TUBERCULOSIS

Pathogenesis

 M. tuberculosis is an aerobic, intracellular pathogen. Due to their relative impermeability to

acid-based dyes in the laboratory, these organisms are often termed “acid-fast bacilli”.
 TB is an airborne infection spread by coughing via respiratory droplets.
 Only a small number of bacteria need to be inhaled for infection to develop, but nor all those
who are infected develop active disease.

Primary tuberculosis

 Described as the first infection with TB.

 When the bacteria reach the alveolar macrophages, they are ingested and the subsequent
inflammatory reaction results in tissue necrosis and formation of a GRANULOMA.
 This granuloma lesions consist of a central area of necrotic material called CASEATION,
surrounded by epithelioid cells and
Langhans giant cells.
 Subsequently the caseated area heals
completely and many become calcified.
Some of this calcified nodules contain
bacteria, which are contained by the
immune system (and the hypoxic acidic
environment created within the
granuloma) and are capable of lying
dormant for many years.
 This is known as the primary focus or
the Ghon focus of the disease.
 On a chest X-ray the Ghon focus can be
evident as a small, calcified nodule.
 On initial contact with infection, less than 5% of patients develop active disease. This
increases to 10% within the first year of exposure.

Reactivation TB
 In the majority of people who are infected by Mycobaterium spp., the immune system
contains the infection and the patient develops cell-mediated immune memory of the
bacteria. This is termed latent TB.
 The majority of active TB cases
are due to reactivation of latent
infection, where the initial
contact usually occurred many
years or decades earlier.
 Most patients are young and
previously healthy but many
have one ore more risk factors
 implicated in the development of the active disease. In patients with HIV infection, newly
acquired TB is also common.
 The majority of active TB occurs in the lungs, but extrapulmonary infection occurs with
spread to the lymph nodes, particularly in the cervical and intrathoracic chains, where it
causes active disease in 20-25% (UK figures) and also via bloodstream to more distant sites
such as the brain, bones and skin.

General clinical features

 Patients are frequently symptomatic with a productive cough and occasionally hemoptysis,
along with systemic symptoms.
 Cardinal symptoms: cough, hemoptysis
 Systemic symptoms: fever, night sweats and weight loss
 However, in extrapulmonary sites the symptoms are often absent and the systemic
symptoms are often ignored.
 Where there is laryngeal involvement a hoarse voice and a severe cough are found.
 If the disease involves the pleura, then pleuritic pain is a frequent presenting complaint.
 The chest X-ray can show consolidation with or without cavitation, pleural effusion or
thickening or widening of the mediastinum caused by hilar or paratracheal adenopathy.
 In all cases of suspected TB it is essential, depending on the site of the disease, to obtain
sputum, biopsy samples or fluid for microscopy, smear and cultures, to obtain information on
sensitivity. Tissue samples should also be sent for histopathological examination, either dry
or in saline.
 Chest X-ray
demonstrating patchy
right mid and upper zone
consolidation and a cavity
at the right apex in a
patient with tuberculosis

Pulmonary TB

 Serial sputum
samples should
be collected on at
least three
occasions (ideally,
first thing in the
morning); if the
patient is unable
to produce
sputum, it may be
necessary to
organize an
induced sputum
or perform
bronchoscopy to obtain samples.

 Patients whose sputum is smear-positive for TB are considered to be infectious and

should be isolated in hospital.

 Those who are smear-negative but subsequently culture-positive are less infectious
and generally so not need to be isolated, although care should be taken when
contacts include immunocompromised individuals.
Lymph node Tb – clinical features

 The second most commonly affected organs.

 Extrathoracic nodes are more commonly involved then intrathoracic and mediastinal
nodes.
 Usually present as firm, non-tender, enlargement of a cervical or supraclavicular
node. They can be enlarged for several months prior to diagnosis.
 The nodes become necrotic centrally and can liquefy and be fluctuant if peripheral.
The overlying skin is frequently indurated or there can be a sinus tract formation
with purulent discharge, but characteristically there is no erythema (“cold abscess”
formation).
 On CT the central area appears necrotic (Box 28.42). Samples should be obtained via
either ultrasound-guided fine needle aspiration (FNA), core biopsy or, if necessary,
removal of the whole node.
 Miliary TB

 Miliary disease occurs through hematogenous spread of the bacilli to multiple sites,
including the central nervous system (CNS) in 20% of cases.

 It often presents with systemic symptoms and the chest X-ray demonstrates multiple
nodules, which appear like millet seeds: hence the term “military”.

 Other findings are liver and splenic microabscesses with deranged liver enzymes,
cholestasis and gastrointestinal symptoms.

 All patients should have brain imaging (MRI), to look for evidence of cerebral disease,
which can present as an asymptomatic brain tuberculoma.

PRIMARY TB
  This image shows consolidation of the upper zone
with ipsilateral hilar enlargement due to
lymphadenopathy
 These are typical features of primary TB

Note: The chest X- ray may be normal in primary TB, in fact

most patients infected are never unwell enough to
require a chest X- ray

 Following an
immune response to primary infection, a caseating
granuloma forms which calcifies over time – this is
known as a ‘Ghon focus’ – TB has gone!
 A Ghon focus is a rounded, well-defined focus of
calcific density (as dense as bone) usually located in
the periphery of the lung
 This chest X-ray shows a large, rounded calcified
focus near the right hilum
 The CT (not usually necessary) shows
it is located in the lung peripherally
 This is a particularly large Ghon focus

Post-primary TB

 Post-primary TB (secondary TB or reactivation TB) is more common in

immunocompromised individuals – for example those with HIV/AIDS,
those on immunosuppressing drugs, or those with malnutrition or
diabetes
 The upper lobes are more commonly affected
 Consolidation often extends to the hilum
 The hilar structures may be distorted due to volume loss of

Post-primary TB – lung cavity

  Cavities are a common finding in mycobacterial infection

Healed post-primary TB

 Following an immune response to post-primary infection,

the affected area often becomes scarred (fibrotic) and
calcified

 The combined fibrosis and calcification can be described as

“fibro-calcific changes”

Investigations

 Stains

Auramine-rhodamine staining is more sensitive but less specific then Ziehl-Neelsen. As result is more
widely used.

It requires fluorescence microscopy and highlights bacilli as yellow-orange on a green background.

 Culture

The majority of the developed world uses liquid/broth

culture of mycobacteria in addition to a solid
media (Lowenstein- Jensen slopes or Middlebrook agar).
Time for a liquid culture is shorter then for a solid culture
(1-3 weeks compared to 3-8 weeks).

Using liquid culture in the presence of antimycobacterial drugs

(usually first line therapy) establishes the drug sensitivity
for that stain and usually takes approximately 3 weeks.

 Tuberculin skin test (TST; purified protein

derivative (PPD) or Mantoux test)
1. Intradermal injection of tuberculin antigen
Miliary TB

 Miliary TB is due to disseminated spread of mycobacterial infection

 It can occur either at the time of primary infection or on disease
reactivation – prognosis is poor
 Very fine nodules are typically seen scattered throughout the lungs
 2. Can detect active or latent infection
3. Measure induration area in 48–72 hours; positive if:

 5 mm in patients with HIV, immunosuppression, or recent contact with TB

  10 mm in patients from high-risk countries, IV drug users, medical and lab workers
 15 mm in patients with no known risk factors for TB

lnterferon-y release assay (IGRA): no distinction between active and inactive TB

 Nucleic acid amplification and polymerase chain reaction

 Nucleic acid amplification testing (NAAT) id increasingly used for rapid identification
of MTB complex and is useful is differentiating between M. tuberculosis complex and
non-tuberculous mycobacteria, as well as identifying TB in smear-negative sputum
specimens.
 It works by using the polymerase chain reaction (PCR) to replicate and the identify
mycobacterium DNA.
 Cultures and staining are still necessary and should not be replaced by PCR.
 PCR is useful only at the initial stage of diagnosis, as it frequently remains positive
despite treatment, due to the detection of dead organisms.

Management

All patients should have (before treatment):

 Routine blood tests

 Viral hepatitis screen
 Offer an HIV test

Patients with viral active hepatitis are much more likely to develop a fatal drug-induced
hepatitis and need careful monitoring and counselling.
Those with fully sensitive TB require 6 months
of treatment; the exception is TB infection of
the CNS for which the recommended duration
is at least 12 months.
First line drugs:
ISONIAZID
RIFAMPICIN
Quadruple therapy
PYRAZINAMIDE
ETHAMBUTOL

In CNS and pericardial disease,

corticosteroids are used as an
adjunct at treatment initiation to
reduce long-term complications.

Isoniazid
  Can cause a polyneuropathy
due to B6 deficiency, as
isoniazid interacts with
pyridoxal phosphate;
 Vitamin B6, pyridoxine 10–25
mg daily, should be
prescribed concomitantly to
prevent polyneuropathy.
 Occasionally, isoniazid gives
rise to allergic reactions, such as a skin rash and fever.
 Hepatitis occurs in less than 1% of cases but may lead to liver transplantation or death if the
drug is continued.

Rifampicin

 Induces liver enzymes, which may be transiently elevated in the serum of many patients. This
also means that concomitant drug treatment may be made less effective and a careful review
of a patient’s therapy will need to be undertaken, particularly with antidepressants,
anticoagulants and antiepileptics.
 Oral contraception will not be effective, so alternative birth-control methods should be used.
 Rifampicin stains body secretions red/pink and patients should be warned of the change in
colour of their urine, tears (affecting contact lenses) and sweat.
 Thrombocytopenia has been reported.

Pyrazinamide

 Most common side-effects are: itching, rash, arthralgia

 Pyrazinamide reduces the renal excretion of urate and may precipitate hyperuricaemic gout.
 May cause hepatic toxicity

Ethambutol

 Can cause a dose-related optic retrobulbar neuritis that presents with: blindness for green,
reduction in visual acuity, central scotoma.
 Patients should have their visual acuity and colour vision checked prior to treatment using
Snellen and Ishihara charts. This condition usually reverses, provided the drug is stopped
when symptoms develop;
 All patients prescribed the drug should be seen by an ophthalmologist prior to treatment and
doses of 15 mg/kg should be used, with a maximum dose of 1.2 g.