Mycobacterium tuberculosis complex (MTC)

mycobacterial lipopeptide 19 kDa binds to TLR1/TLR2 heterodimer
MPB64
MPB70
23-kDa superoxide dismutase (SOD)
27-kDa
inducers of DCs maturation

antigen 85 (Ag85) complex / mycolyl-transferase is composed of a group of secreted proteins that are known to bind fibronectin.

Ag85a / MPT44
Ag85b / MPT59
Ag85c / MPT45

MPT51 / 26 kDa
MPT64 / 26 kDa
latency associated hspX (a-cristallin)
region of deletion-1 (RD1) locus consists of at least 11 genes, including esxA and esxB genes, which encode the strong T-cell antigens 6-kDa early secretory antigenic target (ESAT-6) (unknown function) and its binding partner 10-kDa culture filtrate protein (CFP-10) respectively, as well as a variable number of flanking genes encoding a secretory apparatus
Mycobacterium tuberculosis secretory Ag (MTSA)

phosphate transport receptor (PstS)
the mycobacterial proteasome degrades proteins that are irreversibly oxidized, nitrated, or nitrosated, protecting the organism against ROS and reactive nitrogen intermediates (RNIs)
peptide methionine sulfoxide reductase (msrA) protects bacteria against oxidative damage from reactive nitrogen intermediates (RNIs)
heparin-binding haemagglutinin (HBHA) : methylation is crucial for the induction of protective T-cell immunity to this pathogen. HBHA is a cell-surface protein antigen, and the native protein (nHBHA) is post-translationally modified by methylation of lysine-rich repeats in the carboxy-terminal : the methylated portion of HBHA forms part of the T-cell epitopes. The distinct abilities of nHBHA and unmethylated recombinant HBHA (rHBHA) produced by Escherichia coli to induce protection correlated with splenocytes from nHBHA-immunized mice producing considerably more IFN-g in response to bone-marrow-derived macrophages pulsed with M. tuberculosis and more-efficiently lysing BCG-loaded macrophages^ref.
Mycobacterium tuberculosis mechanisms targeting MHC class II expression are effective at inhibiting antigen presentation, but only after a delay of at least 10 h. By comparison, the effectiveness of mechanisms targeting other cellular processes is immediate, but may be attenuated under certain conditions^ref

Transmission : recent observations in Spain showed that Mycobacterium tuberculosis strains of bovine and caprine origin circulate in the same local wildlife populations and that 6 out of 11 spoligotypes were similar to types described in human cases. The isolation of M.tuberculosis complex strains (belonging either to M. bovis or to M. caprae), in fenced estates, from cervids and wild boars that have not had contact with domestic livestock for at least 2 decades, strongly suggest that the M. tuberculosis complex is able to survive in these populations^ref. The Environmental Council will advance the wild boar hunting season in Els Ports national hunting reserve to September 2005, allowing intensification of their capture rate. This, in order to reduce the wild boar population and stop dissemination of tuberculosis, which was initially detected at the end of 2004.Wildlife management aimed at reducing the density of susceptible animals within an infected area may contribute to the control of infectious diseases in animals and -- if zoonotic -- their spillover to humans. The major predator of wild boars, in places where you don't have wolves and mountain lions, happens to be male wild boars, who frequently unearth, kill, and eat the litters of territorial rivals. (This is why boars and young are always separated at pig farms.) In addition, the size of surviving boar litters is closely governed by the accessibility of food to the females. The more boars you shoot, accordingly, the more boars you end up with. The males are much more likely to be shot, being more often diurnal in habits and much less likely to spend their days underground. The females will benefit by food abundance, will raise larger litters, the litters will be subject to markedly less predation, and within a year there will be more boars in the habitat than ever, spreading more TB than ever (unless you have a major food crop failure, e.g., an acute shortage of acorns.) Swine behavior is certainly territorial and subscribes to survival of the meanest and fittest. It is not my intention to imply this is the way all breeds of swine behave; this is only an observation of behavior of wild boars and may provide food for thought for those in the council as to how they want to implement their plan with regard to swine tuberculosis. There may need to be more information on the documentation on what the author has sent, as based upon these comments alone, it would be possible to ban hunting altogether. I am not sure that is the proper approach either. A lot of work on management of feral pigs (which seem to have similar ecology) has been carried out in Australia. They have also prepared a detailed emergency plan in case FMD is introduced into their large pig population. They compared various pig control methods, such as hunting with dogs, trapping, and poisoned baits (mainly warfarin). A typical conclusion was: "Hunting was generally not as effective in reducing pig numbers as poisoning with warfarin, but could be useful for obtaining samples of pigs for monitoring disease during the first few days of an exotic disease outbreak, and also for killing pigs that have survived other control methods". (JC Mcilroy and RJ Saillard, 1989: The Effect of Hunting With Dogs on the Numbers and Movements of Feral Pigs, Sus-Scrofa, and the Subsequent Success of Poisoning Exercises in Namadgi-National-Park. Australian Wildlife Research 16(3) 353-363). European wild boars do not "[un]earth" nor do they live "underground," and there are limited records of cannibalism (Gortazar et al., Ann NY
Acad Sci, 2002). Food availability is probably the main factor affecting wild boar densities, even more than hunting and far more than predation and cannibalism. Litter size is not only affected by food availability but also by disease prevalence and population structure. Adult females have larger litters (Ruiz-Fons et al., Theriogenology, in press). Hunting usually reduces the proportion of adults in a population. Hence, the sentence "the more boars you shoot, the more boars you end up with" is also not correct. If shooting (or any other means of population control) is done in areas with abundant food (sometimes provided by the hunters), I agree that it makes little sense for density reduction. But, if a ban of artificial feeding takes place at the same time you increase hunting pressure, I am sure you will be able to affect the wild boar population dynamics and achieve a lower density^ref. The management of wild boar and/or feral pig populations has been studied and discussed, in recent years in various countries, also in relation to the control or prevention of several animal diseases besides bovine tuberculosis: hog cholera, trichinellosis, African swine fever, FMD (extensive studies in Australia since 1992) and others.

Epidemiology :

prevalence of infection : 1.7 billion people (dropped by > 20% since 1990 to 2005^ref), 12 million are coinfected with HIV-1 (66% live in Sub-Saharan Africa). Middle East accounted for 7% of all incident cases of tuberculosis globally as of 2002^ref

China : a 3-month-long survey covering nearly 400,000 school children has found that nearly 9% of students under the age of 14 in primary and middle schools in Harbin tested highly positive for tuberculosis (TB) at a tuberculin forearm skin test. The X-rays revealed > 100 children have already begun to show symptoms of TB. Chinese babies are usually given the BCG vaccine for the prevention of TB within 24 hours of birth. Those who tested negative have been advised to get vaccinated as soon as possible, albeit on a voluntary basis
Italy : 12-13%
USA : foreign-born persons account for > 50% the cases of tuberculosis in the USA reported to the CDC, a rate that is 9 times that among those born in the USA^ref. In Massachusetts, 80% of the cases reported in 2003 occurred in foreign-born persons, most of whom had resided in the USA for 1-4 years^ref.
Botswana : 60% of TB patients are infected with HIV. Resistance to at least one drug in new patients rose from 3.7% in 1995 to 10.4% in 2002. Interventions for tuberculosis control are urgently needed in Botswana to prevent further emergence of drug resistance^ref.

incidence of infection : 8 million new cases / yr (12÷33%); reemerging in HIV-1 ⁺ individuals => chemoprophylaxis when [CD4⁺]_blood < 200 / mL ; people who are infected but have not developed disease are not infectious; risk of developing disease following infections : < 10%. Half of these, about 5%, will have active disease in the first 2 years and the other half, sometime during the rest of their lives. If, however, the contacts are profoundly immunocompromised such as HIV-infected individuals, the risk of active TB is closer to 10% per year as opposed to 10% per lifetime.

China 485,000 new cases every year
Italy 20 new cases per year every 100,000 inhabitants

prevalence of disease : 20÷30 millions (60÷80% acquire infection within age 20 : 20% in westernized countries (in Italy 5÷6 cases every 100,000 inhabitants, expecially reactivations in elderlies), 80% in developing countries (Latin America, subsaharian Africa and Southern Asia)) ; a person with active disease infects up to 10÷15 individuals / yr. 75% of male Indian smokers who become ill with TB would not have done so if they had not smoked : in some parts of the world the main way smoking kills is not via cancer and heart disease, but by damaging the lung's defenses against chronic TB infection. Smokers are about 4 times as likely to become ill with TB as are non-smokers, and consequently 4 times as likely to die from the disease. If infected, children aged < 2 years are at high risk for severe tuberculosis (TB) disease (e.g., TB meningitis)^ref.
mortality : 1.6÷3 million / yr (5% of infected; 50% of disease cases;

Italy : 0.5%
Asia : > 1 million

India has more TB deaths than any other country. 400,000 are co-infected with HIV-1

Africa : 400,000

outbreaks : the largest TB investigation in Dutch history begins in Zeist on Mon 31 Jan 2005. A 25-year-old employee of a C1000 supermarket in was diagnosed with a very infectious form of TB in November 2004. In Dec 2004, a "1st ring" contact investigation^ref, using tuberculin skin testing (Mantoux) and/or chest x-ray, revealed that all family members and close contacts of the index case (n=12) tested positive for LTBI, and 1 active case of TB was diagnosed. A "2nd ring" contact investigation was then performed, where all current and former colleagues of the index patient were tested and 44/77 current employees and 14/26 former employees tested positive for LTBI by Mantoux test. 1 active case of TB was also diagnosed in this group. Because of these results, an investigation of a "3rd ring" of contacts, which included all people who had visited this supermarket between 1 Jan and 18 Nov 2004, was launched. Zeist City Council and the health authority GGD Midden-Nederland decided to examine every customer who shopped at the supermarket between 18 Nov 2004 and 1 Jan 2005 based on a telephone survey. Between 31 Jan and 4 Feb 2005, over 21 000 people in the city of Zeist in the Netherlands were tested for latent tuberculosis infection (LTBI) or active tuberculosis (TB) : 5% were expected to have been infected with the bacteria, but it could also be 10% : the infection rate is dependent on many factors. This includes how closely the infected supermarket employee came into contact with customers. 75% of the C1000 customers urged to report for an examination will undergo Mantoux tests. Mantoux tests were performed on 15,515 people and 6000 people aged > 60 were screened by chest x-ray taken in a mobile health clinic. In total, 350/14 128 people (2.5%) whose Mantoux tests were evaluated had a positive reaction (> 14 mm). Those 350 people with suspected infections, and an additional 58 people (patients with suspected pulmonary problems, abnormal chest x-ray, or patients with risk factors for TB in conjunction with a Mantoux 5-14mm) were invited for further diagnostic tests at the tuberculosis clinic of the Municipal Health Department in Utrecht during Feb 2005. To date, about 2/3 of the 408 patients with either positive Mantoux test or abnormal chest x-ray have been examined for TB, and 5 new cases have been diagnosed. 1 of these 5 patients has open TB, and contact tracing linked to this case has also been initiated. So far, no conclusion can be drawn about the extent to which there has been an increased transmission of tuberculosis to customers in this supermarket. Data collection is continuing, and descriptive analysis of the 408 possible cases of LTBI has begun. It would be useful to assess a similar cohort of individuals in the community who did not shop at this supermarket for comparison with the group of 408 additional shoppers. It is not stated in the posting whether the index case had laryngeal tuberculosis or not. Having a positive Mantoux skin test for TB, assuming that the test was performed and read appropriately, reflects previous exposure to TB, not necessarily active infection at that time. Individuals with a positive skin test (Lutwick LI: Tuberculin skin testing. In, Tuberculosis, A Clinical Handbook. Lutwick LI (ed), Chapam & Hall, London, UK, 1995) have an approximately 10% chance of developing active tuberculosis in their lifetimes, 5% in the 1st 2 years and 5% afterwards. The risk of reactivation can be as high as 10% per year in AIDS patients. It is not clear how an estimate of 5-10% skin test reactivity after this exposure for those shopping in the store is suggested, as infectivity correlates with degree of exposure. Family and close friends having a high degree of skin test reactivity (it is likely the case that none of them have been found to have overt infection) does not necessarily suggest a high degree of transmission to much more casual contacts in less confined areas

Transmission :

inhalation of desiccated Pflüger droplets with Ø < 6 mm (1 droplet nucleus contains no more than 3 bacilli); Schrön-Much's granules (gram-positive, nonacid-fast granules and rods found in tuberculous sputum and thought to be modified tubercle bacilli)
ingestion of milk or meat contaminated by M.bovis
ingestion of urine from patients affected by renal TB
through the conjunctiva or broken skin.

=> tuberculosis (TB) / "White Plague" : the bacillus may colonize (primary tuberculosis) every organ (rare in exocrine glands and URT) except muscle tissues due to lactic acid sensitivity :

cutaneous tuberculosis / tuberculoderma
aerogenic or inhalation tuberculosis : tuberculosis caused by aspiration of the tubercle bacilli into the lungs => pulmonary tuberculosis (PTB) (68%)

diffusion by contiguity =>

tuberculosis of serous membranes : tuberculosis involving the pleura, peritoneum, pericardium, and cerebral meninges, producing inflammation of those structures.

tubercular pleurisy => pleural empyema
tubercular pericarditis

chronic laryngitis (tuberculous laryngitis / laryngeal tuberculosis / tuberculosis of larynx). It has been generally accepted that laryngeal TB is the most highly infectious form, but since most cases are associated with far advanced open cavitary pulmonary disease, the infectivity of laryngeal TB alone has not been clearly proven. In 2 patients with laryngeal TB without pulmonary disease, no evidence of intrafamilial spread was found, suggesting the laryngeal disease in itself may not be so infectious^ref. In a similar case isolated laryngeal TB was diagnosed, and despite a delay in making the diagnosis, no family and hospital spread was found
tubercular pharyngitis (pharyngeal tuberculosis)

disseminated tuberculosis : hematogenous (hematogenous tuberculosis) or lymphohematogenous spread of tubercle bacilli from a primary focus of infection; its incidence is increased among immunocompromised patients (< 20% in immunocompetent, 60-70% in immunocompromised) => extrapulmonary tuberculosis

disseminated or miliary tuberculosis : a type that varies from a chronic, slowly progressive debilitating infection to an acute fulminating disease; it is caused by hematogenous or lymphohematogenous dissemination of infected caseous material into the bloodstream and seeding of many organs (including tuberculosis miliaris disseminata ) with millet seed–like tubercles (Ø = 1÷2 mm). Complications : fibrothorax , bronchiectasia (=> increased bronchial secretions => Pseudomonas spp. and Aspergillus spp. infections), recurrent hemophtoe, coma vigil / "typhoid status".

superficial lymph nodes tuberculosis (painless lymphadenitis ; when laterocervical and/or submandibular lymph nodes are involved, they appear adherent to derma and create a sow-like look (scrofulosis / scrofula) evolving to draining fistulae)
cerebral tuberculosis / tubercular meningitis (expecially in babies and immunodepressed) : even in resource-rich countries, where there is easy access to paediatric subspecialty care, infants with tuberculous meningitis continue to have high mortality and morbidity, with deaths happening in about 15% of patients and up to 50% of infants left with serious neurological sequelae^ref1,
ref2
tuberculosis of bones and joints : tuberculosis involving the bones and joints, producing strumous arthritis, or white swelling, and cold abscess.

tubercular osteomyelitis in dorsolumbar spine
tubercular septic arthritis (1% of all TB cases, 10% of extrapulmonary TB cases)

chronic granulomatous monoarthritis (including carpal tunnel syndrome (CTS))
Grocco-Poncet disease
tubercular spondylitis / Pott's disease infiltrating psoas muscle => hunchback

adrenal glands tuberculosis (primary Addison disease )
genitourinary tuberculosis : tuberculosis involving the genitourinary tract, often the result of hemic dissemination of pulmonary tuberculosis

genital tuberculosis

in females : tuberculous endometritis => female sterility
in males : prostatitis (hematogenous >> urinary route), epididymitis (retrograde spreading of urinary tuberculosis) => fistulizing orchitis (tuberculocele)

urinary tuberculosis => Mycobacteria in urines

renal tuberculosis (chronic suppurative nephritis )
cicatricial ureteral stenosis
ulcerative urethrocystitis (cystophthisis) => fibrosis

ocular tuberculosis (dacryocystitis , scrofulous ophthalmia , diffuse scleritis , nodular iritis , miliary or disseminated choroiditis )
oral tuberculosis : a rare condition usually occurring as a bloodborne complication of pulmonary tuberculosis, most often involving the gingivae (tuberculous gingivitis ) and tongue, and characterized by the presence of small, crateriform, painless ulcers that bleed readily and are surrounded by edema or reddish nodules

swallowing of phlegm =>

intestinal tuberculosis / tuberculosis of intestines : a form that involves the intestines, with diarrhea , formation of spreading ulcers (especially of the lymphoid tissue as Mycobacteria localize into isolated lymphoid follicles (ILFs) disposed along transversal axis), and sometimes eventual cicatricial stricture => tabes mesenterica or mesaraica (tuberculosis of the mesenteric glands in children, resulting in digestive derangement and wasting of the body) => Crohn -like disease in terminal ileum and caecum => tubercular peritonitis .

reinfection tuberculosis : a new infection with tuberculosis in a patient who was previously infected and cured
Ranke's stages : the hypothesis that tuberculosis of the lungs develops in 3 stages: (1) the primary focus, (2) generalized spread of the tubercle bacillus, and (3) isolated organ tuberculosis, chiefly of the lungs.

Resistance in HLA-DR4 haplotype, susceptibility in HLA-Bw15⁺. The supersusceptibility to tuberculosis 1 (sst1) genetic locus on mouse chromosome 1 contains the intracellular pathogen resistance 1 (Ipr1) gene, whose expression is upregulated in the sst1 resistant macrophages after activation and infection (but is not expressed in the sst1 susceptible macrophages) limiting the multiplication not only of M. tuberculosis but also of other intracellular bacteria as Listeria monocytogenes, switching a cell death pathway of the infected macrophages from necrosis to apoptosis^ref. RF

in 10-25%.
Susceptibility : genetic defects in the IFN-g

response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. Acquired defects such as anti-IFN-g autoantibodies may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency^ref.

Laboratory examinations :

direct diagnosis :

culturing (sputum, BAL, CSF, gastric juices, stools) : albumin and oleic acid , Petragnani , Löwenstein-Jensen medium or Middlebrook's media or BACTEC system (a medium containing radio-labeled palmitate as the sole C source. As it multiplies, it breaks down the palmitate and liberates radio-labeled CO₂. Using the BACTEC system, growth can be detected in 9-16 days vs 4-8 weeks using conventional media). It is important to create an antibiogram.
acid-fast (Ziehl-Neelsen stainable ) bacilli (AFB) in at least 1 out of 3 sputum, BAL, gastric juice, urine or pleural fluid samples
auramin O fluorescent staining
PCR
neopterin levels in BAL, serum and particularly in urine may reflect PTB activity before exact diagnosis of the disease by culture results, and correlates with radiological extent

clinical diagnosis

risk factors : immunodepressions , COPDs .
symptoms & signs

fatigue, weight loss, afternoon fever , night sweats, chest pain, hemophtoe, dyspnea , anorexia => malnutrition => muscular hypotrophy => cachexia / phthisis , pallor.
chest auscultation : fine crackles => coarse crackles , amphoric breathing due to fistulas and pleural effusion

laboratory examinations

chest X-ray : atypical or typical (alternations of cavities and densities in post-primary TB, mediastinic lymphadenitis )
anemia, leukocytosis, increased ESR and CRP
⁶⁷Ga scintigraphy (to distinguish foci which are still active)

indirect diagnosis :

subcutaneous injection of Koch's Old tuberculin (OT) (a heat-concentrated filtrate of tubercle bacillus culture grown on a special medium. It was Robert Koch in 1891, following his identification of the human tubercle bacillus, who felt that he could develop a cure for TB using a filtrate of killed organisms (Koch R. Weitere mitteilungen uber ein Heilmittel gegen Tuberculose. Dtsch Med Wschr 1891; 17:101-102). This was not to be the case, but testing was found to be used as a diagnostic test, first observed by European veterinarians^ref; nowadays it has been replaced by the "purified" protein derivative (PPD^®) / Seibert's tuberculin, a soluble purified protein fraction precipitated by trichloracetic acid from filtrate of tubercle bacillus culture grown on a special medium) (tuberculin skin test (TST)) :

Koch's phenomenon or reaction : if a guinea pig that has been previously infected with tuberculosis organisms is reinjected intracutaneously, the skin over the injected area undergoes necrosis and a superficial ulcer develops; the ulcer heals quickly and infection of regional lymph nodes is retarded. The phenomenon demonstrates development of ability to localize tubercle bacilli, which is the principle underlying tuberculin tests
cockade reaction : the reaction of a sensitized guinea pig to intradermal injection of tuberculin; it consists of a large papule with a necrotic, hemorrhagic center.

von Pirquet reaction : deposition after scarification.

Moro-Vollmer strip-reaction : saturated strip (unknown absorbed [ ] !) over sternum or upper edge of trapezius muscle
Mantoux intradermoreaction (nowadays replaced by tine-test / multiple puncture TB test (MPT)): on the contrary of the 2 above mentioned methods, in this one the quantity of administered Ag doesn't depend on epidermis thickness and operative pressure. Within 48÷72 hrs after injection of 1 TU (first strength tuberculin, used for young children or persons in whom extreme hypersensitivity is expected : same potency as 0.01 mg OT prepared by Statens Seruminstitut in Copenhagen) in 0.1 mL, a type IV hypersensitivity (induration and erythema with Ø > 10 mm : 90% sensitivity; 100% sensitivity if Ø > 15 mm) occurs if within 3÷7 years after BCG vaccination or 4÷6 weeks after infection. If Ø < 5 mm, the result is negative, while if 10 < Ø < 5 mm, assay must be repeated using 5 TU (= 0.0001 mg of PPD, intermediate strength tuberculin = the standard test dose) and (if the second result is still doubtful) with 250 TU (second strength tuberculin) : sensitization during such a treatment shouldn't cause granuloma because immune responses against proteic antigens are usually humoral. Toning is late if infection is recent.
pe3yrbt^® (?, Russia)
Pirket^® (?, Russia)
RM^® (?, Russia)
Test-PPD^® (Chiron, Italy, Asia)
Tubergen Test/Tuberkulin^® (Chiron, Germany)

It generally requires about 6 weeks or more to convert a TST to positive after exposure.

IgMs and IgGs (TB-Test^®)
ELISpot to look for blood T lymphocytes specific for Mycobacterium tuberculosis antigens that are absent from Mycobacterium bovis BCG and most environmental mycobacteria. The test is less likely to give false positives than the skin-prick test, which includes proteins that are used in the BCG vaccine and is therefore confounded by TB vaccination. The test also works well in individuals with weak immune systems. As the test can monitor how the number of specific T cells changes with time, it might also be used to monitor treatment efficacy. Although the test is more expensive than the skin prick, it should save money in the long term by eliminating the unnecessary treatment of false positives^ref. Overall agreement with the skin test was similar (T-SPOT.TB k=0·508, QuantiFERON-TB Gold k=0·460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p<0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p<0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p<0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010)^ref.

ex adiuvantibus criterion : improvement within 90 days of treatment with a polychemotherapy mix administered as directly observed therapy, short course (DOTS) : DOTS is a newer arrival on the anti-TB scene and utilizes directly supervised therapy to assure that the affected individual is actually taking his/her medications and requires the availability of medications and political and economic commitments for effectiveness. In numerous studies in quite difficult areas to treat tuberculosis (including refugee camps in Asia and USA inner cities), DOTS produces a higher cure rate, lower incidence of relapse and, should relapse occur, less development of drug resistance. All of these results contribute directly to the overall public health^ref. Even in settings with moderate rates of MDR tuberculosis, DOTS can rapidly reduce the transmission and incidence of both drug-susceptible and drug-resistant tuberculosis. However, further interventions, such as drug-susceptibility testing and standardised or individualised treatment regimens, are needed to reduce mortality rates for MDR tuberculosis^ref.

first choice (per os, all days in early phases or every 2 days in late phases, for 2 months)

primary chemotherapy is followed by secondary chemotherapy (INH + RIF) for 4-10 months. Treatment for a patient infected with a non-resistant strain takes six months and costs around US$10.
second choice (for multi-drug resistant TB (MDR-TB / MDRTB), which does not respond to treatment with either of the 2 main TB drugs, isoniazid (INH) and rifampin (RIF). Although other drugs are available, the treatment takes up to 2 years and can cost anything between $500 and $6,000. 14% of new cases in eastern Europe and central Asia involve MDR strains. The top 10 hotspots for MDR strains are in 6 Republics of the old Soviet Union (Kazakhstan, Uzbekistan, Estonia, Lithuania, Latvia and Russia) and 2 China provinces (Liaoning and Henan). In May 2004 the EU opens its borders to 3 of the top 10 geographical hotspots (Estonia, Latvia, and Lithuania). 'Hot zones' are areas that have >5% prevalence (or incidence) of MDRTB. Paradoxically areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities^ref. Even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease^ref.

p-aminosalicylic acid (PAS) for 6÷12 months
kanamycin
quinolones (ofloxacin, moxifloxacin )
pleuromutilins
isocitrate lyase inhibitors

surgical tuberculosis : tuberculosis that can be treated by surgical means

therapeutic pneumothorax is no longer used

^ref

Relapse

resistance

Glucocorticoids

meningitis

pericarditis

Prevention :

attenuated live vaccine . Good overall health and adequate living conditions without crowding are the 2 most important historical parameters in decreasing the amount of tuberculosis in a community. This is best shown by the decrease in Mycobacterium tuberculosis infections in the USA starting at the beginning of the 20th century, 4 decades before the 1st anti-tuberculosis drugs were utilized
the role of secretory proteins of Mycobacterium tuberculosis in pathogenesis and stimulation of specific host responses is well documented. They are also shown to activate different cell types, which subsequently present mycobacterial antigens to T cells. Therefore identification of T cell epitopes from this set of proteins may serve to define candidate antigens with vaccine potential. 52 secretory proteins of M. tuberculosis H37Rv were analyzed computationally for the presence of HLA class I binding nonameric peptides. All possible overlapping nonameric peptide sequences from 52 secretory proteins were generated in silico and analyzed for their ability to bind to 33 alleles belonging to A, B and C loci of HLA class I. 15% of generated peptides are predicted to bind to HLA with halftime of dissociation t_1/2 >/= 100 min and 73% of the peptides predicted to bind are mono-allelic in their binding. The structural basis for recognition of nonamers by different HLA molecules was studied employing structural modeling of HLA class I-peptide complexes and there exists a good correlation between structural analysis and binding prediction. Pathogen peptides that could behave as self- or partially self-peptides in the host were eliminated using a comparative study with the human proteome, thus reducing the number of peptides for analysis. The implications of the finding for vaccine development are discussed vis-a-vis the limitations of the use of subunit vaccine and DNA vaccine^ref.
post-exposure chemoprevention

Web resources :