BACTERIAL INFECTIONS

Extrapulmonary Key points

tuberculosis C Symptoms of extrapulmonary tuberculosis (EPTB) are often
non-specific, and clinical presentation can mimic that of other
Mary Peirse diseases, making diagnosis challenging and potentially
Angela Houston delayed

C HIV and expanding use of immunomodulatory drugs such as

anti-tumour necrosis factor have contributed to the increase in
Abstract
EPTB
Extrapulmonary tuberculosis (EPTB) now represents over half of all
diagnosed cases of TB in the UK and is increasingly seen in patients
C Always try to get samples for microbiology in patients with
with immunosuppression or HIV. It is usually caused by reactivation of
suspected TB; this is even more important in the current era of
latent infection and can cause disease at almost any site, most
increasing incidence of multidrug-resistant tuberculosis (TB)
commonly the lymph nodes (23%), pleura (8.2%), gastrointestinal
tract (5.9%), bone (6.7%), central nervous system (4.4%) and genito-
C Always look for pulmonary TB in patients with EPTB as con-
urinary system (2.1%). Manifestations depend on the site of disease,
current pulmonary TB has implications for infectivity, isolation
making diagnosis challenging as EPTB can mimic many other dis-
and contact tracing
eases. Hence TB should be considered in the differential diagnosis
of any sick patient. A diagnosis of EPTB should trigger a search for
C Always perform an HIV test in anyone with TB
concomitant pulmonary disease, which has implications for infectivity,
and an HIV test (as with any TB diagnosis). Obtaining appropriate sam-
C Check vitamin D concentration, and replace it if low in patients
ples for microbiological diagnosis is vital for effective management,
with TB
especially as drug resistance becomes more common. Treatment is
generally with standard quadruple therapy for 6 months (extended in
TB meningitis); adjunctive corticosteroid therapy is of proven value
in TB pericarditis and meningitis.
General principles of EPTB
Keywords Extrapulmonary tuberculosis; granuloma; HIV; lymphad-
enitis; miliary tuberculosis; MRCP; pericarditis; spondylodiscitis; Epidemiology
tuberculosis; Xpert MTB/RIF! TB remains a major global health problem: an estimated 10.4
million new cases were reported worldwide in 2015.2 Although
the incidence of TB overall in the UK has been gradually
decreasing over the past few years, 58.3% of cases reported in
Introduction England in 2015 were extrapulmonary;1 this proportion has
increased since 2005. The most important risk factors for EPTB
The most common site for infection with Mycobacterium tuber-
are shown in Table 1. Immunodeficiency increases the risk of
culosis worldwide is the lungs, but dissemination can occur to
both TB (primary, reactivation) and extrapulmonary spread if
any part of the body, resulting in extrapulmonary tuberculosis
active disease occurs. In otherwise healthy people, most EPTB is
(EPTB). In the UK, the proportion of EPTB has increased relative
presumed to arise from reactivation of latent infection, acquired
to that of pulmonary tuberculosis (TB). In the UK, the most
during a primary infection that could have occurred many years
common sites of infection include the lymph nodes (23%),
earlier.
pleura (8.2%), gastrointestinal tract (5.9%), bone (6.7%), cen-
tral nervous system (CNS; 4.4%) and genitourinary system
(2.1%) (Figure 1).1 Disseminated or miliary disease (approxi- Pathology
mately 3%) can also affect any organ. EPTB is under-recognized As with pulmonary disease, the inflammatory response to
as symptoms are often non-specific, so diagnosis is often mycobacterial invasion usually takes the form of granuloma
delayed. Therefore, it is important to appreciate the variety of formation. Although other diseases, such as sarcoid, can
different organ-specific clinical scenarios with which it can pre- generate granulomas, caseation is strongly indicative of TB. Pus
sent, as well as the non-specific systemic symptoms of TB, such formation is characteristic and can cause extensive tissue dam-
as fevers, night sweats and weight loss. age; absence of an acute inflammatory infiltrate explains why
such abscesses can be ‘cold’. Disease can range from multi-
bacillary, as in miliary disease, to paucibacillary, in which a very
small number of bacteria generate a disproportionate destructive
Mary Peirse MB ChB DTM&H MRCP (UK) is an SpR in Infectious Diseases
local inflammatory response.
and Medical Microbiology, Clinical Infection Unit, St George’s
Hospital, London, UK. Competing interests: none declared.
Diagnostics
Angela Houston BSc (Hons) MB ChB DTM&H MRCP (UK) MSc FRCPath is a
Consultant in Infectious Diseases and Medical Microbiology, Clinical The importance of obtaining a positive TB culture cannot be
Infection Unit, St George’s Hospital, London, UK. Competing over-estimated, not least to exclude drug-resistant TB. EPTB is
interests: none declared. often hard to diagnose by microscopy because tissue can be

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 BACTERIAL INFECTIONS

TB notifications to Public Health England 2015 Diagnostic recommendations for different sites in
suspected EPTB (summary of National Institute for
Pulmonary Health and Care Excellence guidelines)3

Total extra- Suspected Imaging Specimen Test

pulmonary site of EPTB
Lymph node
(extrathoracic) Pleural Chest X-ray Pleural biopsy Microscopy
Bronchoscopy Culture
Pleural Histology
Pleural fluid Microscopy
Bone Culture
Cytology
Gastrointestinal CNS CT Biopsy suspected Microscopy
MRI tuberculoma Culture
CNS Histology
EPTB
Cerebrospinal Microscopy
Miliary PTB
fluid Culture
Cytology
Genitourinary
Lymph node Ultrasound Biopsy Microscopy
CT Culture
0 500 1000 1500 2000 2500 3000 3500 4000
MRI Histology
Number of cases by site Aspirate Microscopy
with or without disease at another site
Culture
Cytology
Figure 1
Pericardial Echocardiogram Biopsy of Microscopy
pericardium Culture
Histology
Pericardial fluid Microscopy
Risk factors for EPTB
Culture
C HIV infection Cytology
C Tumour necrosis factor-a antagonists (e.g. infliximab) Gastrointestinal Ultrasound Biopsy of site Microscopy
C Corticosteroids CT of disease Culture
C Malignancy Laparoscopy (e.g. omentum, Histology
C Female sex bowel, liver)
C Non-smoker Ascitic fluid Microscopy
Culture
Table 1 Cytology
Genitourinary Ultrasound Early-morning urine Culture
Laparoscopy Biopsy from site of Microscopy
difficult to sample and tissue bacillary burden is often low. Intravenous disease (e.g. renal Culture
Characteristic histology (granuloma ! caseation) and imaging urography biopsy) Histology
may be sufficient to mandate treatment while awaiting cultures. Bone/joint X-ray Biopsy of bone Culture
See Table 2 for the recommendations for diagnostic sampling in CT Aspirate of fluid
EPTB. MRI or abscess
Molecular techniques have advanced diagnostic abilities and
CT, computed tomography; MRI, magnetic resonance imaging.
are now part of routine practice in diagnosing TB. Xpert MTB/
RIF! is a rapid automated diagnostic test that detects the pres- Table 2
ence of M. tuberculosis DNA as well as mutations in the rpoB
gene (which confers rifampicin resistance). With EPTB samples, Treatment
Xpert MTB/RIF! has a high specificity but limited sensitivity The treatment of EPTB is the same as for pulmonary TB, except
compared with standard culture.4 that the duration of treatment is extended for disease at some sites
The use of whole-genome sequencing (WGS; Table 3) in (12 months for TB meningitis; some advocate extended treatment
higher income settings is the latest advance in TB diagnostics. It for TB of bone). Standard TB treatment comprises four drugs:
is used in research and epidemiology; it is not yet in mainstream isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol
use in clinical settings but is being rolled out in reference labs by (E): HRZE is given for a 2-month intensive phase, followed by HR
Public Health England. It will be particularly valuable for contact for 4 months (continuation phase). Corticosteroids are generally
tracing and identifying drug resistance earlier (see Further only used adjunctively in TB meningitis and pericardial TB as
reading). there is proven value in these sites (see Further reading).

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 BACTERIAL INFECTIONS

New developments: WGS in EPTB

C WGS has become much more widely available and is used in many research and epidemiological areas, including TB
C Implications for clinical use in TB include accurate contact tracing and identification of drug-resistance mutations
C The cost of WGS currently limits its use to higher income countries

Table 3

The incidence of drug-resistant TB is rising, and this is more
challenging to treat. Multidrug-resistant TB is resistant to rifam-
picin and isoniazid, so alternative regimens must be used.5
Specific EPTB syndromes by disease site
Miliary tuberculosis
Miliary TB results from lympho-haematogeneous spread
throughout the body and is often associated with immuno-
deficiency. Infection is multibacillary, with foci in many or-
gans, and mortality is high. The term ‘miliary’, introduced by
Manget in 1700, refers to the resemblance of pulmonary and
hepatic nodules to millet seeds. Classically, these appear on
chest radiology as multiple small ("2 mm), discrete opacities.
A lumbar puncture should be carried out in all patients with
a diagnosis of miliary TB as around 25% of cases have CNS
involvement, which therefore requires extended treatment.
The presence of miliary changes should be considered one of
the medical emergencies seen in TB infection outlined in
Table 4.
Tuberculous lymphadenitis
Lymphadenitis is the most common presentation of EPTB in both
children and adults (23% of cases of TB in England). It usually
represents reactivation of latent TB, although cervical disease
can be caused by local spread from direct infection of the tonsils
or adenoids. The most common sites are the anterior or posterior
cervical and submandibular nodes.
TB lymphadenitis is usually painless. On palpation, nodes are
firm, but groups can become matted together, with induration of
overlying skin. Tissue necrosis with formation of fluctuant ab-
scesses is common, and abscesses can discharge, with sinus
formation. Symptoms depend upon site: mediastinal TB lymph-
adenitis can present with dysphagia or recurrent laryngeal nerve
involvement; abdominal/peritoneal disease, usually affecting the
periportal, mesenteric or peri-pancreatic nodes, often causes
non-specific abdominal pain. Rarely, enlarged lymph nodes
cause obstructive symptoms in the liver (presenting with jaun-
dice) or renal vasculature.
Aspiration or biopsy of the affected node is recommended for
mycobacterial molecular diagnostics and culture, and to exclude
differential diagnoses such as malignancy or other infections
(e.g. Bartonella, Toxoplasma) (Table 2). The yield of acid-fast
bacilli from a smear is poor but increases in patients co-
infected with HIV.
TB lymphadenitis often follows a waxing and waning course,
even during treatment. Worsening on treatment may be attrib-
utable to paradoxical reactions (enhanced immune response to
dying mycobacteria). Aspiration of abscesses can relieve symp-
toms temporarily, although repeated aspiration carries a small
risk of sinus or fistula formation.
Pleural tuberculosis
Symptoms of pleural TB include pleuritic chest pain and
breathlessness, associated with fevers and night sweats. Radi-
ology may show pleural effusions, even in the absence of lung
parenchymal changes. The pleural fluid is an exudate with high
protein, low glucose and often lymphocytosis. Acid-fast bacilli
are rarely visible, but pleural fluid becomes culture-positive in up
to 75% of patients; adenosine deaminase analysis is useful,
having 88% sensitivity for TB diagnosis. Diagnosis can be aided
by pleural biopsy (for histology and culture) and the use of
video-assisted thoracic surgery.
The differential diagnosis of pleural effusion is obviously
wide, notably including parapneumonic effusions, adenocarci-
noma and malignant mesothelioma.
Spinal and bone tuberculosis
TB affecting bones accounts for 12% of EPTB and 6% of all TB
notifications in the UK.1 The most common site of infection is the
spine (4.5% of EPTB), followed by other large joints such as the
hip, knee and shoulder. Spinal TB comprises several pathological
entities including vertebral osteomyelitis, spondylitis and discitis
(or spondylodiscitis, ‘Pott’s disease’) (Figure 2).

Medical emergencies in EPTB e the ‘alarm bells’

Syndromes or complications that need urgent intervention include:
C Miliary disease e which can paradoxically worsen on initiation of treatment e consider corticosteroids
C TB meningitis e beware of increased intracranial pressure (see MEDICINE 45(11): 670e673)
C Spinal cord compression in spinal TB e check for this, consider surgical decompression and add corticosteroids
C Cardiac tamponade in pericardial TB e check for this, give corticosteroids and consider drainage/pericardiectomy
C Hydronephrosis in renal/urogenital TB e stenting may be needed
C Adrenal disease e this can cause an addisonian crisis, which is easy to overlook e corticosteroid replacement may be required
C Vascular obstruction e caused by mass lesions (cold abscesses) or lymphadenopathy

Table 4

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 BACTERIAL INFECTIONS
The infection usually begins in the anterior aspect of the
vertebral body adjacent to the subchondral plate, spreading to
the adjacent disc, although in children the sequence can be
reversed, progressing from vascularized disc to bone. Progres-
sive bone destruction can lead to vertebral collapse and
kyphosis with formation of a spinal gibbus (anterior angula-
tion). Destructive cold abscesses can form and commonly
extend into adjacent ligaments and soft tissues, especially the
psoas muscle (psoas abscess). Narrowing of the spinal canal by
deformity, abscess formation, granulation tissue or direct dural
invasion can result in spinal cord compression, a neurosurgical
emergency.
Typically, there is a long history (#6 months) of fluctuating
non-specific back pain, accompanied by constitutional symp-
toms. TB treatment should be started immediately, with standard
quadruple therapy for 6e9 months. Adjuvant corticosteroids are
recommended if there is evidence of CNS or dural involvement.
Joint management with orthopaedic or neurosurgeons experi-
enced in the management of TB of the spine is essential to assess
spinal stability and the need for external support or operative
stabilization.
Figure 2 Magnetic resonance imaging in tuberculous spondylodiscitis.
The lumbar spine is most commonly affected, but involvement can
occur at multiple sites, as seen here (arrows). Importantly, look for
evidence of spinal cord compression, which is a neurosurgical
emergency.
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TB affecting other bones and joints is less common. Most
cases present with bone or soft tissue swelling, often with sinus
formation. There is no clear evidence to support the role of
surgery and drainage or sinus repair.
Abdominal tuberculosis
Gastrointestinal TB has a predilection for the terminal ileum;
thickening or ulceration in this area can easily be mistaken for
Crohn’s disease. Conversely, large bowel disease can be diag-
nosed radiologically as cancer. Complications include perfora-
tion and TB peritonitis. Diagnosis is difficult as symptoms
(abdominal pain, fevers, weight loss) are non-specific. Radio-
logical findings include bowel thickening, lymphadenopathy,
ascites, free gas suggestive of perforation, and abscess forma-
tion, but the most important diagnostic aspect is a high index of
suspicion in patients with risk factors for TB. Laparoscopic or
colonoscopic biopsies are useful for histology and culture. .
Peritoneal TB can present with either thickened, inflamed
omentum or with ascites.
Urogenital tuberculosis
Urogenital TB comprises renal disease, ureteric disease and
genital infection. The diagnosis of renal disease is easily missed,
as back or flank pain, dysuria or constitutional symptoms occur
in only 30% of patients.
Pericardial tuberculosis
Although rare (<1% of EPTB), pericardial TB merits consider-
ation because it is potentially life-threatening. TB pericarditis can
present either acutely, with massive pericardial fluid accumula-
tion causing cardiac tamponade, or subacutely with constrictive
pericarditis. In acute disease, the chest X-ray shows car-
diomegaly (Figure 3) and echocardiography reveals a large
Figure 3 Tuberculous pericarditis. Chest radiograph showing cardio-
megaly and pleural effusion.
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 BACTERIAL INFECTIONS
pericardial effusion. Aspiration/drainage may control the acute
situation, but surgical intervention (forming an open pericardial
window to prevent fluid reaccumulation) can also be required
(as well as providing tissue for histology/culture). Corticoste-
roids expedite clinical recovery and might reduce the risk of
constriction and reduce mortality.
Other forms of EPTB
Tuberculous meningitis is not discussed here as it is covered in
MEDICINE 45(11): 670e673. Other EPTB sites that merit
consideration include: TB of the larynx because of its very high
infectivity; cutaneous TB, either as primary disease, ‘scrof-
uloderma’, or local spread from adjacent affected organs; and
adrenal involvement, which, although rare, can result in acute
adrenal insufficiency or the syndrome of inappropriate antidi-
uretic hormone secretion. TB of the eye can be intraocular (most
commonly uveitis) or involve external structures; it can be
difficult to diagnose. A tuberculosis: different aspects and role of 16S-rRNA in urine. Int J
KEY REFERENCES
1 Public Health England. Tuberculosis in England: 2016 report
version 1.1. Public Health England: London.
2 World Health Organization Global tuberculosis report 2016. http://
www.who.int/tb/publications/global_report/en/ (accessed May
2017).
TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.
Question 1
A 40-year-old woman with severe psoriasis attended the rheu-
matology clinic. She fitted the criteria for commencement of
infliximab. Her only other symptom was a mild cough. She had
grown up in the UK, and her brother had had tuberculosis (TB)
as a child; she had lived and worked in India between the ages of
25 and 31 years. She had never been found to have TB. The
rheumatologist carried out screening for active and latent TB
with a chest X-ray and interferon-g release assay test, before
starting immunosuppressive anti-tumour necrosis factor (TNF)
medication.
What is the reason for TB screening?
A. She had spent time in India, a country with a high preva-
lence of TB
B. Her brother had had TB as a child so she was exposed in
childhood and might have latent TB
C. Any patient who is starting anti-TNF medication should be
screened for TB
D. She had a cough and may have active TB
E. The rheumatologist was being overcautious and the test
was not necessary
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3 National Institute for Health and Care Excellence. Tuberculosis.
NICE Guideline 33. January 2016. https://www.nice.org.uk/
guidance/ng33 (accessed Mar 2017).
4 Penz E, Boffa J, Roberts DJ, et al. Diagnostic accuracy of the Xpert
MTB/RIF! assay for extra-pulmonary tuberculosis: a meta-anal-
ysis. Int J Tuberc Lung Dis 2015; 19: 278e84.
5 World Health Organization. WHO treatment guidelines for drug-
resistant tuberculosis. 2016 update. http://apps.who.int/iris/
bitstream/10665/250125/1/9789241549639-eng.pdf?ua¼1
(accessed Mar 2017).
FURTHER READING
Butt T, Kazmi SY, Ahmad RN, Mahmood A, Karamat KA, Anwar M.
Frequency and antibiotic susceptibility pattern of mycobacterial
isolates from extra-pulmonary tuberculosis cases. J Pak Med
Assoc 2003; 53: 328e32.
Fortun J, Martín-Da!vila P, Go
! mez-Mampaso E, et al. Extra-pulmonary
Tuberc Lung Dis 2014; 18: 478e85.
Lee RS, Behr MA. The implications of whole-genome sequencing in
the control of tuberculosis. Ther Adv Infect Dis 2016; 3: 47e62.
Quddus MA, Uddin MJ, Bhuiyan MM. Evaluation of extra pulmonary
tuberculosis in Bangladeshi patients. Mymensingh Med J 2014; 23:
758e63.
Trautner BW, Darouiche RO. Tuberculous pericarditis: optimal diag-
nosis and management. Clin Infect Dis 2001; 33: 954e61.
Question 2
A 21-year-old woman presented with cervical lymphadenopathy
and night sweats. She was originally from India, and had been
resident in London for 7 years.
Investigations
% Lymph node biopsy grew Mycobacterium tuberculosis,
Xpert MTB/RIF! positive with no rpoB gene mutations
She was treated with standard tuberculosis treatment, but 6
weeks later the lymphadenopathy had worsened.
What is the next most appropriate step?
A. Repeat the biopsy for concurrent disease, e.g. lymphoma
B. Change the TB therapy to a drug-resistant regimen
C. Commence corticosteroids
D. Watch and wait
E. Check full drug sensitivities
Question 3
A 53-year-old man presented with back pain and night
sweats. He was originally from Kenya. On clinical
5 " 2017 Published by Elsevier Ltd.
 BACTERIAL INFECTIONS

examination, there was tenderness over the lower thoracic What is the most appropriate investigation to assess for
region of the back. infectivity?
A. Chest X-ray
Investigations B. Tuberculin test
% X-rays of the spine showed non-specific changes C. Interferon-g release assay
% MR scan of the spine showed an epidural abscess with no D. Three early-morning urine specimens for acid- and alcohol-
spinal cord compromise fast bacilli (AAFB)
% Aspirate from the abscess showed Mycobacterium E. Three sputum specimens for AAFB
tuberculosis

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