TUBERCULOSIS

INTRODUCTION TB (for Tubercle Bacillus or Tuberculosis); Common and often deadly infectious disease caused by

Mycobacteria species. Mycobacterium tuberculosis (most common), Mycobacterium

bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti.

Pulmonary TB – attacks the lungs; Extra-pulmonary TB – CNS, Lymphatic system, skin,

pericardium, pleura, Circulatory system, GU system, GI system, bones, joints, kidney, eyes, etc...

If untreated, death within 5 years; majority of cases – 18 months.

Epidemiology : 3 million deaths annually (10% children); 26% avoidable deaths in adults; leading cause of death in HIV patients.

SYNONYMS Consumption - consumed people from within, w/ a bloody

cough, fever, pallor and long relentless wasting. Phthisis (Greek word meaning consumption) and phthisis

pulmonalis; scrofula (in adults)- affecting the lymphatic system → swollen neck glands;

Tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague (victims appeared markedly pale).

King's evil (it was believed that a king's touch would heal scrofula).

Pott's disease Gibbus of the spine and joints Miliary TB (disseminated TB)— infection invades the

circulatory system → lesions which have the appearance of millet seeds on X-ray.

Koch's disease (after the scientist Robert Koch).

Introduction (contd.)

RISK FACTORSRISK FACTORS Close contactsClose contacts with Infectious TB patients. with Infectious TB patients. People born in areas where TB is common (People born in areas where TB is common (EndemicEndemic).). People with People with poor access to health carepoor access to health care.. People who inject illicit drugs (People who inject illicit drugs (Drug abusersDrug abusers; sharing ; sharing needles).needles). People who live or work in residential facilities, People who live or work in residential facilities, congestedcongested areas.areas. Health care professionalsHealth care professionals. . The The elderlyelderly ImmunocompromisedImmunocompromised, DM, Silicosis patients., DM, Silicosis patients. People with CXR that show People with CXR that show previous TB infectionprevious TB infection. .

THE BACTERIAL SPECIES M.tuberculosis • Aerobic, small, rod-like bacterium; • Very slow division rate (every 16 to 20 hours; other bacteria

divide in less than an hour).• Very weak Gram-positive bacterium – Has cell wall but lacks

phospholipid outer membrane. • Sometimes, won’t retain Gram staining dye due to the high

lipid & mycolic acid content of its cell wall. • Acid-Fast Bacillus (AFB) – retains certain stains after being

treated with acidic solution; Ziehl-Nielsen stain AFBs a bright red that stands out clearly against a blue background.

Can withstand weak disinfectants and survive in a dry state for weeks.

Growth : Only within host organism (In nature); but M. tuberculosis can be cultured in vitro.

M.Tuberculosis

Introduction (contd.)

M. tuberculosis complex (includes M.TB, M. africanum, M. bovis and M. microti).

M. africanum – not widespread, but in parts of Africa; is a significant cause of tuberculosis.

M. bovis – once a common cause of TB; in unpasteurized milk;

(Pasteurized milk largely eliminated this as a public health problem in developed countries).

M. microti – mostly in immunodeficient people;

Other known pathogenic mycobacteria – M.leprae, M. avium and M. kansasii.

M. avium and M. kansasii are also referred to as Nontuberculous mycobacteria (NTM) group.

NTM cause neither TB nor leprosy, but they cause pulmonary diseases resembling TB.

PATHOLOGY (Pul. TB)1] Primary TB infection: Lungs; occasionally tonsils or alimentary

tract (ileocaecal TB).• Subsequent Infection : Primay TB + Caseous lesions in lymph

nodes.• Most people – primary TB + subsequent infections which heal and

calcify. • Few people – incomplete healing → TB bacilli enter blood stream

and lesions develop elsewhere.• Haematogenous lesions – lungs, bones, joints and kidneys; months / years after 1° infection.• Infection may be carried by Lymphatics from TB nodes to pleura

(pleurisy); pericardium (pericarditis).• Complications – Tonsil lesion→ Cold abscess of neck; Gut lesion → TB peritonitis.• Caseous TB lesions rupture into vein → dissemination → Acute

miliary TB.

Pathology (contd.)

2] Progressive Pulmonary TB:• Develops directly from a primary lesion OR• Occurs following reactivation of completely healed primary focus

(LATENT).

3] Post-primary Pulmonary TB:• TB cavity;• Caseating (‘cheese-like’) lesion discharges into a bronchus;• Infection extends to pleura (TB pleurisy → TB pleural effusion → TB

Pleural empyema)

Pleural Effusion : Excess fluid accumulates in the pleural cavity. Lung expansion gets limited during inhalation.

Pleural Empyema : Also called Pyothorax / Purulent pleuritis; pus

accumulates within the pleural cavity.

L. sided Pleural Effusion

ACTIVE Vs LATENT TB

ACTIVE TB • Unhealthy Person• Bacilli overwhelm the immune system.• Bacilli break out of tubercules in alveoli and spread through the

blood stream.

LATENT TB • Healthy Person• Initial infection is controlled by Immune system.• Bacilli remain confined in tubercules for long periods (many years).• Bacilli get reactivated on stimulation.

PATHOGENESIS & IMMUNITY (THEORY – I)

Stage I : Healthy person inhalesDroplet nuclei from

TB patient

Majority of inhaled bacilli trapped in U.airway & expelled

by ciliated mucosal cells

Fraction of the inhaled bacilli reach the alveoli

Non-specific alveolar macrophages activated

(to ingest bacilli)

Produce proteolytic enzymes, cytokines to check bacterial multiplication

Bacilli multiply quickly, kill the macrophages

(LYSIS)

Non-specific Mo from blood stream move to this site & try to ingest

bacteria from lysed macrophages

Pathogenesis & Immunity (contd.)

Stage II : After 2 – 4 weeks; balance b/n both responses determines TB type

HOST RESPONSE Tissue-damaging response

(delayed type hypersensitivity;destroy non-activated macrophages)

Macrophage-activating response(CMI; Macrophages activated)

Stage III : Post-Infection• CD4 + T-Lymphocytes → produce IFN-γ (stimulates macrophages to produce TNF-α, 1,25-dihydroxy Vit.D→ good mycobacterial inhibitors).• Alveolar macrophages secrete Cytokines; IL-1 (fever); IL-6 (hyperglobulinaemia); TNF-α (kills mycobacteria).• Fever, weight loss.

THEORY – II1] Mycobacteria reach pulmonary alveoli.2] Mycobacteria invade and replicate within endosomes of alveolar

macrophages. [Endosomes: membrane-bound compartments].3] Establish the ‘Ghon Focus’ (1° site of infection in lung); 4] Dendritic cells pick up the bacteria. [Dendritic cells are immune cells].5] Dendritic cells don’t allow replication; but transport bacteria to local lymph nodes. 6] Bacteria spread (via blood stream) to other tissues and organs; 2° TB

lesions develop (mostly in apex of upper lobe of lungs; peripheral lymph nodes; kidneys; brain and bone).

7] Granulomas: - TB is a granulomatous inflammatory condition. - Macrophages, T lymphocytes, B lymphocytes and fibroblasts and other cells aggregate to form a Granuloma, with lymphocytes surrounding the infected macrophages. - Granuloma prevents mycobacterial dissemination; provides

a local environment for immune cells of the body to aggregate.

Within the Granuloma :* T-lymphocytes (CD4+) secrete cytokines (IFN – γ)

Directly kill infected cells Activates Macrophages which

destroy the bacteria.* Caseous Necrosis : cell death in tubercle centre w/ soft white cheesy

texture.* Bacteria can remain dormant within the granuloma (not always

eliminated).• Miliary TB: Via blood stream, TB is spread through the body and

sets up many foci of infection (appearing as tiny white tubercles in the tissues); severe form of TB; most common in infants and the elderly.

[Granuloma: ball-like collection of immune cells, trying to destroy a

foreign substance].

Gradually, i) the infection subsides. ii) tissue destruction and necrosis are balanced by healing and

fibrosis. iii) affected tissues are replaced by scarring, and cavities are filled

w/ cheese-like white necrotic material. iv) During active disease, some of these cavities are joined to the

bronchi and this material can be coughed up. It contains living bacteria

and can pass on infection. Tx w/ appropriate antibiotics kills bacteria; healing takes place. Upon cure, scar tissue replaces affected areas.

CLINICAL FEATURES Local effects: Chest pain; cough w/ expectoration (> 3 weeks);

haemoptysis. Systemic effects: Anorexia, fever, weight loss, chills, lassitude, sleep

sweats, evening pyrexia.

Miliary TB • High pyrexia w/ drenching night sweats;• Diarrhoeal stool; Weight loss; progressive anaemia;• Marked tachycardia; pancreatitis;• Cough; breathlessness (‘Crepitations/ Crackles/ Rales in the lungs’);• Hepato-splenomegaly; Lymphadenopathy;• Ophthalmoscopy – ‘Choroidal Tubercules’.

[Crepitations : Clicking / rattling / crackling noises heard on

lung auscultations; caused by the ‘popping open’ of small airways and alveoli collapsed by fluid, exudate, or lack of aeration during expiration].

Symptoms (contd.)

CNS TB • Meningitis, Tuberculoma, fever, headache, confusion, coma, focal

neurological deficits.

Genitourinary TB • Insidious onset – persists for long time without symptoms.• Urinary frequency; Dysuria; Loin discomfort. • Painless intermittent microscopic haematuria. • Red cells in urine, but no bacterial growth on routine bacterial

culture. • Persistent cystitis – unresponsive to antibiotics. • Ureteral strictures; Kidneys, ureter and bladder damage. • A painless, non-tender, irregular, and sometimes fluctuating mass

on one side of the scrotum.• Malaise and general symptoms of TB;

TB lymphatic system • ‘Scrofula’ or ‘Cold abscess’ – Chronic, painless

mass in the neck, persistent and usually grows with time; no accompanying local color or warmth and the overlying skin acquires a violaceous (bluish-purple) color.

• Fever, chills, malaise and weight loss. • As the lesion progresses, skin becomes adhered

to the mass and may rupture, forming a sinus and an open wound.

Pott’s disease (TB of Bones and Joints) • Back pain, fever, night sweats, anorexia, wt.

loss, • Spinal mass - associated with numbness,

tingling, muscle weakness of legs.• Vertebral collapse → Kyphosis • Spinal cord compression; sinus

formation; osteomyelitis; Cold abscess • Paraplegia (‘Pott's paraplegia’)

Extra-pulmonary TB (contd.)

TB of the eye : Conjuctivitis, Iritis, Choroiditis. Pericardial TB : Pericardial effusion; Pericardial tamponade; Fever. TB of bone marrow : Anaemia; Thrombocytopenia. Skin TB : Lupus vulgaris; Erythema nodosum. GIT TB : Intestinal obstruction; Ascites. Adrenal TB : Addison’s disease.

COMPLICATIONS OF TB• Pleurisy, Pneumothorax, Empyema (pus collection within a cavity),

TB laryngitis, TB enteritis,• Ischiorectal abscess, Aspergillosis (fungal infection of lung), Bullae. Bullae – round or irregularly-shaped blister containing

serous or seropurulent fluid; > 1cm in diameter.

LAB INVESTIGATIONS1] Medical history; P/E2] CXR : PA view; Fluffy shadows; ring-like structure; cavities in upper lobe (opacification of airspaces within lung

parenchyma w/ hazy borders); lesions (regular or irregular margins) appear anywhere in lungs; Miliary mottling – millet-sized nodules throughout the parenchyma

4] Sputum and Pus: AFB test (Ziehl-Nielsen stain); 3 consecutive days sampling;

5] U/S abdomen: miliary mottling; lymph node enlargement.

6] Blood tests: ↑ TC, DC and ESR (Leucocytosis); ↓Hb (Anaemia).

7] CT scan: TB abscess.

8] Excision Biopsy: FNAC (Fine Needle Aspiration Cytology)

9] PCR: to detect specific DNA segment

10] Mycobacterial culture 11] Gastric lavage

12] Mantoux Test: • Mantoux screening test, Tuberculin Sensitivity Test, Pirquet test or

PPD test (for Purified Protein Derivative); • Diagnostic tool for TB; has replaced multi-puncture Tine test. • Tuberculin – glycerine extract of the tubercule bacilli.• PPD – precipitate of ‘non-species-specific’ molecules obtained from

filtrates of sterilized, concentrated cultures of Mtb. • The test is named after Charles Mantoux.• Procedure – i) Std. dose of 5 Tuberculin units (0.1 ml) via

intradermal; results are read 48 to 72 hours later. ii) Person exposed to the bacteria is expected to show an immune response in the skin containing the bacterial

proteins. iii) Measure the diameter of ‘Induration’ (palpable raised hardened area) across the forearm (perpendicular to the

long axis) in millimeters.

Mantoux test (contd.)

iv) No induration – result should be recorded as ‘0 mm’. Erythema (redness) should not be measured.• If a person has had a history of a positive tuberculin skin test,

another skin test is not needed.


Classification of tuberculin reaction : Increment of induration (5mm / 10mm / 15 mm).

5 mm or more is positive in : HIV (+)persons; Recent contacts of TB cases; Old healed TB; Organ transplants and other immunosuppressed patients.

10 mm or more is positive in : Injection drug users; Mycobacteriology lab personnel; Recent arrivals (< 5 yrs) from high-prevalence countries; Residents and employees of high-risk congregate settings (egs.: prisons, nursing homes, hospitals, homeless shelters, etc.); High risk clinical conditions (DM, prolonged corticosteroid Tx, leukemia, end-stage renal disease, chronic malabsorption syndromes,

low body weight, etc); Children < 4 years of age; adults in high-risk categories


15 mm or more is positive in : Persons with no known risk factors for TB.

False positive result : by NTB or previous administration of BCG vaccine. Prior vaccination

with BCG may result in a false-positive result for many years afterwards.

13] Tine Test:• Multiple puncture tuberculin skin test; aids in the medical Dx

of TB.• Uses a small button that has 4 – 6 short needles coated with

TB antigens (tuberculin). The needles are pressed into the skin (usually on the inner side of the forearm), forcing the antigens into skin.

• The test is read by measuring the size of the largest papule. A negative result is the presence of no papules.

• Not possible to control the amount of tuberculin used; a positive test should be verified using the Mantoux test.

14] HEAF TEST: Diagnostic skin test performed in order to determine whether or not a

child has been exposed to TB. Patients who exhibit a negative reaction to the test may be offered BCG vaccination.

The test is named after F. R.G. Heaf. Procedure : • A Heaf gun ( w/ disposable single use heads) is used to inject multiple

samples of testing serum (PPD) under the skin at once. • The gun injects PPD equivalent to 100,000 U per ml to the skin over

the left forearm in a circular pattern of six. The test is read between 2 – 7 days later. The injection must not be into sites containing superficial veins.

• The reading of the Heaf test is defined by a scale:• Negative : No induration, maybe 6 minute puncture scars • Grade 1 : 4-6 papules (also considered negative) • Grade 2 : Confluent (joint) papules form indurated ring (positive) • Grade 3 : Central filling to form disc (positive) • Grade 4 : Disc >10 mm with or without blistering (strongly positive)

Heaf Test (contd’.)

• Grades 1 and 2 may be the result of previous BCG or avian TB.• Children who have a grade 3 or 4 reaction require X-ray and

follow-up.

The equivalent Mantoux test positive levels done with 10 TU (0.1 mL of 100 TU/mL) are : • 0 - 4 mm induration (Heaf 0-1) • 5 -14 mm induration (Heaf 2) • >15 mm induration (Heaf 3-4)

TREATMENTAnti-TB Drugs : LFT, Ophthalmic and ENT opinions before starting ATT.

1] 1st Line Drugs : High anti-TB efficacy; Low toxicity

a) Rifampicin (RMP or R): • Bactericidal drug; Inhibits DNA-dependent RNA synthesis.• Dose: 10 – 20 mg/kg; 450 mg (wt. < 50 kgs); 600 mg (wt. > 50kgs).• Administer 30 minutes before breakfast.• AEs: Hepatitis, Thrombocytosis, Eye redness, ↑es metabolism of other

drugs, NV and Vasculitis. • Dark Orange-red urine (harmless; advise the patient regarding this).

b) Isoniazid (INH or H):• Tuberculocidal; MOA is unknown (maybe inhibits mycolic acid synthesis).• Dose: 10 mg/kg; usual dose is 300 mg.• AEs: Hepatitis, Psychosis (give pyridoxine 100 mg/day), Polyneuropathy.

NOTE: Isoniazid competes with pyridoxyl phosphate for the

enzyme apotryptophanase which may lead to symptoms of pyridoxine (vitamin B6) deficiency.

Pyridoxine administration can prevent and reverse peripheral neuropathy associated with INH use.

Prophylactic pyridoxine administration (e.g., 10 to 50 mg/day) should be given routinely in individuals predisposed to develop peripheral neuropathies secondary to isoniazid therapy (e.g., patients who are malnourished, pregnant, alcoholic, diabetic, HIV-infected, or patients receiving higher doses of isoniazid).

Anti-TB drugs (contd.)

c) Pyrazinamide (PZA or Z):• Weak tuberculocidal; very effective in the first 2 months of infection;• Dose: 20 – 35 mg/kg.• AEs: Hepatitis, Hyperuricaemia, Hypersensitivity reactions.

d) Ethambutol (EMB or E):• Tuberculostatic; interferes w/ mycolic acid incorporation into cell

wall and RNA synthesis.• Dose: 25 mg/kg• AEs: Loss of colour and vision; Optic neuritis.

e) Streptomycin (STM or S): • Tuberculocidal; acts only on extracellular bacteria; Dose: 30 mg/kg • Transports aminoglycosides thru bacterial cell wall and cytoplasmic membrane.• Binds to ribosomes and inhibits protein synthesis.• AEs: Oto and nephro toxicity; Vestibular disturbances.


2] 2nd Line Drugs : Less effective; more toxic side effects than 1st line drugs.

Aminoglycosides: Amikacin, Kanamycin Fluoroquinolones: Ciprofloxacin 1500 mg;

Ofloxacin 800 mg Q24H; Macrolides: Clarithromycin 500 mg BD;

Azithromycin 500 mg OD Polypeptides: Capreomycin , Viomycin,

Enviomycin Thioamides: Ethionamide, Prothionamide Thiacetazone PAS 10 – 12 gms Cycloserine, Elofazamine Rifabutin 300 mg per day

Linezolid (LZD), Thioridazine Arginine, Vitamin D


6 MONTHS REGIMEN (2HREZ/4HR3)• 2 (for two months); 3 (thrice a week); No subscript (daily dosing).1] Initial Phase (daily for 2 months) : INH + Rifampicin + Ethambutol (or Streptomycin) + Pyrazinamide

2] Continuation Phase (thrice a week for 4 months) : INH + Rifampicin

9 MONTHS REGIMEN (2HREZ/7HR3)1] Initial Phase (2 months) : INH + Rifampicin + Ethambutol (or Streptomycin) + Pyrazinamide2] Continuation Phase (7 months) : INH + Rifampicin

12 MONTHS REGIMEN (2SH2/10HT) 1] Twice Weekly : Streptomycin 1 g + INH 300mg (+ Pyridoxine 10

mg) Tx is effective in absence of primary drug resistance. 2] Daily : INH 300 mg + Thiacetazone 150 mg single dose by mouth.


CORTICOSTEROIDS i) Adjunct Tx in Fulminant infections.ii) Prednisolone 20 mg daily for 6 – 12 weeks, then taper the dose.iii)Used in Pleural and pericardial effusions

SPINAL TB: 2HREZ / 4HR (UK); 2HREZ / 7HR (USA) CNS TB: 2HREZ / 10 HR + Steroids; Effective anti-TB drugs in CNS

TB –• INH; PZA; S; LZD; Cycloserine; Ethionamide; PAS LATENT TB: 6H, 9H, 6 to 9H2, 4R,3HR, 2RZ.

DOTS (Directly Observed Treatment Short-course) • WHO-recommended TB control strategy that combines five

components:a) Government commitment b) Case detection by sputum smear microscopy c) Standardized treatment regimen with directly observed treatment

for at least the first two months.d) A regular drug supply e) A standardized recording and reporting system that allows

assessment of treatment results.• Regimen: intermittent dosing (thrice weekly or 2HREZ/4HR3). • Twice weekly dosing is effective but not recommended by the

WHO because there is no margin for error (accidentally omitting one dose per week results in once weekly dosing, which is ineffective).

• DOTS-PLUS is for (MDR-TB).

GENERAL TREATMENT• Rest – especially for skeletal TB (Pott’s spine; paraplegia).• Isolation – for people in over-crowded houses and sputum AFB (+) send to sanatoriums;• Diet – nutritious diet rich in proteins.

SURGICAL OPTIONS : Pulmonary resection; Lymph node excision; Abscess drainage; Nephrectomy; TB spine correction ( to prevent paraplegia).

THANK YOU!!!

Health & Medicine

TUBERCULOSIS