Tuberculosis and its manifestations with treatment (Revised)

1. Moderator: Prof. (Dr) A.K. Sen
Presenters: Kolli Ajit Kumar (36)
Krishna Nath (37)
Lavita Hazarika (38)
Lipika Devi (39)
Luish Bor Boruah (40)

2. INTRODUCTION
• Tuberculosis, one of the oldest disease known
to affect humans, is a major cause of death
worldwide.

3. DEFINITION
• It is a chronic bacterial infection caused by
Mycobacterium tuberculosis, that is
characterised by the formation of granulomas
in infected tissues and by cell mediated
hypersensitivity.
• The usual site of the disease is the lungs, but
other organs maybe involved.

4. ETIOLOGIC AGENT
• Mycobacteria belong to the family Mycobacteriaceae
and the order Actinomycetales. Of the pathogenic
species belonging to the M. tuberculosis complex，
which comprises eight distinct subgroups， the most
common and important agent of human disease is M.
tuberculosis.
• The complex includes M. bovis (the bovine tubercle
bacillus-characteristically resistant to pyrazinamide，
once an important cause of TB transmitted by
unpasteurized milk, and currently the cause of a small
percentage of human cases worldwide).

5. • M. tuberculosis is a rod-shaped, non-spore-
forming, thin aerobic bacterium measuring 0.5
micrometer by 3 micrometer.
• Mycobacteria, including M. tuberculosis, are
often neutral on Gram's staining. However，
once stained, the bacilli cannot be decolorized
by acid alcohol; this characteristic justifies
their classification as acid-fast bacilli.

6. EPIDEMIOLOGY
• More than 5.7 million new cases of TB (all
forms, both pulmonary and extrapulmonary)
were reported to the World Health
Organization (WHO) in 20 13; 95% of cases
were reported from developing countries.

7. TRANSMISSION
• M. tuberculosis is most commonly transmitted from a person with
infectious pulmonary TB by droplet nuclei which are aerosolized by
coughing, sneezing, or speaking. The tiny droplets dry rapidly; the
smallest (<5- 10 micrometer in diameter) may remain suspended in
the air for several hours and may reach the terminal air passages
when inhaled.
• There may be as many as 3000 infectious nuclei per cough. Other
routes of transmission of tubercle bacilli (e.g. through the skin or
the placenta)are uncommon and of no epidemiologic significance.
• The risk of acquiring M.Tuberculosis infection is determined mainly
by exogenous factors. It is said that, upto 20 contacts maybe
infected by each AFB positive case before the index case is found to
have TB.

8. PATHOGENESIS
• Unlike the risk of acquiring infection with M. tuberculosis, the risk
of developing disease after being infected depends largely on
endogenous factors, such as the individual's innate immunologic
and non-immunologic defenses and the level at which the
individual's cell-mediated immunity (CMI) is functioning.
• Clinical illness directly following infection is classified as primary TB
and is common among children upto 4 years of age and among
immunocompromised persons. Although primary TB may be severe
and disseminated, it generally is not associated with high-level
transmissibility.
• When infection is acquired later in life,the chance is greater that the
mature immune system will contain it at least temporarily. Bacilli，
however, may persist for years before reactivating to produce
secondary (or post-primary) TB, which, because of frequent
cavitation, is more often infectious than is primary disease.

9. PATHOLOGY
• The entry of tubercle bacilli into the lungs or
other site of a previously uninfected individual
elicits a non-specific acute inflammatory
response.

10. Bacteria inhaled, lodged in alveoli, initiates the recruitment
of macrophages and lymphotcytes
Macrophages undergo transformation into epithelioid and
Langhan cells, which aggregate with lymphocytes to form
tuberculous granuloma.
Numerous granuloma aggregate to form a primary lesion or
ghon’s focus, which is situated in the periphery of the lung.
(pale yellow, caseous nodule, 1-2cm diameter)
Reparative processes encase the primary complex in a
fibrous capsule, limiting the spread of bacilli: called Latent
TB.
Healing then occurs with late calcification of granulomas.
The combination of a calcified peripheral lung lesion and
calcified hilar lymph nodes is known as “Ghon’s complex”

11. • Lymphatic and
haematogenous spread
occur before immunity is
established, seeding
secondary foci in other
organs including lymph
node, meninges, bones,
liver, kidney, serous
membranes which may lie
dormant for years.
• If this reparative process
fails, primary progressive
disease ensues.

13. Clinical features

14. Pulmonary tuberculosis :
• Primary pulmonary TB: a few patients develop a self
limiting febrile illness. Clinical disease occur if there
is any hypersensitivity or progression of infection.
• Patient presents with influenza like illness,
lymphadenopathy, collapse, consolidation,
emphysema of lung, erythema nodosum,
phlyctenular conjunctivitis etc.

15. • Miliary TB: blood born dissemination gives rise to miliary
TB. This is characterised by- 2-3 weeks of fever, night
sweats, anorexia, weight loss and dry cough.
• Hepatosplenomegaly and headache may indicates
meningitis.
• Widespread crackles in auscultation are heard in more
advanced cases.
• Classical appearances on chest x-ray are of fine 1-2 mm
lesions(millet seed) distributed throughout the lung field.
• “Cryptic miliary” TB is an unusual presentation seen in
old age.

16. • Post primary pulmonary TB: it is characteristically
occurs in the apex of an upper lobe. The patient
appears with chronic cough often with hemoptysis,
PUO, unresolved pneumonia, exudative pleural
effusion, weight loss, general debility and
spontaneous pneumothorax.
• In advance cases consolidation ,collapse and
cavitation are present in varying degrees. In marked
collapse significant displacement of trachea and
mediastinum occurs.

17. Extra pulmonary TB :
• Lymphadenitis : most commonly cervical and
mediastinal glands are involved followed by axillary
and inguinal.
• Lymphnodes are mostly painless, initially mobile but
become matted together with time. when caseation
and liquifaction occur they become fluctuant and
form abscess and discharging sinus.
• Constitutional symptoms like night sweats and fever
are not very common.

18. • Gastrointestinal TB: involvement of upper GI tract
is rare. Illeocaecal disease accounts for almost half of
the abdominal tb cases. Patient presents with fever,
night sweats,anorexia and weight loss, sometimes a
right iliac fossa mass may be palpable.
• Tuberculous peritonitis is characterised by
abdominal distension,pain and constitutional
symptoms.
• Ocassionally patients may be icteric with mixed
hepatic or cholestatic picture

19. • Bone and joint involvement: mostly involved bone
is the spine. Patient presents with chronic back pain.
The infection starts as a discitis and then it involves
adjacent anterior vertebral bodies,causing angulation
of the vertebrae with subsequent kyphosis.
• Para vertebral and psoas abscess formation is
common.
• TB can involve any joints but most frequently
involves hip or knee. Prsentation is insidious with
pain and swelling.

20. • TB also involves pericardium causing
pericarditis, CNS presenting as meningeal
disease and genitourinary system.

21. DIAGNOSIS OF TUBERCULOSIS

22. • The key to the diagnosis of TB remains a high
index of suspicion. Often, the diagnosis is first
entertained when the chest radiograph of a
patient being evaluated for respiratory
symptoms is abnormal.
• Early case detection is vital to interrupt the
transmission of TB disease. Screening and
diagnosing patients with appropriate tests and
strategies will largely determine the response
to appropriate treatment.
• All efforts should be undertaken for
microbiologically confirming the diagnosis.

23. AFB Microscopy
• A presumptive diagnosis is commonly based on the finding of AFB on
microscopic examination of a smear of expectorated sputum from a
presumpive case of PTB. Although inexpensive, AFB microscopy has
relatively low sensitivity (40-60%) in culture-confirmed cases of pulmonary
TB.
• The traditional method-light microscopy of specimens stained with Ziehl-
Neelson dyes is nevertheless satisfactory, although time-consuming. The
probability of detecting acid-fast bacilli is proportional to the bacillary
burden in the sputum (typically positive when 5000–10,000 organisms are
present).
• Most modern laboratories processing large numbers of diagnostic
specimens use auramine-rhodamine staining and fluorescence
microscopy; this approach is more sensitive than the Ziehl-Neelsen
method. However, it is expensive because it requires high cost mercury
vapor light sources and a dark room.
• Less expensive light-emitting diode(LED) fluorescence microscopes are
now available.

24. • For patients with suspected pulmonary TB, it has been
recommended that two or three sputum specimens, preferably
collected early in the morning, should be submitted after proper
labelling. Two specimens collected on the same visit may be as
effective as three. Sputum should be preferably 2ml in quantity and
mucopurulent in nature.
• All efforts should be made to establish microbiological confirmation
in case of presumptive EPTB. Appropriate specimens from the
presumed sites of involvement should be obtained from all
presumptive EPTB patients for CBNAAT/Smear microscopy/Culture
and DST for MTB/ histo-pathological examination, based on type of
specimen and availability of facilities. If tissue is obtained, it is
critical that the portion of the specimen intended for culture not be
put in formaldehyde. The use of AFB microscopy in examining urine
or gastric lavage fluid is limited by the presence of commensal
mycobacteria that can cause false-positive results.

25. Acid Fast Bacilli (AFB) seen as bright
red rods (Beaded appearance) with
Zeihl Neelson Staining under oil
immersion field.

26. Mycobacterial culture
• Specimens may be inoculated onto egg- or agar-based medium (e.g.
Lowenstein-Jensen or Middlebrook 7H I0) and incubated at 37°C
(under 5% CO2, for Middlebrook medium). Because most species of
mycobacteria, including M. tuberculosis, grow slowly, 4-8 weeks
may be required before growth is detected.
• The new Automated Liquid culture Systems are: BACTEC MGIT 960,
BactiAlert or Versatrek etc.
• In modern, well-equipped laboratories, liquid culture for isolation
and species identification by molecular methods or high-pressure
liquid chromatography of mycolic acids has replaced isolation on
solid media and identification by biochemical tests. These new
methods, have decreased the time required for bacteriologic
confirmation of TB to 2-3 weeks.

27. Drug susceptibility testing
• Any initial isolate of M. tuberculosis should be tested
for susceptibility to Isoniazid and Rifampicin in order to
detect drug resistance and/or MDR-TB.
• Susceptibility testing may be conducted directly (with
the clinical specimen) or indirectly (with mycobacterial
cultures) on solid or liquid medium. Results are
obtained rapidly by direct susceptibility testing on
liquid medium, with an average reporting time of 3
weeks. With indirect testing on solid medium, results
may be unavailable for ≥8 weeks.

28. Radiographic procedures
• The initial suspicion of pulmonary TB is often based on abnormal
chest X-Ray findings in a patient with respiratory symptoms.
• Although the "classic" picture is that of upper-Iobe disease with
infiltrates and cavities, virtually any radiographic pattern-from a
normal film or a solitary pulmonary nodule to diffuse alveolar
infiltrates in a patient with adult respiratory distress syndrome-may
be seen.
• Any abnormality should be further evaluated for TB, including
microbiological confirmation. In absence of microbiological
confirmation, careful clinical assessment should be done.
• Diagnosis of TB based on X-ray will be termed as “ Clinically
diagnosed TB”

30. • In the era of AIDS, no radiographic pattern can
be considered pathognomonic.
• CT may be useful in interpreting questionable
findings on plain chest radiography and maybe
helpful in diagnosing some forms of
extrapulmonary TB (eg: Pott’s disease)
• MRI useful in the diagnosis of intracranial TB.

32. Rapid Molecular Diagnostic Testing
1. Line Probe Assay for MTB Complex and detection of RIF and INH
resistance.
2. Nucleic Acid Amplification Test (NAAT) Xpert MTB/Rif testing using
the GeneXpert system: it provides accurate and rapid diagnosis of TB
by detecting M. tuberculosis and Rifampicin resistance conferring
mutations, in sputum specimens as well as specimens from extra-
pulmonary sites. Presently, under RNTCP its use is recommended for
diagnosis of DR-TB in presumptive DR-TB patients and TB
preferentially in key populations such as children, PLHIV and EPTB.

33. • Sensitivity of CBNAAT
for TB diagnosis is high
in FNAC/biopsy
specimen from lymph
nodes, other tissues
and CSF, but lower in
pericardial, ascitic and
synovial fluid samples
and still lower in
pleural fluid.
• A positive CBNAAT
result provides useful
information, but
negative test doesn’t
rule out TB, since the
sensitivity of liquid
culture itself in extra-
pulmonary specimen is
not very high.

34. Serologic and other diagnostic tests for
Active TB
• A number of serologic tests based on detection of
antibodies to a variety of mycobacterial antigens. The
Govt. of India has banned the manufacture,
importation, distribution and use of currently available
commercial serological tests for diagnosisng TB as
these are not recommended for diagnosis.
• Determinations of ADA and IFN-y levels in pleural fluid
may be useful adjunctive tests in the diagnosis of
pleural TB; their utility in the diagnosis of other forms
of extra-pulmonary TB (e.g. pericardial, peritoneal, and
meningeal) is less clear.

35. Diagnosis of latent TB
1. Tuberculin skin test:
• It is a intradermal, reliable means of recognizing prior
mycobacterial infection. It does not measure immunity to TB but
the degree of hypersensitivity to tuberculin.
• Preferred antigen is Tuberculin purified protein derivative (PPD).
• 0.1ml PPD solution is injected intradermally (needle at 15°) on the
forearm, about 2-4 inch below the elbow. Reaction should be read
by measuring the transverse diameter of induration as detected
by gentle palpation at 48-72 hours, using the turberculin skin
scale.

37. INTERPRETATION OF TUBERCULIN REACTION:
There is no correlation between the size of induration and
likelihood of current active TB disease, but the reaction size is
correlated with the future risk of developing TB disease.
The person’s medical risk factors determine the size of induration.
The result is positive if the size of induration is 5mm, 10mm or
15mm.
False positive results seen in : infection with MOTT; previous BCG
vaccination; incorrect method of adminstration; incorrect
interpretation.
False negative results seen in: recent TB infection (within 8-10
weeks of exposure); very old TB infection; very young age (<6
months age); some viral illness (measles, chicken pox); incorrect
interpretation, insufficient dose, etc.

38. 2. Interferon ϒ Release assays (IGRA):
• Two in vitro assays that measure T cell release of IFN -y in
response to stimulation with the highly TB-specific antigens
are available.
• These tests likely measure the response of re-circulating
memory T cells-normally part of a reservoir in the spleen,
bone marrow, and lymph nodes-to persisting bacilli
producing antigenic signals.
• These are used in place of skin tests in low prevalence
countries to detect TB infection. In high burden countries
like India, it is not recommended.
• A sample of whole blood is taken and sent to the
laboratory, where it is exposed to antigens derived from
M.tuberculosis. WBCs that recognise thsese antigens
because of prior exposure to the bacteria will release
interfeon-gamma produced to assess whether the
individual has been exposed to TB in the past.

39. treatment of
Tuberculosis
Drugs used
in the
• Rifampicin
• Isoniazid
• Pyrizinamide
• Ethambutol
• Streptomycin
First Line Drugs • Fluoroquinolones
• Capreomycin
• Amikacin and
Kanamycin
• Cycloserine
• Thioacetazone
• Macrolides
• Bedquiline
Second Line Drugs

40. Categorisation under DOTS
TB patients post their evaluation and diagnosis are placed in either of the
two categories:
Category 1 Patients
(New Cases)
Red Box
•New Sputum Smear Positive
•New Sputum Smear Negative
•New Extra Pulmonary
•New Others
Category 2 Patients
(Previously Treated)
Blue Box
•Sputum smear positive Relapse
•Sputum smear positive Failure
•Sputum smear positive treatment after loss
to follow up
•Others

41. Treatment under DOTS
Two Phase Chemotherapy:
Intensive Phase
• Short Aggressive or
intense phase
• 1-3 months
• Aim is to kill off as many
bacilli as possible and
decrease risk of relapses.
Continuation Phase
• 4-5 months
• Aim is to sterilize the
smaller number of
dormant or persisting
bacilli.

42. Treatment under Dots (cont...)
The numbers before the letters refer to the number of months of treatment. The subscript after the letters refer to
doses per week. H: Isoniazid(600mg), R: Rifampicin : 450-600mg), Pyrizinamide (1500 mg), E : Ethambutol
(1200mg), Streptomycin (500-750mg)
Treatment Regimen Sputum Examination for pulmonary TB after start of regimen
Category of
Treatment
Regimen
Test at
Month
Result Then
Category 1
2(HRZE)3
+
4(HR)3
2
Negative Start CP, Test sputum at 4 and 6 months
Positive
Continue IP for 1 more month. Complete treatment in 7
months
Category 2
2(HRZES)3
+1(HRZE)3
+5(HRE)3
3
Negative
Start CP, test sputum again at 5 months, 6 moths,
completion of treatment
Positive
Continue IP for 1 more month, test sputum at 4 months and
if positive send for C-DST for MDR TB

43. Introduction of the Daily Regimen in
RNTCP(2016)
Background rationale:
The daily regimen has been introduced in 104 districts
across the country particularly for PLHIV and paediatric TB
patients.
The principle behind this is to administer FDC of the
First line anti tubercular drugs according to appropriate
weight bands and maintain a constant serum concentration
of the drug.

44. Daily Regimen under RNTCP
Type of TB case
Treatment Regime in Intensive
Phase
Treatment Regime in
Continuation Phase
New (2)HRZE (4) HRE
Previously Treated (2)HRZES+ (1) HRZE (5) HRE
The numbers before the letters refer to the number of months of treatment. H: Isoniazid(600mg), R:
Rifampicin : 450-600mg), Pyrizinamide (1500 mg), E : Ethambutol (1200mg), Streptomycin (500-750mg)

45. Multi Drug resistant TB
• When the organism is resistant to atleast both
Rifampicin and Isoniazid
• It is of two types:
– Primary
– Acquired

46. MDR TB
Treatment
of
(6-9) Kanamycin,
Levofloxacin, Ethionamide,
Cycloserine, Pyrizinamide,
Ethambutol
Treatment Regimen in
Intensive Phase
(18) Levofloxacin
Ethambutol, Cycloserine,
Ethionamide
Treatment Regimen
in Continuation
Phase

47. Treatment of XDR TB
• Intensive Phase : (6-12) Months
Capreomycin, Para-aminosalicylic acid, Moxifloxacin,
Clofazimine, High dose Isoniazid, Linezolid, Amox/Clav
• Continuation Phase : (18 Months)
Para-aminosalicylic acid, Moxifloxacin, Clofazimine, High
dose Isoniazid, Linezolid, Amox/Clav

48. Treatment of Tuberculosis in Pregnancy
• All the first line drugs are safe in pregnancy except
Streptomycin
• In case of lactating women, after ruling out active TB,
the baby should be given 6 months of preventive
Isoniazid therapy followed by BCG vaccination.
• Mothers receiving INH and their breastfed infants
should be supplemented with vitamin B6
(pyridoxine)

49. Pregnancy with MDR-TB
• Duration of pregnancy < 20 weeks
• Advice MTP and start treatment
• Patient unwilling for MTP
<12 weeks- Omit Kanamycin and
Ethionamide; PAS is added
>12 weeks- Only Kanamycin is
omitted; PAS is added
PAS is replaced with Kanamycin
after delivery
• Duration of pregnancy > 20 w
• Kanamycin is omitted and PAS is
added
• PAS is replaced with Kanamycin
after delivery

50. Treatment of Pediatric TB
• Fixed dose combination daily dose Regimen
A- Adult FDC (HRZE= 75/150/400/275 ; HRE= 75/150/275)
Weight Category
Number of Tablets
Inj. Strep.Intensive Phase Continuation Phase
HRZ E HRE
50/75/150 100 50/175/100 mg
4-7 kg 1 1` 1 100
8-11 kg 2 2 2 150
12-15 kg 3 3 3 200
16-24 kg 4 4 4 300
25-29 kg 3 + 1A 3 3 + 1A 400
30-39 kg 2 + 2A 2 2 + 2A 500

51. Treatment with Bedaquiline
• The following subgroups of patients will be
eligible for BDQ
• MDR/RR TB with resistance to all FQ
• MDR/RR TB with resistance to all SLI
• Treatment failure of MDR TB + FQ/SLI resistance
• Treatment failure of XDR TB

52. • The Dose and Duration of treatment with BDQ
is as follows
o Week 0-2 : BDQ 400 mg (4 tablets of 100 mg) daily (7 days per week) +
OBR (Optimized Background Regimen)
o Week 3-24 : BDQ 200 mg (2 tablets of 100 mg) 3 times per week (with
at least 48 hours between the doses) + OBR
o Week 25 (Start of 7th Month) to the end of treatment : Continue other
second line anti TB drugs

53. Tuberculosis in HIV Patients
• Tuberculosis and HIV interact in following ways
Primary infection : People with HIV are at a risk of being
newly infected
Reactivation of latent infection
• Emphasis is laid on coordinated TB-HIV interventions
• Treatment schedule is same
• Isoniazid preventive therapy is given to all PLHIV
• IRIS : A temporary exacerbation of symptoms, signs
of radiographic manifestations of TB after beginning
of TB Treatment

54. Complications of Tuberculosis
• Hemoptysis
• Pleural effusion
• Empyema
• Pneumothorax
• Aspergilloma
• Endobronchitis
• Brochiectasis
• Laryngitis
• Cor pulmonale
• Ca bronchus
• Enteritis

55. Haemoptysis -
• Usual in advanced disease
• Min, moderate or massive
• Min: inflammation → capillary break down –
diapedisis
• Massive – erosion of arteries in necrotic areas /wall of cavity
Bronchiectasis –
It occurs due to weakening of the bronchial walls by
tubercular granualation tissue and post tubercular fibrosis

56. Pleural Effusion
• It is a manifestation of mycobacterial infection within
the pleural space, which is acquired from initial
parenchymal lesions and results in a delayed
hypersensitivity reaction to the mycobacteria or
mycobacterial antigens in the pleural space.

57. Pneumothorax
• Spon. Pneumothorax: rupture of sub Pleural
tuberculosis lesions
• Clinical Features
‐ Acute chest pain
‐ Tightness in chest
‐ Marked resp. distress
‐ Tachycardia & Cyanosis
• Treatment
‐ ATT
‐I.C.D.
‐ Min: conservative

58. Pulmonary Aspergillosis :
–Most common species implicated- Aspergillus fumigatus
– May manifest as simple aspergilloma(fungal ball) or chronic
cavitary aspergillosis
– C/F- cough, hemoptysis, wheezing
– CXR-Air crescent sign(fungal ball)
Changes position on change of posture
Cor Pulmonale
• 5‐7% cases of cor pulmonale in India due to P.T.
• Mechanism:
– Extensive lung destruction→ scarring
– Destruction of Pul. Vasculature, tuberculous end arteritis & vaso
constriction

59. Tubercular Endobronchitis
• Cause
– Direct implantation of bronchi with TB bacilli (sputum)
– Lymphatic
– L.N. rupture
– Hematogenous
• Clinical Features
– degree of obstruction
– Cough, expectoration
– Wheeze, haemoptysis

60. Tuberculous Enteritis
• Secondary from Pulmonary Tuberculosis
• Swallowing of sputum (AFB +ve)
• Usually ileo‐caecal area
• Ulceration→ fibrosis → SAIO
• S/S
– Abdominal pain
– Alternating diarrhaea & constipation
– Loss of appetite & weight
• Treatment
– ATT
– Internal obstruction → surgery