Tuberculosis

Epidemiology
• Tuberculosis (TB) is caused by infection with Mycobacterium
tuberculosis (MTB).

• An estimated 9.6 million new cases were recorded in 2014, with

the majority presenting in the world’s poorest nations, which
struggle to cover the costs associated with management and
control programmes.

• In the same year, 1.5 million men, women and children died of
TB, and TB continues to rank alongside HIV as a leading cause
of death worldwide.
 Pathology and pathogenesis
• M. bovis arises non-sterilised milk from infected cows.

• M. tuberculosis is spread by the inhalation of aerosolised

• Once inhaled, the organisms lodge in the alveoli and initiate the
recruitment of macrophages and lymphocytes.

• Macrophages undergo transformation into epithelioid and Langhans

cells, which aggregate with the lymphocytes to form the classical
tuberculous granuloma .

• Numerous granulomas aggregate to form a primary lesion or ‘Ghon

focus’ (a pale yellow, caseous nodule, usually a few millimetres to 1–2
cm in diameter), which is characteristically situated in the periphery of
the lung.
• Spread of organisms to the hilar lymph nodes is followed
by a similar pathological reaction, and the combination of
the primary lesion and regional lymph nodes is referred to
as the ‘primary complex of Ranke’.

• Reparative processes encase the primary complex in a

fibrous capsule, limiting the spread of bacilli. If no further
complications ensue, this lesion eventually calcifies and is
clearly seen on a chest X-ray.

• Lymphatic or haematogenous spread may occur before

immunity is established, however, seeding secondary foci
in other organs, including lymph nodes, serous
membranes, meninges, bones, liver, kidneys and lungs,
which may lie dormant for years.
• The only clue that infection has occurred may be the
appearance of a cell-mediated, delayed-type
hypersensitivity reaction to tuberculin, demonstrated
by tuberculin skin testing or an interferon gamma
release assay (IGRA): so-called latent TB

• If these reparative processes fail, primary progressive

disease ensues.

• The estimated lifetime risk of developing disease after

primary infection is 10%, with roughly half of this risk
occurring in the first 2 years after infection.
 Clinicaly TB presented as :

Pulmonary TB
Extra pulmonary TB:
• Lymphadenitis
• Gastrointestinal tuberculosis
• Pericardial disease
• Central nervous system disease
• Bone and joint disease
• Genitourinary disease
 Pulmonary Disease
Primary pulmonary TB

• Primary TB refers to the infection of a previously

uninfected (tuberculin-negative) individual. A few
patients develop a self-limiting febrile illness but
clinical disease occurs only if there is a hypersensitivity
reaction or progressive infection.

• Progressive primary disease may appear during the

course of the initial illness or after a latent period of
weeks or months.
 Miliary TB
•Blood-borne dissemination gives rise to miliary TB, which may present
acutely but more frequently is characterised by 2–3 weeks of fever, night
sweats, anorexia, weight loss and adry cough.
•Hepatosplenomegaly may develop

•headache may indicate coexistent tuberculous meningitis.

•Auscultation of the chest is frequently normal but in more advanced disease
widespread crackles are evident.

•Fundoscopy may show choroidal tubercles. The classical appearances on

chest X-ray are of fine 1–2 mm lesions (‘millet seed’) distributed throughout
the lung fields, although occasionally the appearances are coarser.
•Anaemia and leucopenia reflect bone marrow involvement. ‘Cryptic’ miliary
TB is an unusual presentation sometimes seen in old age
 Post-primary pulmonary TB
• Post-primary disease refers to exogenous (‘new’ infection) or endogenous
(reactivation of a dormant primary lesion) infection in a person who has
been sensitised by earlier exposure.

• It is most frequently pulmonary and characteristically occurs in the apex of

an upper lobe,

• The onset is usually insidious, developing slowly over several weeks.

• Systemic symptoms include fever, night sweats, malaise and loss of

appetite and weight, and are accompanied by progressive pulmonary
symptoms.

• Very occasionally, this form of TB may present with one of the

complications.
• Radiological changes include ill-defined opacification in
one or both of the upper lobes, and as progression occurs,
consolidation, collapse and cavitation develop to varying
degrees.

• In extensive disease, collapse may be marked and results

in significant displacement of the trachea and
mediastinum. Occasionally, a caseous lymph node may
drain into an adjoining bronchus, leading to tuberculous
pneumonia.
 Extrapulmonary Disease
Extrapulmonary TB accounts for 20% of
cases in those who are

HIV-negative but is more common in

HIV-positive patients.
 Lymphadenitis
• Lymph nodes are the most common extrapulmonary site of disease.

• Cervical and mediastinal glands are affected most frequently, followed by

axillary and inguinal, and more than one region may be involved.

• Disease may represent primary infection, spread from contiguous sites or

reactivation. Supraclavicular lymphadenopathy is often the result of spread
from mediastinal disease.

• The nodes are usually painless and initially mobile but become matted
together with time.

• When caseation and liquefaction occur, the swelling becomes fluctuant and
may discharge through the skin with the formation of a ‘collar-stud’ abscess
and sinus formation.
• Approximately half of cases fail to show any constitutional
features, such as fevers or night sweats.

• The tuberculin test is usually strongly positive.

• During or after treatment, paradoxical enlargement,

development of new nodes and suppuration may all occur
but without evidence of continued infection; surgical
excision is rarely necessary.
Gastrointestinal
tuberculosis
• TB can affect any part of the bowel and patients may
present with a wide range of symptoms and signs.

• Upper gastrointestinal tract involvement is rare and is

usually an unexpected histological finding in an
endoscopic or laparotomy specimen.

• Ileocaecal disease accounts for approximately half of

abdominal TB cases.

• Fever, night sweats, anorexia and weight loss are usually

prominent and a right iliac fossa mass may be palpable.
Up to 30% of cases present with an acute abdomen.
• Ultrasound or CT may reveal thickened bowel wall, abdominal
lymphadenopathy, mesenteric thickening or ascites.

• Barium enema and small bowel enema reveal narrowing, shortening and
distortion of the bowel, with caecal involvement predominating.

• Diagnosis rests on obtaining histology by either colonoscopy or mini-

laparotomy. The main differential diagnosis is Crohn’s disease.

• Tuberculous peritonitis is characterised by abdominal distension, pain and

constitutional symptoms.

• The ascitic fluid is exudative and cellular, with a predominance of lymphocytes.

• Laparoscopy reveals multiple white ‘tubercles’ over the peritoneal and omental
surfaces. Low-grade hepatic dysfunction is common in miliary disease, in which
biopsy reveals granulomas.

• Occasionally, patients may be frankly icteric, with a mixed hepatic/cholestatic

picture.
 Pericardial disease
• Disease occurs in two forms : pericardial effusion and constrictive
pericarditis.

• Fever and night sweats are rarely prominent and the presentation is usually
insidious, with breathlessness and abdominal swelling. Coexistent
pulmonary disease is very rare, with the exception of pleural effusion.

• Pulsus paradoxus, a raised JVP, hepatomegaly, prominent ascites and

peripheral oedema are common to both types.

• Pericardial effusion is associated with increased pericardial dullness and a

globular enlarged heart on chest X-ray, and pericardial calcification occurs
in around 25% of cases. Constriction is associated with an early third heart
sound and, occasionally, atrial fibrillation.
• Diagnosis is based on the clinical, radiological and
echocardiographic findings.

• The effusion is frequently blood-stained. Open pericardial

biopsy can be performed where there is diagnostic
uncertainty.

• The addition of glucocorticoids to antituberculosis treatment

has been shown to help both forms of pericardial disease.
 Central nervous system
disease

• Meningeal disease represents the most important

form of central nervous system TB.

• Unrecognised and untreated, it is rapidly fatal.

• Even when appropriate treatment is prescribed,

mortality rates of 30% have been reported, while
survivors may be left with neurological sequelae.
Bone and joint disease
• The spine is the most common site for bony TB (Pott’s disease), which
usually presents with chronic back pain and typically involves the lower
thoracic and lumbar spine .

• The infection starts as a discitis and then spreads along the spinal
ligaments to involve the adjacent anterior vertebral bodies, causing
angulation of the vertebrae with subsequent kyphosis.

• Paravertebral and psoas abscess formation is common and the disease

may present with a large (cold) abscess in the inguinal region.

• CT or MRI is valuable in gauging the extent of disease, the amount of cord

compression, and the site for needle biopsy or open exploration, if required.

• The major differential diagnosis is malignancy, which tends to affect the

vertebral body and leave the disc intact. Important complications include
spinal instability or cord compression.
• TB can affect any joint but most frequently involves
the hip or knee.

• Presentation is usually insidious, with pain and

swelling; fever and night sweats are uncommon.

• Radiological changes are often non-specific but, as

disease progresses, reduction in joint space and
erosions appear.

• Poncet’s arthropathy is an immunologically mediated

polyarthritis that usually resolves within 2 months of
starting treatment.
 Genitourinary disease

• Fever and night sweats are rare with renal tract TB and patients
are often only mildly symptomatic for many years.

• Haematuria, frequency and dysuria are often present, with sterile

pyuria found on urine microscopy and culture.

• In women, infertility from endometritis, or pelvic pain and

swelling from salpingitis or a tubo-ovarian abscess occurs
occasionally.

• In men, genitourinary TB may present as epididymitis or

prostatitis.
Investigations
• unexplained cough for more than 2–3 weeks, particularly in regions
where TB is prevalent, or typical chest X-ray or CT changes .

• Direct microscopy of a sputum smear remains the most important first

step. At least two sputum samples (

• Induced sputum may be used in those unable to expectorate. In selected

cases, bronchoscopy and lavage or aspiration of a lymph node by EBUS
may be used.

• Light-emitting diode fluorescent microscopy with auramine staining is

increasingly replacing the more traditional standard light microscopy and
Ziehl–Neelsen stain or the use of mercury-vapour fluorescent
microscopy.
• A positive smear is sufficient for the presumptive diagnosis of
TB but definitive diagnosis requires culture.

• The probability of detecting acid-fast bacilli is proportional to

the bacillary burden in the sputum. Smear-negative sputum
should also be cultured, as only 10–100 viable organisms are
required for sputum to be culture-positive.

• A diagnosis of smear-negative TB may be made in advance of

culture if the chest X-ray appearances are typical of TB.

• The slow growth of MTB on solid (typically between 4 and 6

weeks) and automated and semi-automated liquid (typically
around 2 weeks) culture media has prompted the development
of rapid NAATs.
• Xpert MTB/RIF (a DNA detection-based NAAT) has the
capacity to detect MTB (and rifampicin resistance) in less than
2 hours. However, while it is specific to MTB, it is not
sufficiently sensitive to have replaced culture.

• The diagnosis of extrapulmonary TB can be more challenging.

There are generally fewer organisms (particularly in meningeal
or pleural fluid), so culture, histopathological examination of
tissue and/or NAAT may be required.

• Stimulation of T cells by mycobacterial antigens leads to

increased levels of adenosine deaminase in pleural,
pericardial, cerebrospinal and ascitic fluid, and so may assist in
confirming suspected TB.
• In the presence of HIV, examination of
sputum may still be useful, as subclinical
pulmonary disease is common.

• Lateral flow urinary lipoarabinomannan assay

(LF-LAM) may be useful in the severely ill
patient with a CD4 count of 100 cells/μL or
less.
 Drug sensitivity testing
• The rapid detection of drug resistance is central both
to the management of the individual with TB and to
control of the disease in the population.

• The gold standard remains culture, in either solid or

liquid media, but the use of other phenotypic tests,
such as microscopically observed drug susceptibility
(MODS), colorimetric redox indicator (CRI) methods
and nitrate reductase assay, offer low-cost alternatives,
depending on the resource and expertise available.
• The potential for molecular tests to provide rapid drug
sensitivity testing (DST) is improving, particularly with
regard to the detection of rifampicin resistance, which is
important because rifampicin forms the cornerstone of
6-month chemotherapy.

• Rapid identification of rifampicin resistance is provided

by Xpert MTB/RIF. Line probe assays (LPAs) use PCR
and reverse hybridisation to detect genetic sequences
linked to resistance to both rifampicin and isoniazid, and
increasingly to resistance to pyrazinamide, ethambutol
and other second-line agents.
Management
 Chemotherapy
• The treatment of TB is based :

 an initial intensive phase to reduce the bacterial population rapidly,

continuation phase to destroy any remaining bacteria.

• Standard treatment involves 6 months’ treatment with isoniazid and

rifampicin, supplemented in the first 2 months with pyrazinamide and
ethambutol.

• Fixed-dose tablets combining two or three drugs are preferred.

• Treatment should be commenced immediately in any patient who is

smear-positive, and in those who are smear-negative but with typical
chest X-ray changes and no response to standard antibiotics.
• Six months of therapy is appropriate for all patients with new-onset
pulmonary TB and most cases of extrapulmonary TB.

• However, 12 months of therapy is recommended for meningeal TB,

including involvement of the spinal cord in cases of spinal TB; in
these cases, ethambutol may be replaced by streptomycin.

• Pyridoxine should be prescribed in pregnant women and

malnourished patients to reduce the risk of peripheral neuropathy
with isoniazid.

• Where drug resistance is not anticipated, patients can be assumed to

be non-infectious after 2 weeks of appropriate therapy.
• Most patients can be treated at home.

• Admission to a hospital unit with appropriate isolation facilities should be

considered where there is :

1. uncertainty about the diagnosis,

2. intolerance of medication,

3. questionable treatment adherence,

4. adverse social conditions or

5. a significant risk of multidrug-resistant TB (culture-positive after 2

months on treatment, or contact with known multidrug-resistant TB).
• Patients treated with rifampicin should be advised
that their urine, tears and other secretions will
develop a bright, orange/ red coloration, and
women taking the oral contraceptive pill must be
warned that its efficacy will be reduced and
alternative contraception may be necessary.

• Ethambutol and streptomycin should be used

with caution in renal impairment, with
appropriatedose reduction and monitoring of drug
levels.
• Adverse drug reactions occur in about 10% of patients but are
significantly more common with HIV co-infection.

• Baseline liver function and regular monitoring are important for

patients treated with standard therapy.

• Rifampicin may cause asymptomatic hyperbilirubinaemia but,

along with isoniazid and pyrazinamide, may also cause hepatitis.
Mild asymptomatic increases in transaminases are common but
significant hepatotoxicity only occurs in 2–5%.

• It is appropriate to stop treatment and allow any symptoms to

subside and the liver function tests to recover before commencing
a stepwise re-introduction of the individual drugs. Less
hepatotoxic regimens may be considered, including streptomycin,
ethambutol and fluoroquinolones.
• Glucocorticoids reduce inflammation and limit tissue
damage; they are currently recommended when
treating pericardial or meningeal disease, and in
children with endobronchial disease.

• They may confer benefit in TB of the ureter, pleural

effusions and extensive pulmonary disease, and can
suppress hypersensitivity drug reactions.
• Surgery should be considered in cases complicated by:

1. massive haemoptysis,

2. loculated empyema,

3. constrictive pericarditis,

4. lymph node suppuration, and

5. spinal disease with cord compression,

• but usually only after a full course of antituberculosis treatment.

• The effectiveness of therapy for pulmonary TB is
assessed by further sputum smear at 2 months and at
5 months.

• Treatment failure is defined as a positive sputum

smear or culture at 5 months or any patient with a
multidrug-resistant strain, regardless of whether they
are smear-positive or negative.

• Extrapulmonary TB must be assessed clinically or

radiographically, as appropriate.