This document provides information on pulmonary tuberculosis (PTB), including: - Causative agents, epidemiology, pathogenesis, diagnosis, treatment of drug-susceptible and drug-resistant PTB - Clinical manifestations and spread of primary and post-primary PTB - Interactions and management of PTB in HIV co-infected individuals - Potential adverse drug reactions to anti-tuberculosis medications and their management

1. PULMONARY TUBERCULOSIS
By Dr. Pugazhenthi Department of Family Medicine
Moderator: Dr. Reshma, Pulmonologist.
References:
Harrison’s principle of internal medicine 21st ed
NTEP TRAINING MODULE July 2020
NTEP PROGRAMMATIC MANAGEMENT OF DRTB 2021

2. Introduction
• Tuberculosis (TB), which is caused by bacteria of the Mycobacterium
tuberculosis complex.
• Chronic granulomatous inflammation, induces cell mediated
immunity and delayed hypersensitivity.
• Oldest diseases[70000 Years ago] known to affect humans and the
top cause of infectious death [untreated fatality 70% ] worldwide
excluding COVID-19.
• This disease most often affects the lungs, although other organs are
involved in up to one-third of the cases.
• First discovered in 1882 by Robert Koch.

3. Etiologic agent
• Pathogenic species belonging to the M. tuberculosis complex, which
comprises eight distinct subgroup.
• M. tuberculosis – Most common cause.
• M. africanum - West, Central, and East Africa
• M. bovis- Cattles-TB transmitted by unpasteurized milk, Resistant to
Pyrazinamide
• M. caprae- Related to M.bovis
• M. pinnipedii – Sea lions and Seals.
• M. mungi - banded mongooses in southern Africa.
• M. orygis – oryxes in Africa and asia.
• M. microti- “vole” bacillus, a less virulent organism.
• M. canetti-East Africa , produces unusual smooth colonies on solid.

4. Epidemiology

5. Estimated tuberculosis (TB) mortality rates in (HIV-negative people in 2018. Global
Tuberculosis Report 2019. Geneva, World Health Organization; 2019

6. Pathogenesis
• M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic, Acid fast
bacterium measuring 0.5 μm by 3 μm.
• Acid fastness - high content of mycolic acids, long-chain cross-linked fatty acids,
and other cell-wall lipids.
• In the mycobacterial cell wall, lipids (e.g., mycolic acids) are linked to underlying
arabinogalactan and peptidoglycan.
• This structure results in very low permeability of the cell wall, thus reducing the
effectiveness of most antibiotics.
• Another molecule in the mycobacterial cell wall, lipoarabinomannan, is involved
in the pathogen–host interaction and facilitates the survival of M. tuberculosis
within macrophages.

7. Other Acid Fast Structures
• Cryptosporidia
• Microspora
• Isosporanocardia
• Rhodococcus
• Legionellana
• Embryophore of T.saginnata
• Hooklets of E.Granulosus
• Keratin

8. Spread of TB infection
• M. tuberculosis is most commonly transmitted from a person with infectious pulmonary TB by
droplet nuclei containing M. tuberculosis bacteria, which are aerosolized by coughing,
sneezing, or speaking.
• The tiny droplets dry rapidly; the smallest (<5–10 μm in diameter)may remain suspended in
the air for several hours and may reach the terminal air passages when inhaled.
• 3000 nuclei per cough is produced.
• Sputum positive cases have 10⁵–10⁷ AFB/mL.
• Sputum negative has less infectivity but responsible for overall 20% of transmission.

9. Mode of transmission
• Inhalation - pulmonary TB
• Ingestion - intestinal and oropharyngeal disease.
• Inoculation - rare.
• Skin or placental transmission - rare .
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10. Primary TB
• Primary infection is an infection occurring for the first time in susceptible
individuals who are exposed to tubercle bacilli. Droplet nuclei that are inhaled
into the lungs, that evade the muco-ciliary defences of the bronchi and lodge in
the terminal bronchiole or alveoli of the lungs.
• Subsequently, the bacilli multiply and invade the hilar lymph nodes through the
lymphatics.
• The subpleural lung lesion, lymphangitis and hilar adenopathy together
constitute a “primary complex” - Ghon's complex
• In most cases, the host’s immune defences overcome the primary infection,
which generally passes unnoticed .

11. Primary TB- continuation
• Secondary bacillary multiplication that occurs at the regional lymph nodes causes
bacillaemia resulting in the implantation of seedlings of bacilli in different parts of
the body, such as the apical & sub-apical areas of the lungs, the meninges &
cerebral cortex, intervertebral discs, renal parenchyma and the epiphysial ends of
long bones.
• In such environments, the bacilli continue to multiply as these environments
favour their continued growth and multiplication.
• In a few cases, the infection may develop into progressive primary forms of TB
disease such as meningitis and miliary TB.
• Majority of the cases, the multiplication of the bacilli is contained by the host
defence mechanism.

12. Post Primary TB
• Post-primary TB disease occurs after a latent period of many months
or even years after the primary infection.
• Disease may occur either due to endogenous reactivation of dormant
tubercle bacilli acquired from a primary infection or by exogenous re-
infection.
• Post-primary TB disease usually affects the lungs, but can involve any
part of the body except nails and hair.

13. Clinical manifestation of PTB
• PRIMARY TB
• Asymptomatic or may present with fever and occasionally pleuritic chest pain.
• Most commonly in children.
• Most inspired air is distributed to the middle and lower lung zones, these areas
are most commonly involved in primary TB.
• The lesion forming after initial infection (Ghon focus) is usually peripheral and
accompanied by transient hilar or paratracheal lymphadenopathy.
• Some patients develop erythema nodosum on the legs or phlyctenular
conjunctivitis.
• The lesion heals spontaneously and becomes evident only as a small calcified
nodule.

15. Clinical manifestation of primary TB
• The initial lesion increases in size and can evolve in different ways.
• Pleural effusion, results from the penetration of bacilli into the pleural space from
an adjacent subpleural focus.
• In severe cases central portion undergoes necrosis, and cavitation Progressive
primary Tb.
• Enlarged lymph nodes may compress bronchi, causing total obstruction with distal
collapse, partial obstruction with large-airway wheezing, or a ball-valve effect with
segmental/lobar hyperinflation.
• Lymph nodes may also rupture into the airway with development of pneumonia,
often including areas of necrosis and cavitation, distal to the obstruction.
• Decreased acquired immunity -miliary TB, Small granulomatous lesions develop in
multiple organs and may cause locally progressive disease or result in tuberculous
meningitis

17. Clinical manifestation of Post Primary or
secondary or reactivation TB
• Located in the apical and posterior segments of the upper lobes and superior
segments of the lower lobes.
• With cavity formation, liquefied necrotic contents are ultimately discharged into
the airways and may undergo bronchogenic spread, resulting in satellite lesions
within the lungs that may in turn undergo cavitation.
• some pulmonary lesions become fibrotic and may later calcify, but cavities persist
in other parts of the lungs.
• Individuals with such chronic disease continue to discharge tubercle bacilli into
the environment.
• Most patients respond to treatment, with defervescence, decreasing cough,
weight gain, and a general improvement in well-being within several weeks.

18. Secondary TB
• Symptoms and signs are fever, often diurnal and night sweats due to
defervescence, weight loss, anorexia, general malaise, and weakness.
• Up to 90% of cases, cough eventually develops—often initially nonproductive and
limited to the morning and subsequently accompanied by the production of
purulent sputum.
• Hemoptysis, also result from rupture of a dilated vessel in a cavity (Rasmussen’s
aneurysm) or from aspergilloma formation in an old cavity.
• Systemic features include fever (often lowgrade and intermittent) in up to 80% of
cases and wasting.
• Detectable rales in the involved areas during inspiration, especially after
coughing.

19. Diagnosis of PTB
• Presumptive Pulmonary TB: refers to a person with any of the symptoms and
signs suggestive of TB, including:
• Cough for 2 weeks or more.
• Fever for 2 weeks or more.
• Significant weight loss.
• Haemoptysis.
• Any abnormality in chest radiograph.
• Contacts of Microbiologically confirmed TB patients having cough of any duration.
• Presumptive /confirmed extra-pulmonary TB having cough of any duration .
• HIV positive patient having cough of any duration.

20. Screening for vulnerable population:

21. Tool for diagnosis of PTB
• Sputum smear microscopy
• Nucleic Acid Amplification Test (NAAT)
• Sputum culture and DST for diagnosis of Drug Resistant TB.
• Line Probe Assay for diagnosis of MDR/XDR TB
• Supportive tools for the clinical diagnosis of TB

22. Tools for microbiological confirmation of TB
Under the programme acceptable methods for microbiological
diagnosis of TB are:
A. Sputum Smear Microscopy (for AFB):
• Zeihl-Neelsen Staining
• Fluorescence staining
B. Culture:
• Solid (Lowenstein Jensen) media
• Automated Liquid culture systems e.g. BACTEC MGIT 960, BacT Alert
or Versatrek etc.
C. Drug Sensitivity Testing:

23. Smear microscopy
• Being the most commonly used method for microbiological diagnosis of TB for
the last several decades, has had enormous value in TB diagnosis but with limited
sensitivity, more so in children and PLHIV.
• Under the programme, two methods of microscopy are currently being used- ZN
stain-based microscopy using conventional microscope and Light Emitting Diode
based Fluorescent Microscopy (LED FM).
Culture
• Though highly sensitive and specific method for TB diagnosis, requires 2-8 weeks
to yield results and hence does not help in early diagnosis.
• However, culture will be used for follow up of patients on drug resistant TB
treatment to detect early recurrence. In addition, it is also used for long term
follow up for DS TB patients as per programme guidelines, to ensure relapse free
cure.

26. • Liquid culture system
• Mycobacteria Growth Indicator Tube system (MGIT-B is an automated culture
system that detects the growth of mycobacteria.
• The culture results are usually available up to 42 days. DST results are available
14-26 days after the cultures turn positive.
• Molecular Assays
• Polymerase Chain Reaction (PCR) based technologies using various modifications
are used for detecting the presence of putative resistance genes (rpoB for
rifampicin, katG and inhA for Isoniazid etc.,).
• The most widely evaluated and used assays are Line Probe Assays (LPA) which are
based on insitu hybridization on nitrocellulose strips of specific genetic targets for
resistance genes.
• These are now available for RIF and INH resistance (MDR-TB) and also for XDR-TB
(gyrA and gyrB for Fluoroquinolones, rrs(second line injectable) and eis(low level
kanamycin resistance)for second line injectable).

30. Other Diagnostic Methods:
• There is no role for inaccurate / inconsistent diagnostics like serology (IgM,
IgG, IgA antibodies against MTB antigens- these serological tests are banned
in India), various in-house or nonvalidated commercial PCR tests and BCG
test.
• Currently there is no role of IGRAs in clinical practice for the diagnosis of TB.
• Lateral low urine lipoarabinomannan (LF-LAM) assay can only be used for
diagnosis of TB in HIV positive patients with signs and symptoms of TB
(pulmonary and/or extra-pulmonary) who have a CD4 cell count less than or
equal to 100 cells/μL.
• C-Tb is the next-generation skin test for detection of Tuberculosis. It has
high specificity and contains the same antigens used in IGRA i.e., ESTA 6 and

34. TREATMENT OF PTB

35. Classification by H/O previous TB treatment
• New case - A TB patient who has never had treatment for TB or has taken anti-TB drugs for less than one
month.
• Previously treated patients have received 1 month or more of anti-TB drugs from any source in the past.
— Recurrent TB case - A TB Patient previously declared as successfully treated (cured/treatment
completed) and is subsequently found to be microbiologically confirmed TB case.
– Treatment After failure- those patients who have previously been treated for TB and
whose treatment failed at the end of their most recent course of treatment.
– Treatment after lost to follow-up A TB patient previously treated for TB for 1 month or
more and was declared lost to follow-up in their most recent course of treatment and
subsequently found microbiologically confimed TB case.
– Other previously treated patients are those who have previously been treated for TB but who cannot be
classified into any of the above classification.

36. Classification based on drug resistance
Mono-resistant (MR): A TB patient,
whose biological specimen is resistant
to one fistline anti-TB drug only.
Poly-Drug Resistant (PDR): A TB patient,
whose biological specimen is resistant

37. Treatment protocol

38. • IN NTEP, for Adults - 4-FDC (given in IP) consists of HRZE and 3-FDC (given in CP) consists of HRE
• For paediatric patients -Dispersible 3 FDC consists of HRZ and Dispersible 2 FDC consists of HR.

41. ADVERSE DRUG REACTION OF ATT DRUGS

42. ADR Management:
Gastrointestinal (vomiting , abdominal discomfort)- Any ATT
Maintain hydration and Consider treatment with anti-emetics (e.g. domperidone) and proton
pump inhibitors (e.g. Omeprazole)
tching/Rashes - Isoniazid (and other drugs also)
tching without rash or a mild rash
• Continue treatment and give antihistamines
tching with moderate to severe rash
• Stop all drugs till symptoms subside and Treat with antihistamines
• Patients with mucosal involvement, fever and hypotension will require treatment with
corticosteroids
• When the reaction subsides reintroduce drugs one by one in this Order INH. Rifampicin
Pyrazinamide Ethambutol
• Re-introduce each drug in a small dose and gradually increase over 3 days before introducing the
next drug.

43. Tingling/burning/numbness in the hands and feet-Isoniazid
• Give pyridoxine 100 mg/day orally or parenterally until symptoms subside.Patients not
responding to pyridoxine will require treatment with amitryptiline.
Joint pains - Pyrazinamide
• Give NSAIDS like aspirin, paracetamol and ibuprofen.
• In severe cases give Indomethacin for 7 to 10 days.
• If Uric acid level is raised treat with NSAIDS and colchicine,as allopurinol is not effective.
Impaired vision - Ethambutol
• Refer to ophthalmologist evaluation.
• Impaired vision may or major return to normal after weeks .
• Don't restart Ethambutol .

44. Ringing in ear , Deafness, Dizziness and loss of balance -Streptomycin
• Refer to ENT opinion.
• As Deafness is irreversible don't restart streptomycin.
Hepatitis , Anorexia, Jaundice- Isoniazid, Rifampicin or Pyrazinamide.
• Rule out other causes of hepatitis.
• Don't restart untill symptoms and liver enzymes become normal.
• Start with single drug at a time in order of rifampicin, INH and Pyrazinamide.
• In case of severe disease in whom treatment cannot be stopped start with non

45. PTB co-exist with PLHIV
First line ART in PTB case: TENOFOVIR 300mg + LAMIVUDINE 300 mg + EFAVIRENZ
600 mg (FDC)

46. IRIS (Immune reconstitution inflammatory syndrome)

47. Drug Resistant TB Treatment Prtotocol

48. Other drugs that are not included in Groups A–C are:
• Kanamycin and capreomycin, which were associated with poorer outcomes when used and
are therefore no longer recommended for use in MDR-TB regimens.
• Gatifloxacin and high-dose Isoniazid (Hh) were used in very few patients and thioacetazone
was not used at all.
Quality-assured preparations of gatifloxacin are not currently available following its withdrawal
from the market due to concerns about dysglycaemias.
• Clavulanic acid should be included in MDR/RR-TB regimens only as a companion agent to the
carbapenems (Imp-Cln and Mpm).
• When used in this way, it should be given with every dose of carbapenem and should not be
counted as an additional effective TB agent.

49. Newer drugs
• Bedaquiline (Bdq) is a diarylquinoline that specifically targets mycobacterial ATP synthase.
• Strong bactericidal and sterilizing activities against M.tb have been shown in pre-clinical, laboratory and animal
experiments.
• The drug has a high volume of distribution, with extensive tissue distribution, highly bound to plasma proteins and
is hepatically metabolized.
• The drug has an extended half-life, which means that it is still present in the plasma up to 5.5 months post stopping
Bdq.
• Bdq is now well incorporated within NTEP as a part of standard longer oral M/ XDR-TB regimen for eligible patients.
• Delamanid (Dlm) is the first approved drug in the class of nitro-dihydro-imidazo-oxazoles
• for the treatment of MDR-TB.
• It is bactericidal drug with 36 hours of half-life and act with two different mechanism of action.
• It blocks the synthesis of mycolic acids (i.e., stopping the bacteria from creating building blocks important for their
cell walls) as well as poison the bacilli with nitric oxide, which the drugs release when metabolized.

55. THANK YOU