until the arrival of pioneers .
some years later , in 1867 , theodor albrecht edwin klebs was one of the early scientists to try to isolate the tb bacillus , sowing tuberculous material on egg white , stored in sterile flasks . in his experiments , the culture was quickly muddy and it was possible to recognize mobile bacilli , which , after inoculation into the peritoneal cavity , caused the disease in guinea pigs .
using the methylene blue staining recommended by paul ehrlich , he identified , isolated and cultivated the bacillus in animal serum .
robert koch presented this extraordinary result to the society of physiology in berlin on 24 march 1882 , determining a milestone in the fight against tb . in the decades following this discovery , the pirquet and mantoux tuberculin skin tests ,
albert calmette and camille gurin ( bcg ) vaccine , selman waksman streptomycin and other anti - tuberculous drugs were developed .
koch contributed also to the elucidation of the infectious etiology of tb and for his scientific results , he was awarded the nobel prize in medicine in 1905 [ 33 , 51 ] .
nowadays tb is still a major public health problem , for this reason a combined strategy , based on improving drug treatment , diagnostic instruments , and prevention strategy , is necessary , in order to eradicate m. tuberculosis by the year 2050 , as committed by the world health organization ( who ) .
 summarytuberculosis ( tb ) is a contagious , infectious disease , due to mycobacterium tuberculosis ( mt ) that has always been a permanent challenge over the course of human history , because of its severe social implications . 
 it has been hypothesized that the genus mycobacterium originated more than 150 million years ago . in the middle ages , scrofula , 
 a disease affecting cervical lymph nodes , was described as a new clinical form of tb . 
 the illness was known in england and france as " king 's evil " , and it was widely believed that persons affected could heal after a royal touch . in 1720 , for the first time , the infectious origin of tb was conjectured by the english physician benjamin marten , while the first successful remedy against tb was the introduction of the sanatorium cure . 
 the famous scientist robert koch was able to isolate the tubercle bacillus and presented this extraordinary result to the society of physiology in berlin on 24 march 1882 . in the decades following this discovery , the pirquet and mantoux tuberculin skin tests , albert calmette and camille gurin bcg vaccine , 
 selman waksman streptomycin and other anti - tuberculous drugs were developed . 