Pulmonary Tuberculosis

Dr. Ahmed Shabarga

Tuberculosis: epidemiology and
pathophysiology
Tuberculosis (TB) is one of the top ten causes
of death and is the leading single infectious
cause of death worldwide, despite being a
potentially curable disease. It kills around
1.6 million people per year, of whom 300,000
are human immunodeficiency virus (hIV)
positive. Rising rates of hIV infection and
immigration mean TB remains a large
proportion of the workload for respiratory
physicians in some parts of the UK. The
disease is a great ‘mimicker’ and should often
be considered as part of the differential
diagnosis in patients with respiratory disease.
Epidemiology
 Globally, the World health Organization (WhO) estimated that
10 million people developed TB in 2017. Over 2/ 3rds of the global
cases of TB are from India, China, Se asia, pakistan, Bangladesh,
Nigeria, and South africa. Russia and former Soviet Union
countries have rapidly increasing rates, with around 25%
multidrug resistance (MDR- TB) in these regions. Worldwide, 50%
of MDR- TB cases are from China, India, and Russia. Co- infection
with hIV is common, affecting 9% of TB patients, and particularly
affects patients in africa with a hIV co- infection rate in africa of
72%. TB rates are now at the lowest recorded level in england,
with 5,102 cases of TB in 2017, 9.2 per 100,000. however, while
the total number of cases and the total number of deaths from TB
are falling, there are significant inequalities that need to be
addressed. The majority of cases in the UK are in people born
abroad, but 30% of all cases occur in people born in the UK.
particular at- risk groups include the homeless, those with
substance misuse, prisoners, and vulnerable migrants. TB is
concentrated in the major cities, with 40% of cases in London and
some inner- city the incidence of TB exceeds 40 per 100,000.
Pathophysiology
 The disease is spread by airborne droplets containing
Mycobacterium tuberculosis (MTB). Droplets remain
airborne for hours after expectoration because of
their small size. Infectious droplets are inhaled and
become lodged in the distal airways. MTB is taken up
by alveolar macrophages, triggering the innate
immune system, and spreads via the lymphatics to
hilar lymph nodes. Later, a cell- mediated immune
process leads to granuloma formation by activated T-
lymphocytes and macrophages, which limits further
bacterial replication and disease spread. Most (over
90%) immunocompetent individuals successfully
contain the infection (either eliminated or contained
in a latent state); 10% progress to active ° disease
(1° progressive TB).
Many factors influence whether or not
infection leads to active disease, including
age, host immunity, and time since infection
(risk highest in first few years after infection).
The estimated lifetime risk of clinical disease
in a child newly infected with MTB is about
0%. active disease occurs when the host’s
immune response is unable to contain MTB
replication, with absent or poorly formed
granulomas. active disease occurs most often
in the lung parenchyma (due to high O2
content, in which the bacillus grows well) and
hilar lymph nodes. It can occur in any
organ from haematogenous spread. This is most
common in young children and
immunosuppressed adults. Most disease in adults
is due to reactivation of childhood disease, so-
called ‘post- primary disease’, from activation of
latent TB (the Ghon focus) lying dormant in the
lung. The term smear- positive TB refers to the
identification of aFB on sputum smear (ZN stain).
patient will require isolation if admitted to
hospital. Culture- positive TB refers to when aFB
not seen on smear (smear- negative) but TB is
grown on culture (may take up to 9 weeks). Much
less infectious than smear- positive disease,
although transmission can still occur.
Main risk factors for active TB in the UK

• place and date of birth:

 • Caucasian population: increasing prevalence with age
(♂ > ♀)
 • afro- Caribbean immigrants: highest prevalence in
the young (♂ = ♀)
 • Indian subcontinent: highest prevalence in middle
age (♂ = ♀)
 • hIV/ aIDS
 • poverty, undernutrition, and overcrowding
 • heavy alcohol consumption and smoking
 • Medical factors— diabetes, end- stage renal failure,
malignant disease, systemic chemotherapy, steroids,
and TNF- α antagonists, e.g. infliximab, vitamin D
deficiency (vitamin D has pleiotropic effects on the
immune system, including macrophage activation)
TB: pulmonary disease
Symptoms
Most cases present with
pulmonary disease, classically:
 • productive cough
 • haemoptysis
 • Breathlessness
 • Systemic symptoms— weight
loss, night sweats, and malaise
 • Chest pain.
Haemoptysis
 More common with cavitatory disease, and
up to two- thirds will be smear- positive.
Most haemoptysis is small volume. Massive
haemoptysis is rare and is most common
as a consequence of destruction of a lobe,
with consequent bronchiectasis formation
(possibly with 2° Aspergillus infection or
mycetoma in a healed TB cavity). This is
seen in those untreated in the pre-
chemotherapy era. Most haemoptysis will
resolve with antituberculous chemotherapy.
Signs
Often non- specific.
 • examination may be normal
 • Lymphadenopathy (particularly cervical)
 • Crackles
 • Signs of a pleural effusion
 • Signs of consolidation (with extensive
disease)
 • Signs of weight loss/ underlying
immunocompromise
 • Look for evidence of extrapulmonary
disease, e.g. skin, joints, CNS, retina, and
spinal disease.
Complications
 Long- term sequelae of inadequately treated infection
include:
 • Bronchiectasis, bronchial obstruction, and airway
stenosis (uncommon) may result from endobronchial
disease, though this is much less common in the post-
chemotherapy era. It is more common in the presence of
extensive parenchymal disease and is associated with
lymph node enlargement, with compromise of airway size
 • Pleural disease is due to either 1° progressive disease
or reactivation of latent infection. It probably represents
an increased immune response— a delayed- type
hypersensitivity reaction to mycobacterial antigens, rather
than a diminished one, which is the case in other forms of
TB infection. Culture is more likely from pleural tissue than
fluid (where the organism burden is lower)
• Pneumothorax is rare (<1% in the
developed world) and results from the
rupture of a peripheral cavity. Can lead to
the formation of a bronchopleural fistula
 • Draining abscess
 • Right middle lobe syndrome—
compression of the right middle lobe
bronchus by hilar lymph nodes leads to
lobar collapse
 • previous treatment with thoracoplasty
can lead to respiratory failure in later life
due to compromised vital capacity (VC).
TB: extrapulmonary disea
se
extrapulmonary disease is seen in
about 58% of patients with TB in the
UK (either with or without pulmonary
involvement). The tuberculin skin test
is more frequently positive in
extrapulmonary disease, as this most
commonly represents reactivated
disease and less commonly 1°
disease. anergy is more likely in those
with poor nutritional status, underlying
disease (including hIV), and the elderly
CNS disease
 The most serious manifestation and includes
meningeal involvement and space- occupying
lesions (tuberculoma) that may lead to cranial
nerve lesions. The clinical manifestations are
due to the presence of MTB and the host’s
inflammatory immune response. TB meningitis
presents with headache, fever, altered
conscious level, and focal neurological signs,
including cranial nerve palsies. Fits are
common. Cerebrospinal fluid (CSF) contains
lymphocytes, high protein, and low glucose.
polymerase chain reaction (pCR) of CSF and
adenosine deaminase levels may be useful but
are not 100% sensitive.
Pericardial TB
 The yield is low from pericardial fluid and
biopsy. 85% have a positive tuberculin test.
adenosine deaminase levels may be helpful.
a large effusion may lead to cardiac
tamponade and may need to be drained.
 Spinal disease
 Can affect any bone or joint; spine
involvement (pott’s disease) is most
common in the thoracic spine. Surgery may
be needed if there is evidence of cord
compression or instability.
Genitourinary disease
 From seeding during haematogenous
spread. Involvement of the renal and
genital tracts is uncommon.
 • In men— may cause prostatitis and
epididymitis.
 • In women— genitourinary TB is a
cause of infertility. Sterile pyuria (white
and red blood cells in the urine, in the
absence of bacterial infection) may
indicate TB infection.
Peripheral cold abscess
Can occur at almost any body site.
Disseminated disease
More common in immunosuppressed
individuals. pulmonary disease is
typically a miliary (millet seed)
pattern, but pulmonary disease is
not universal in disseminated
disease. This has a higher mortality
than localized disease.
TB: investigations
 The diagnosis is usually made in one of three ways: smear
or culture of sputum (or other sample, e.g. pus, CSF, urine,
biopsy tissue), or histology with the identification of
caseating granulomas on biopsy (send biopsy samples for
culture in normal saline as well as histology when TB is
suspected).
 • Chest radiograph (CXR) classically shows upper lobe
infiltrates with cavitation
 • May be associated with hilar or paratracheal
lymphadenopathy • May show changes consistent with
prior TB infection, with fibrous scar tissue and calcification
 • hIV- infected patients typically have less florid CxR
changes and are less likely to have cavitatory disease.
Miliary pattern is more common in later stages of aIDS
 • all patients with non- pulmonary TB should have a CxR
to exclude or confirm pulmonary disease
 Sputum ZN stain and culture is required for
definitive diagnosis and is vital for drug resistance
testing. ZN is only 50– 80% sensitive
 • New sputum processing techniques, along with
fluorescence microscopy, have improved smear
sensitivity and efficient reading of slides
 • Smear- negative disease accounts for about 20%
of disease transmission; smear- positive cases are
more infectious
 • Induced sputum is as effective as
bronchoalveolar lavage (BaL), especially if the CxR
shows changes consistent with active disease (but
should not be used for potential MDR- TB, due to
the danger to health workers)
Conventional culture takes 6 weeks or longer,
although use of the mycobacterial growth
indicator tube (MGIT) culture system can lead
to positive cultures within days • Nucleic acid
amplification techniques are increasingly
used to confirm mycobacteria serotype and
drug susceptibility. The xpert MTB/ RIF assay
can simultaneously detect MTB and identify
rifampicin resistance (which is strongly
associated with MDR- TB) within 2h and is
recommended to be sent if it will change
clinical management (i.e. suspected MDR- TB,
coexistent hIV, or critical illness
 Tuberculin skin test (Mantoux) results
are described in Box 43.. If positive
assess for active TB and if no features of
active TB consider latent TB treatment
Mantoux skin test
 • Read at 48 h
 • Intradermal. Use 0.1 mL of 1 in 1,000
(= 0.1 mL of 100 TU/ mL = 10 TU)
 • Graded: • <5 mm, negative
 • >5 mm, positive (regardless of BCG
history).
 • Interferon gamma release assays (IGRAs) (see %
p. 608) high sensitivity, but low specificity, of IGRas
mean a negative/ low result rules out active or latent
TB, but a positive result cannot differentiate between
the two
 • Bronchoscopy/ endobronchial ultrasound (EBUS) may
be needed to obtain BaL or lymph node samples if
there is a high index of clinical suspicion but a non-
productive cough or unhelpful sputum culture. In
extensive disease, macroscopic bronchoscopic
abnormality may be present, with erythematous or
ulcerated airways. Granulation tissue or enlarged
lymph nodes may be visible. Nodes can perforate or
protrude into the bronchial lumen, extruding caseous
material into the airway
• HIV test should be offered to all
patients
 • CT scan is more sensitive than CxR,
especially for smaller areas of disease. It
may show cavitatory disease and signs
of airway disease— the ‘tree- in- bud’
appearance, useful for differentiating
between active disease and non- active
old disease and guiding area for BaL.
May also be needed to assess
mediastinal or hilar lymphadenopathy.
TB: management 1
 Treatment aims to cure disease without relapse, prevent
transmission, and prevent emergence of drug resistance.
Long- term treatment with a number of drugs is required,
as TB can remain dormant for long periods prior to
treatment, making the emergence of naturally resistant
mutants possible.
 • Send material for bacteriological diagnosis prior to
initiating treatment, if possible, to allow for subsequent
drug susceptibility testing
 • In practice, if there is a high clinical suspicion of TB,
treatment should be started before culture and full
sensitivities are available
 • Never treat with a single drug
 • Never add a single drug to a failing regime
 • The majority of patients can be treated as outpatients
 • every TB patient should have a named TB case manage
 Smear- positive hIV- negative patients should become
smear- negative within 2 weeks of starting treatment (this
does not apply to MDR- TB). These patients should be
isolated either in hospital (if they are admitted) or at home
for this time period
 • all patients should be discussed and managed within a TB
multidisciplinary team
 • From 2007, there are no prescription costs for TB drugs in
the UK
 • all new cases must be notified (including those diagnosed
after death) as this initiates contact tracing. In some
districts, notification triggers specialist nursing input. The
doctor making the diagnosis has a legal responsibility to
notify. It also provides epidemiological and surveillance
data, enabling treatment and screening services to be
planned. a patient can be denotified if the mycobacterium
cultured turns out to be an
Drug treatment
 Usually in two phases:
 • Phase 1— initial intensive phase Designed to
kill actively growing bacteria • This phase lasts
2 months and shortens the duration of infectivity
• at least three drugs are needed, e.g. isoniazid,
rifampicin, and pyrazinamide, and guidelines
recommend four drugs, with ethambutol added
because of risks of drug resistance
 • phase 2— continuation phase is usually with
two drugs, typically isoniazid and rifampicin for
4 months. Fewer bacteria are present in this
phase, and there is therefore a lower chance that
drug- resistant mutants will emerge, so drug
resistance is less of a problem
 Patientadvice to document on starting
TB chemotherapy
 • possibility of nausea and abdominal pain
 • persistent vomiting and/ or jaundice— stop
drugs immediately, and contact doctor
 • Red/orange urine with rifampicin
 • Red/orange contact lenses with rifampicin
 • Contraception advice. If on the oral
contraceptive pill (OCp) as efficacy reduced
 • Visual acuity (Snellen chart) (ethambutol)
 • Visual disturbance (ethambutol)— stop drugs
immediately, and contact doctor
 • potential drug interactions
First- line anti- TB drugs
 • Isoniazid (H) Bactericidal. Single daily dose, well tolerated. Major side
effect is age- dependent hepatitis. Increased toxicity with alcohol.
peripheral neuropathy is uncommon, although increased risk with
diabetes and pregnancy; reduce incidence with 10– 20 mg pyridoxine
daily
 • Rifampicin (R) Bactericidal. Single daily dose, well tolerated.
Increases hepatic microsomal enzymes; therefore, increases clearance
of hepatic metabolized drugs, including prednisolone and the OCp, thus
the risks of pregnancy must be highlighted. Red/orange discoloration of
urine and contact lenses occurs, and gastro- intestinal (GI) upset
 • Pyrazinamide (Z) Bactericidal. Single daily dose. GI upset common.
Major side effect is hepatic toxicity. Renal excretion leads to
hyperuricaemia
 • Ethambutol (E) has some bactericidal effect, mostly bacteriostatic at
usual doses. Single daily dose, well tolerated. Side effect— optic
neuritis, uncommon. Document visual acuity (Snellen chart) before
starting, and warn patient to stop drugs immediately and contact
doctor if any visual disturbance
 • Streptomycin Bactericidal. Given parenterally. Increased risk of
ototoxicity in the foetus and the elderly.
TB: adverse
drug reactions
These occur in around 10% of patients, often
requiring a change of therapy. Reactions are
more common in those on non- standard
therapy and in hIV- positive individuals.
 Isoniazid peripheral neuropathy Increased risk
in those with diabetes, renal failure, alcoholics,
hIV- positive, can be mitigated by pyridoxine
10– 20 mg daily.
Rifampicin May cause shock, acute renal
failure, thrombocytopenia. Withdraw, and do
not reintroduce the drug. Double maintenance
steroid doses at the start of treatment
(because of enzyme induction)
Ethambutol
 Causes rare optic toxicity; recommend
baseline visual acuity assessment with a
Snellen chart. Use only in those with
adequate visual acuity and those able to
report changes in visual acuity or new
visual symptoms. Document that the
patient has been told to cease the drug
immediately at the onset of new visual
symptoms. Check baseline renal function
before starting ethambutol and avoid in
renal failure
HIV- positive patients
 Rifampicin and isoniazid lead to
reduced serum concentrations of
antifungals. Ketoconazole can inhibit
rifampicin absorption. Rifampicin may
reduce drug levels of protease
inhibitors (as they are metabolized via
the cytochrome p450 pathway, which
is induced by rifampicin). Rifabutin can
cause a severe iritis. Liaise closely with
hIV specialist.
THANK YOU