1.

History
• TB is top infectious killer in world.
• India is one of the most affected countries in world
• India is having appx. 2 lakhs deaths/ year with very fast
rise in drug resistant TB.
• Over the years, disease acquired names such as
“galloping consumption, the white plaque, captain of
all these men of death” all addressing its lethal nature.
• The cause remained unknown until 24th March,1882
when Robert Koch discovered mycobacterium
tuberculosis.So,24th march is known as world TB day.
 Definition
• Tuberculosis(TB) is a contagious bacterial
infection caused by Mycobacterium species of
MTB complex, most frequently MTB.
• It is predominantly an airborne disease,
spread by individuals with active TB who expel
bacteria into air for example by coughing.
• It commonly affects lung(pulmonary) but can
also be extrapulmonary.
 Mycobacterium organism
Gram positive rod

spore forming Non spore forming

bacillus subtilis corynebacterium

Clostridium lactobacillus
mycobaterium species
• Pathogenic species of Mycobacterium:
1.M.ulcerans:cause skin ulcers
2.M.leprae:cause leprosy
3.M.tuberculosis: cause tuberculosis.

Mycobacterium tuberculosis complex(MTBC):

M. tuberculosis
M. africanum(human)
M. bovis(cattle)
M. Caprae(goats)
• Characteristics
1.gram neutral although classified under gram
positive.( does not stain much on gram
staining :weakly gram positive)
2.obligate aerobe(oxygen is must for its growth)
3.non spore forming and non motile.
4. facultative intracelluar.
5. acid fast bacilli.
6. slow growing(generation time of 15-20 hrs)
 Structure
• Cell wall antigen layers:
1. Peptidoglycan layer.
2. Arabinogalactan layer
3. Mycolic Acid layer
4. lipomannan
Antigenic Structure of cell wall
 Mycolic acid layer
1.Reason why organism difficult to stain.
2.Reason for acid fastness of organism.
3.reason for slow generation time.
4.reason for intracellular survival.
5.raeson for resistance to chemical disinfection.
6. makes difficult to phagocytose.
So ,it is most important layer of organism.
 2.Natural course
• Entry of organism in body is mostly by
inhalation.
• Droplet nuclei <5 micrometer are most
dangerous
• Infective dose is >10000 organism/ml of
sputum.
• Most infective is people having post primary
Tb or secondary TB or cavitating TB.
 Primary pulmonary tuberculosis
• It occurs when exposure to organism occurs
first time.
• 95% of population is having asymptomatic
primary tuberculosis.
• So it is an mostly an infection not disease. So
can also be called as latent Tb infection.
• It is because of cell mediated immunity.
• So, in this tuberculin skin test will be positive
• BUT there is always a risk of reactivation when
immunity is deficient later on such as in HIV,
CKD, hep B and C ,immunosupressive drugs.
• Only in 5% with defective immunity, primary
TB is symptomatic.
• So, 2 basic forms:
Asyptomatic 95% good immunity
Syptomatic 5% with defective immunity.
 Cell mediated immunity and
granuloma formation
Tb bacilli
Tb bacilli
Tb bacilli
Tb bacilli alveoli alveoli

alveolar macrophages attack tb bacilli

 tb
alveolar macrophage
lysos
ome
phagos
ome

• Tb bacilli comes to macrophage

• In macrophage there is phagosome and lysosome
which fuse to form phagolysosme and kill
organism normally but tb bacilli remains
undetectable and fusion did not occur.
So tb bacilli keeps on multiplying.
So dendritic cells come and take macrophages
alongwith tb bacilli to adjacent lymph nodes
where T cells and B cells are waiting.

T
cells TH 1 cell
interferon gamma
IL-12
activate macrophages

maturation of phagolysome and caseous necrosis occurs

• Interferon gamma makes these macrophages into
epitheloid macrophages.
• epitheloid macrophages secrete TNF alpha that
also make a wall outside to prevent spread
• Fibroblasts also come which secrete collagen to
make a wall to prevent spread.
• Other lymphocytes also come to this site of
inflammation.
• All these make a walled off garnuloma.
• TNF alpha upregultes 1 alpha hydroxylase which
help in calcification of lymph node.
• So bacteria gets trapped and only latent TB
occurs
caseating- cheese like centre
visible macroscopically
• CMI working good: granuloma
formation,asyptomatic tb.
• Antigen:mannose lipoarabanomann (Man
Lam) is part of arabinogalactan layer

Helps organism to survive inside phagosome.

and bind to macrophage.
Ghons focus- caseous granuloma at site of
implantation.
Primary complex or Ghons complex or Rankes
complex –ghons focus+ draining lymph node.
Granuloma heal with fibrosis and lymph node
undergoes calcification
Cavitation does not occur in asymptomatic
primary tb
But mild pleurisy can occur d/t rupture of sub
pleural primary pulmonary focus into pleural
cavity.
Ghons complex
 Lymphadenopathy in primary
tuberculosis
• Hilar>Rt. Paratracheal
• 2/3rd time it is unilateral
• Ass. With ghons focus
• In children,it may be only manifestation.
• Mild pleural reaction or pleurisy may be there.
• Heal by calcification.
 5% symptomatic
• Symptomatic primary tb
• only in 5%
• Cavitating pneumonia of middle and lower
zone d/t liquefaction of caseous material.
• Always ass. With pleural effusion.
• Collapse d/t compression of bronchi may be
there.
• Occur in children, old, immunocomprised.
• This group can be also called progressive
primary tb.
 Secondary tuberculosis/post primary
tuberculosis
• Mostly d/t reactivation of latent tb infection.
• It can also occur due to reinfection(from person
having high bacilli load in sputum).
• This is mostly symptomatic tb.
• Mostly liquefaction alongwith cavitation occurs
(amphoric breathing-superficial cavity)
• Involves apical segment of Rt UL>post segment of
Rt. UL>Sup. Segment of Lt. LL. (d/t V/P mismatch.
ventilation more in upper lobe)
 Presentations
• Pneumonia

• Consolidation

• Cavitation (m/c) reason for cough with hemoptysis(if pulm vessel

involved mostly –mild,
If bronchial vessel- massive hemoptysis)

• Air fluid level/abscess/secondary infections

• Tb maybe sole d/d of non resolving pneumonia
as well as main d/d in lobar pneumonia.
• Focuses/complexes in secondary tb:
1.Simon focus-nodule at apex when there is
primary Tb elsewhere in body
2.Puhls focus- supraclavicular focus in secondary tb
3.Assmans focus- infraclavicular focus in secondary
tb
4.Richs focus- focus in brain cortex in secondary tb
5.Simmonds focus- focus in liver,seen in secondary
tb
6.Wigards focus-blood vessel intima of pulmonary
vein.
•Cavitation implies a high
bacillary load and high
infectivity
•Cavity size range from
mm to cm and with
variable wall thickness
•Air fluid levels rare and
may be indication of
bacterial or fungal
superinfection
•Other presentations like
consolidaion, pleural
thickening,bronchopneu
monia like presentation
may be there.
 Complications of tb
1.Fibrosis
2.haemoptysis:aneurysmal rupture leading to
bleed. Rasmussens aneurysm is pulmonary artery
aneurysm
3.Empyema-extension to pleura
4.Pleural thickening
5.Lung abscess
6.Bronchiectasis
7.BP fistula.
 Miliary tuberculosis
• It can be a complication of both primary and
secondary tb.
• It occurs when infective foci in lungs seed into the
pulmonary venous system comes to heart and
spread.
• Mostly it seeds into liver, bone marrow, spleen
and adrenal gland.
• BUT pathognomic abnormality is choroid
tubercles.
• It is very often sputum negative and steroid
unresponsive and having subacute course.
2 variants of miliary
Non reactive miliary tb :very fatal, major
necrosis of lung, no granuloma.
seen in person with severe immunodeficiency.
Cryptic miliary tb :more chronic course,mostly in
old age, likely involve meninges.

Both are very fatal.

 3.Diagonosis of tuberculosis
1.Sputum smear microscopy
Gram staining
ZN staining
Fluorescence staining
2.Culture
Solid(LJ media)
Automated liquid culture(BACTEC,MGIT )
3.Rapid molecular diagnostic testing
Cartridge Based Nucleic acid amplification(CBNAAT)
Line probe assay(LPA)
4.Latent tb:Tuberculin test/IGRA
 1.Sputum smear microscopy

• Gram staining-MTB weakly gram positive rods d/t

rigid cell wall. Not much significance of gram
staining
• Ziehl Neelsen(ZN) staining:MTB appear as bright
red bacilli(rods).
• Fluorescence staining: LED microscopes are used.
2 stains basically
Auramine O: stains Bright yellow
Auramine O-Rhodamine B: stains yellow orange
• Technique of ZN staining:
1.First stain the slide smear with red coloured
carbol fuschin (phenol+basic fuschin).It has
property to easily mix with lipid rich cell
wall.Slide is heated to properly mix the dye by
making wall soft.
2.Slide is then washed and decolourised with
acidic decolouriser(sulphuric acid) but
doesnot decolourise bacilli.
3.Secondary stain like methylene blue/crystal
violet is added to make background blue.
So bacilli will look red in blue background.
 Limitation

• Senstivity is only 50%.

• It can be increased by BAL specimen by
inducing sputum(65-70%).
• Need nearly 10000 organisms/ml of sputum.
 2.Culture
Only 100 bacilli are sufficient.
1.Traditional media :Solid-(LJ media)
But they take very long time to grow(6-8 wks).

2.Automated:
Radiometric-BACTEC 460
Non Radiometric-MGIT 960
Automated media 10-12 Days for growth and also
tell drug susceptiblity.
MGIT (mycobacterial growth indicator
tube)>BACTEC as cheaper and no problem of
radioactive waste disposal.
 3.Rapid molecular diagnostic testing
CB Nucleic acid amplification(NAAT)/Gene expert/Mtb Rif
assay
• Only 1hr 45 mins required /quick result,only 2ml sample
required.
• Any sample can be used :pleural fluid ,sputum,ascitic
fluid.
• Very useful for HIV pts/extrapulmonary Tb
• 98% sensitivity
• 70% sensitivity in sputum AFB negative.
• Rifampicin(rpoB mutation) resistance can be detected.
• Amplification of nucleic acids is done by PCR.
• Pleural fluid sensitivity is nearly 40%.so in pleural
tb,pleural biopsy is required.
• Cultures also provide information about drug resistances.
 Line probe assay
It is also PCR based technique.
Value only in sputum AFB positive patients.
Results in 2-3 days.
Identify drug resistances: both INH(kat G) and
rifampicin(rpoB) resistance.
Limitation:done at state level whereas cbnaat on
subdistrict level

Newer method :Man-LAM(lipoarabanomann) in

urine.
 suspected tb

sputum smear

smear positive sputum negative

Line probe assay CBNAAT

Inh /rif resistance in 2-3 days
rifampicin resistance

resistant no resistance

send sample for BACTEC or

MGIT for other resistances
 4.Tuberculin test.
• Mostly useful in latent TB infection.
• Positive in 6-12 wks of infection.
• Done by giving .1 ml/5TU of PPD (tuberculin/RT
23) intradermally.width of induration is checked
after 3 days.
• Result equal or >5mm in HIV, post transplant
patient,recent contact with tb ,on steroids,fibrotic
lesion of old tb : consider postive
they can be candidate for inh prophalyxis

_>15 mm in normal low risk patients.

False postive :
high dose of tuberculin
repeat testing(boosting phenomenon)
reading error
BCG vaccination
NTM
False negaive:
improper storage/technique.
infant <3 months(immature immunity).
old age.
anergy-inability to respond in sarcodosis.
• IGRA(intergeron gamma release assay)
2 types –quantiferon gold
T spot (tuberculin spot) better
More specific than mantoux.
Interferon gamma release in response to T cells
checked.
Ag looked are ESAT 6,CFP 10
Less false positive and negatives.
 4.Treatment of TB
• National tb elimination programe guidelines
2021
Tuberculosis

Drug sensitive tb Drug resistant tb(DR tb)

 Drug sensitive tb
Intensive phase:HRZE(4 FDC) X 2 months
Continuation phase HRE(3 FDC) X 4 months
Regimen is same for both new cases or previously
treated case.
Drug daily dosage: in FDC
H:isoniazid: 5mg/kg 75mg
R:Rifampicin:10 mg/kg 150 mg
Z:Pyrazinamide: 25 mg/kg 400mg
E:ethambutol:15mg/kg 275 mg
Intensive phase is never prolonged.
DRUG DOSAGE ACCORDING TO FDC and
WEIGHT BAND
Weight band no.of tables (IP 4drugFDC/CP
3drugFDC)
25-34 2
35-49 3
50-64 4
65-74 5
75 and above 6
 Drug resistant TB
Mono resistant TB :tb patient whose biological specimen is
resistant to one first line anti TB drug.
for eg Mono H resistant.
Multidrug resistance: Tb patient whose biological specimen is
resistant to both H and R with or without resistance to
other first line anti TB drugs.MDR tb may have additional
resistance to any/all FQ or any other any ATT drug.
Pre-XDR tb: Tb patient whose fulfill criteria for MDR and are
also resistant to any FQ.
XDR tb: Tb patient whose fulfill criteria for MDR and are also
resistant to FQ and at least one additional group A
drug(presently to either Bedaquiline or linezolid or both.
 • Mono H resistant tb:
All oral regimen
L:levofloxacin
R:rifampicin
Z:pyrazinamide
E:ethambutol
6 months treatment is must.
May be extended to 9 months if smear positive at
end of 4th month.
May be extended to 12 months in case of skeletal
tb, CNS tb and miliary tb.
NO IP or CP.
 MDR tb

All oral shorter regimen All oral longer regimen

Or oral bedaquiline shorter
regimen

Duration:9-11 months 18-20 months

 All oral shorter regimen
Or oral bedaquiline shorter regimen
Duration:9-11 months
Intensive phase:4- 6 months ,7 drugs(BILCEEZ)
B:bedaquiline- used for 6 months always
I:isoniazid(high dose)
L:levofloxacin
C:clofazamine
E:ethambutol
E:ethionamide
Z:pyrazinamide
Continuation phase:5 months: 4 drugs( L CEZ)
E: ethambutol. So 2 first line drugs still there.

B:bedaquiline dose: 400 mg/daily for 2 wks f/b

200 mg/ 3 times a wk for 3-24 wks
• Conditions in which this regimen cannot be
used, we have to use long oral regimen:
1.Pregnancy and lactation(d/t ethionamide)
not due to bedaquiline.
2. H resistance d/t both Inh A and Kat g
mutation.
3.MDR tb with FQ resistance( like pre XDR)
4.No extensive ,extra pulmonary tb.
5.age< 5 yrs
6.Uncontrolled arrythmia or QT prolongation or
Torsade de pointes,hypokalemia.
• All oral longer regimen
duration:18-20 months
5 drug combination
3 group A+ 2 groupB
L:levoflox or moxiflox
L:linezolid.
B:bedaquiline : used for 6 months only.

C:Clofazamine
C :cycloserine
Myocolic acid synthesis
inhibitor
L:levoflox or moxiflox:tendon rupture
L:linezolid:anemia, thrombocytopenia,optic
neuritis, peripheral neuritis
So pyridoxine is always added to MDR tb
patients.
B:bedaquiline: QT prolongation,arrythmia
B used for 6 months only.

C:Clofazamine:dark brown skin

C :cycloserine:aggravate seizure
• XDR tb but treatment intolerant
or MDR tb treatment non responsive
Latest BPaL regimen
B:bedaquline
Pa:pretomanid
L:linezolid

BUT only to be used after approval of ethical

committee
 5.TB and comorbidities
1.TB and HIV
2.TB in liver disease.
3.TB in renal disease
 TB and HIV
In patients with TB/HIV coinfection, ART is
started irrespective of CD4 count.
Presentation:
1.If CD4>200 ,typical that is cavity but rare.
2.If CD4<200,atypical presentation such as
miliary, pleural effusion. More common.
ATT should be started 2 wks prior to ART.
Concomitant administration may lead to
IRIS(immune reconstitution inflammatory
syndrome)
• IRIS
Mechanism : ART kills virus.CD4 count starts
increasing.
ATT starts lysing bacteria.But initially symptoms
were not there due to immunosuprresion. New
CD4 cells release cytokines in response to these
lysed bacteria as they act as antigen leading to
inflammation.But if this response is excessive,
tissue damage can also occur leading to IRIS.
C/F:high fever, lymphadenopathy, expanding
intrathoracic lesions,and worsening of CXR
findings.
Rx: for severe IRIS, prednisolone 1-2mg/kg for 1-2
weeks f/b tapering.
Evaluation :
In all HIV patients, we have to rule out active tb by 4
symptom complex:
1.Current cough(<24 hrs)
2.Weight loss
3.Fever
4.Night sweats
Diagnosis: Send sample for CBNAAT directly , no
role of smear microscopy as sample is considered
precious sample as it is paucibacillary and more
chances of drug resistance.
• Prophylaxis:
In all HIV patients with sputum CBNAAT negative
Prophyalaxis with Isoniazid 10mg/kg daily for 6 months or
Latest Alternative:3 HP ( isoniazid and rifapentine for 3
months .weekly dose only. So only 12 doses(easy)
• Treatment:
Initially ART was TLE but efavirenz react with
bedaquiline,now TLD is preferred.
So if age>10yrs ,Wt>30 kgs: then TLE that is tenofovir(300
mg),lamivudine(300),dolutegravir(50 mg) once daily.
If age >10 but wt<30:then ALD, abacavir and lamivudine
acc. To weight , dolutegravir 50 daily.
Cotrimoxazole 960 is started in all patients.
Duration and dose of ATT is similar.
 ATT in liver disease
• Baseline Lft is not required in all patients .
• BUT in patients with active diseases such as Hep B, Hep
c baseline LFT are required.
• Pyrazinamide is most hepatotoxic.
• Mechanism of various drugs in causing hepatotoxicity;
1. Isoniazid:converted into hydrazine which is
hepatotoxic
2. Rifampicin :inhibit major bile salt exporter pump.rise
in conjugted bilirubin.type of injury is cholestatic.
3. Pyrazinamide:metabolised and produce free
radicals.direct hepatocellular injury.
 Modes of presentation
1.Hepatic adaptation:asymptomatic transient
elevation in ALT.
2.Drug induced hepatitis:prodromal syptoms-
fever,lethargy,coagulopathy
3.NAFLD:nausea,vomitting
4.Granulomatous hepatitis:present as
hypersensitivity reaction.rash, fever can occur.
5.cholestasis: reversible increase in ALP.
• When to stop ATT:
1.Patient syptomatic and AST/ALT>3 times ULN.
2.Patient asyptomatic and AST/ALT>5 times ULN
and T. bilirubin >2.
When all parameters comes to baseline,ATT can
be reintroduced.
But if parameters again starts deranging, it is
called recurrent hepatitis.
In that condition, we have to reintroduce drugs
one by one.
• Sequence of reintroduction:
First H alongwith etambutol is reintroduced at
lower dose.
Then full dose of H is started.
Then slowly R is introduced.
Then slowly full dose ATT alongwith Z that is
HRZE is started.
If any derangement occurs, we have to find the
culprit drug and stop it. for eg in rifampicin
toxixcity, ALP and conjugated bilirubin will rise
as it is cholestatic.
• If we are unable to achieve normal LFT, then
most hepatosafe is SLE regimen
S:streptomycin
L:levoflox
E:ethambutol

HCV treatment should always started only after

completion of ATT d/t drug drug interaction.
In MDR tb, short oral regimen should be avoided
as bedaquiline is also found to be hepatotoxic.
 ATT in renal disease
DST: HRZE-H and R are renal safe as their excretion
is biliary.
Dose modification is needed, not to stop drug.
We have to modify the dose when crt.
Clearance<30 ml/min or patients receiving
hemodialysis that is stage 4 and 5.
Dose modification: Both Z and E are then given 3
times/week instead of daily regimen.
in patients undergoing dialysis, best to give them 4-
5 hours before dialysis. so that optimum
excretion can be achieved.
• Drug resistant TB:
Short oral regimen in CKD:
B: no dose modification.
I: no dose modification.
L:levoflox 1g/dose 3 times/week
if moxiflox: no dose modification
C: no dose modification
Ethionamide: no dose modification
Ethambutol:15 mg/kg/dose 3times/wk
Z:pyrazinamide:25 mg/kg 3 times/wk.
• Thank you