Tuberculosis (TB) involves
multiple systems and also it is amongst the most common infectious disease that
causes increased mortality10. World Health Organization (WHO) has
estimated that 10.4 million people have TB worldwide in 2016 so it is a major
burden on health globally and the prevalence of drug-resistant TB is also on
rise worldwide10.

           Tuberculosis is defined as a chronic
granulomatous inflammatory disease caused by Mycobacterium tuberculosis complex which
includes following organisms: mycobacterium
tuberculosis, M .Africanum, M .Bovis, M .Microti, M.Caprae and M. Pinnipedi18. A recent study
on the phylogenomic analysis of the mycobacterial species
has demonstrated that these species are heterotypic synonyms of Mycobacterium tuberculosis while this study classified ‘M.
canettii’, ‘M. mungi’, and ‘M. orygis’ as strains of the species M. tuberculosis18,
19.

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Most common site is lung while extra pulmonary TB
occurs as a result of primary or late generalized infection1. Patients
suspected of Tuberculosis should have sputum examination for acid-fast bacilli
(AFB) smear and culture. Xpert MTB is a rapid NAA test. Latent TB can be
diagnosed with mantoux skin test or quantiferon gold test. Treatment regimen
for new TB patients consists of 6 months of therapy with a 4-drug regimen of
Isoniazid, Rifampicin, Pyrazinamide, and ethambutol1. According to
susceptibility testing results and toxicity adjustments are made in the therapy.
There are different regimens for pregnant women, children, HIV-infected patient
and previously treated patients.

CHARACTERISTICS
OF MYCOBACTERIUM

      Mycobacterium contains specific features
which differ from other bacteria. It is an acid fast bacilli with has the
ability to resist decolorization with acid-alcohol mixture after it is
colorized with carbol fuchsin or auaramine O stain20. It is non
motile intracellular pathogen and obligate aerobe. It is resistant to cold but
it is killed by heat, UV Light, sunlight and X-ray beam. It has a special cell
wall which contains mycolic acids, peptidoglycan and arabinogalactan. The
length of rods is 2-4 micrometers and width is 0.2-0.5 um21 .It divides
slowly with doubling time of 16-20 hours22.

 

HISTORICAL
BACKGROUND

TB is an ancient disease. Hippocrates (400 BC)
recognized TB as a contagious disease. It was termed as “phthisis”
(Greek from phthinein, to waste away) at that time1. In
1882 M tuberculosis was
isolated and discovered by Robert Koch who was a German physician so it is also
known as Koch’s disease by his name. News of Koch’s discovery spread rapidly.   Early
treatments of TB included Sanatorium movement, Surgery and lung collapse therapy
and the age of chemotherapy started after the discovery of   Paraaminosalicyclic acids (PAS) and
Streptomycin in 1940s.

 

EPIDEMIOLOGY

               6.3 million new cases of TB were reported
in 2016. Incidence of tuberculosis was 10.4 million in 2016 which was
equivalent to 140 cases per 100 000 population. It included 90% adults,
65% were male, and 10% were people living with HIV 10. 600 000
new cases with resistance to rifampicin (RRTB), of which 490 000 had multidrug-resistant
TB (MDR-TB).

 

                   1.3 million TB deaths among
HIV-negative people and an additional 374 000 deaths among HIV-positive
people in 2016 were reported10.  TB mortality rate is falling at about 3% per
year worldwide and incidence is falling at about 2% per year. The case fatality
ratio CFR   was 16% in 2016. Between 2000
and 2016, TB treatment averted an estimated 44 million deaths among
HIV-negative people. Among HIV-positive people, TB treatment supported by ART
averted an additional 9 million deaths.

 

            Global treatment success rate of 83% was
reported in 2016. There were 476 774 reported cases of HIV-positive TB of
whom 85% were on antiretroviral therapy (ART). A total of 129 689 people
were started on treatment for drug-resistant TB. Treatment success remains low,
at 54% globally10.

 

        In Pakistan incidence of tuberculosis as
518/100 000 population and 6.9/100 000 in HIV Positive tuberculosis patients.
Mortality rate was 44/100 000 in HIV negative and 2.1/100 000 in HIV positive patients10.  510 000 new TB
cases emerge each year in our country and approximately 15 000 develop drug
resistant TB cases every year.  Pakistan
is ranked fifth among TB high-burden countries worldwide and fourth highest
prevalence of multidrug-resistant TB (MDR-TB) globally. This accounts for 61%
of the TB burden in the WHO Eastern Mediterranean Region.

 

GENETIC
FACTORS

 Genetic factors play an important role in developing
increased susceptibility to tuberculosis and drug resistance. Analysis of the
genome sequence is also beneficial for developing new tests, vaccine and drugs.
Various studies describe that human leukocyte antigen (HLA)-DR molecules increase
the susceptibility of tuberculosis by polymorphism23. A study conducted
in India reveals association between susceptibility of tuberculosis and HLA DQ1
and DR antigens24, 25.

        H37Rv
laboratory strain was the first complete genome published in 1998 since then
numerous clinical isolate shave been sequenced26. Studies describe
that in genome of tuberculosis 6% of the genes are involved in lipid
biosynthesis and degradation27. Studies have shown that mycobacteria
don’t possess antigenic variation in contrast to other pathogens this may help
in guiding vaccine development28.

 

         The
characteristics such as
transmissibility and propensity to acquire drug resistance of mycobacteria are linked
to their lineages as described by various studies29.The
lineage classification have been confirmed in studies by using polymorphism and
sequence analysis and genome sequences 30. It includes

 Lineage 1      
Indo-Oceanic

 Lineage 2      
 East Asian

 Lineage 3      
Indian East-African

 Lineage 4        Euro-American

 Lineage 5      
West-African

 Lineage 6     
West-African 2

                 A study in the Gambia on
different lineages found the rate of transmission of M. tuberculosis to
household contacts was similar in different lineages; however 2 year   follow up of their contacts showed varied
proportion in those who developed active tuberculosis. This proportion was 1%
for those with exposure to strains of M. africanum, 6% with exposure to lineage
2 strains and 1% to 4% for strains from lineage 431.

               Another study in San Francisco
found that the strains from sublineage 207 of lineage 2 were more virulent in
comparison with other sublineage of lineage 2 and also they were likely to be
associated with genotypic clustering32. Similarly, strains from
sublineage 183, within lineage 4, caused more secondary cases when compared
with other sublineages32. Another study in Vietnam shows 46.2% of
the isolates belonged to lineage 133.

 

 

RISK
FACTORS

   There are
multiple risk factors associated with the development of Tuberculosis .It
include 
homeless people, injection drug abusers, malnourished, low income populations, contact
with a TB patient, immunocompromised patients, AIDS, head or neck cancer, leukemia, or
hodgkin’s disease, silicosis, smoking, alcoholism, chronic malabsorption
syndrome and some medical treatments; including prolong use of corticosteroids,
interferon
injections, rituximab,
TNF –?
blockers such as Infliximab , Etanercept
and Adalimumab.
Various studies describe association of these risk factors with tuberculosis.

 

            
An observational study in India showed a high prevalence of drug
resistance TB in country. It also showed the role of prior history of TB
infection, alcohol and smoking in increasing the risk of developing
TB and MDR-TB34.

               Biological
therapy has been associated in unmasking latent tuberculosis. Various studies
have been conducted to see association of biological therapy with tuberculosis.
A study on the patients of ulcerative colitis described that Infliximab therapy lead to development of active tuberculosis in in 57% of the patients while 42% patients developed disseminated
tuberculosis35.

            A study showed conversion of tuberculin
skin test from negative to positive after receiving TNF alpha therapy in patients
of rheumatoid arthritis, ankylosing
spondylitis and inflammatory bowel diseases 36.Result showed 31.2%
patients developed positive skin test at 1 year and there was high risk with Adalimumab treatment,
male sex and previous tuberculosis disease
history36.

TRANSMISSION

 Transmission of tuberculosis occurs with the
inhalation of aerosols .Aerosols are generated by coughing, singing, sneezing
or loudly talking of an active TB patient. These aerosols are solid or liquid
particles in a gas. Their size varies from 0.001 to over 100 µm. An active TB
patient a single cough generates 3000 droplet nuclei and a sneeze
40,000droplets37. Droplets dry rapidly in air and become particles
that contain live bacilli and they remain suspended in atmosphere for hours.

 Transmission of TB depends upon the no of
bacilli expelled, duration of contact with the infected air and the
concentration of the bacilli in air. A study involved measurement of
bioaerosoles in patients of tuberculosis and accessed variability of aerosols production
during tidal breathing. It concluded that particle size relates to the degree
of infectivity38.

          Another study found that cough
aerosols predict better transmission than sputum microscopy39. 96 sputum culture-positive index TB cases
and their 442 contacts were enrolled in the study. It showed that 45% patients
with TB yielded M. tuberculosis in aerosols. Contacts of patients with TB who produced
high aerosols (?10 CFU) were 69 %,
low-aerosol (1-9 CFU) and were 25 % aerosol-negative
cases 30%. A high-aerosol patient with TB was the only predictor of new M. tuberculosis infection39.

                       In persons exposed to
bacilli, disease development is dependent upon the host immune response and the
virulence of the bacilli. In a study Escombe and coworkers described the
infectiousness of HIV-infected patients with tuberculosis. Of 97 patients (118
admissions) hospitalized in an HIV tuberculosis ward, 10 caused 90% of the
infections in guinea pigs exposed to air exhausted from the ward. Out of 10
infectious patients, 6 had MDR tuberculosis that was inadequately treated40.

            In another study association
between HIV positive tuberculosis and risk of transmission was studied. It
concluded that in household contacts of tuberculosis patients, the likelihood
of transmission was lower if the source case was HIV infected with a  CD4 T-cell count lower than 250/µL41.

 ENVIRONMENTAL FACTORS

                 The environmental factors play
an important role in decreasing the concentration of tubercle bacilli by
filtration, killing with ultraviolet light.  A study shows that 60% to 71% of aerosolized
M. tuberculosis organisms survived for 3 hours, 48% to 56% for 6 hours, and 28%
to 32% for 9 hours under standard conditions of temperature and humidity42.

PATHOGENESIS

              When a person gets infected with
mycobacterium then depending upon his host immune status, infection can take
different ways43. 70 % of the persons infected who have   adequate innate immunity clear the infection
and do not develop disease while 30% with inadequate  innate immunity get infected, among which 5 %
develop active Tuberculosis within 1 year after infection and 95% contain the
TB and they develop active TB in their life whenever cellular immunity gets
suppressed. 5 % will develop TB over the course of their life when their
cellular immunity is suppressed .90% of the infected people will clear the
bacilli44. In HIV positive patients active tuberculosis will be
developed in 40% patients and 60% will contain mycobacterium. Bacilli are
phagocytized by macrophages after reaching alveoli and they multiply slowly
every 18 to 24 hours45.  

                        Seminal studies by
Armstrong and D’Arcy-Hart and colleagues revealed that pathogenic mycobacteria
survive and replicate in host phagocytes46,47. Ghon focus is a
primary focus made up of inflammatory cells. Macrophages drain bacteria to the
nearest lymph node through the lymphatic system and form Ghon complex.  T-lymphocytes recognize antigen inside lymph
node leading to CD4 and CD8 lymphocytes transformation and release of interferon-?.
Activation of the macrophages leads to inhibition of growth of the phagocytized
bacilli. HIV-infected individuals have a reduced number of CD4 lymphocytes so
they are more likely to develop TB following infection47.

In the primary focus,
inflammatory tissue is formed and later replaced by scar tissue. Some become
latent bacilli that can survive for years. 
Same event occur in the lymph node leading to formation of caseating
lymph nodes43. These resolve toward fibrosis followed by
calcification.

             An epithelioid granuloma contain
an inner zone of epithelioid macrophages and Langhans giant cells mixed with
lymphocytes and an outer zone of lymphocytes, plasma cells, and immature
macrophages. Smaller tubercles may get resolved completely. When hydrolytic
enzymes dissolve tubercles then fibrosis develops. These fibrocaseous nodules
usually containing live mycobacteria which may lead to reactivation. Some nodules
calcify48.

 

            Studies
in basic cell biology have revealed that phagosome membrane proteins and
phospholipids form phagolysosome by a series of interaction49. These
studies describe the role of Rab7( low-molecular-weight GTPase) in the late
step of phagolysosome formation49. M. tuberculosis disrupts recruitment
of Rab7 to the phagosome membrane50.

             M. tuberculosis survives and
replicates intracellularly by interfering with conversion of phagosome membrane
phosphatidylinositol to phosphatidylinositol-3-phosphate50.Recent
studies also reveale requirement for the ESCRT (Endosomal Sorting Complex
Required for Transport) pathway of intracellular vesicle trafficking in
phagosome maturation, and there is strong evidence that EsxH, a protein
secreted by M. tuberculosis, disrupts the ESCRT pathway51,52.

 

LATENCY/DORMANCY
AND REACTIVATION

                      Mycobacteria possess the ability
to reactivate. Various studies describe association of hypoxia with
reactivation of tuberculosis53.Studies have described that changes
in gene expression  reverse on  reoxygenation and this  causes mycobacteria to reversibly adapt to its
environment. A study conducted to observe
correlation between the Enduring Hypoxic Response (EHR) and DosR. It showed that hypoxia caused by DosR-mediated
initial hypoxic response
is not related Enduring Hypoxic response (EHR) 54.

 IMMUNITY