1

Dr MPS Chawla

MD, FIACM, FICP

•An astute clinician, a keen academician and a popular teacher.

Several Publications in Indexed journals

•Associate Editor of API Medicine Update 2009

•Associate Editor of Clinical Medicine Update 2013

•Associate Editor, journal of Indian Association of Clinical

Medicine

•Hon Gen Secretary, API Delhi State Chapter

•Member. Governing Body, API

Senior Internist PGIMER, Dr RML Hospital

New Delhi

Photogr

2

Challenges and Perspectives in The

Diagnosis of Extrapulmonary TB

Dr MPS Chawla

MD, FIACM, FICP

Senior Internist

PGIMER, Dr RML Hospital, New Delhi

3

Tuberculosis

One of the world’s deadliest communicable disease, 2nd

biggest killer among infectious agents

In 2014, an estimated 9.6 million people developed

TB(5.4 m men,3.2 m women and 1 m children ) and 1.5

million died from the disease, 360 000 of whom were

HIV-positive, 37% of new cases remained undiagnosed

or not reported. 4,80,000 cases of MDR TB

1/3 rd of world’s population infected with MTB

India—highest burden country

4

Case Definitions

Pulmonary tuberculosis (PTB) refers to a case of TB involving the lung

parenchyma.

Extrapulmonary tuberculosis (EPTB) refers to a case of TB involving

organs other than the lungs

Diagnosis should be based on at least one specimen with confirmed

M. tuberculosis or histological or strong clinical evidence consistent

with active EPTB, followed by decision by clinician to treat with full

course of TB chemotherapy

Can/should still treat presumptively if strong clinical evidence

5

Case Definitions

If several sites affected, case definition of an EPTB case depends on

the site representing the most severe form of disease.

Miliary tuberculosis is classified as pulmonary TB because there are

lesions in the lung parenchyma.

Tuberculous intrathoracic lymphadenopathy (mediastinal and/or hilar)

or tuberculous pleural effusion, without radiographic abnormalities in

the lungs, constitutes a case of EPTB.

A patient with both pulmonary and extrapulmonary TB should be

classified as a case of pulmonary TB.

6

Overview

TB can occur in any site, including:

– Lymph Nodes (most common)

– Pleura

– Bones and joints

– CNS (usually meningitis, but can occur in brain or spine)

– Larynx

– Pericardium

– Abdominal sites; Kidneys

– Genitourinary tract

– Disseminated (miliary)

7

Extrapulmonary TB

Especially common in children and people living with HIV

EPTB occurs ~15-20 % in HIV(-)

But in HIV(+), ≥ 50 %

– 33% with extrapulmonary alone

– 33% with pulmonary alone

– 33% both pulmonary and extrapulmonary

(many with negative CXRs)

8

Diagnostic Challenges

Often more difficult to diagnose EPTB--

Variable clinical presentation

Pauci-bacillary

Often occurs in inaccessible body sites

Lack of diagnostic facilities in resource-limited settings

9

Transmission of EPTB

usually not infectious, unless person has:

Concomitant pulmonary disease,

disease in the oral cavity or larynx, or

disease with open site, especially with aerosolized fluid

10

Clinical Clues to Prompt Suspicion of EPTB

Ascites with lymphocyte predominance and negative bacterial cultures

Chronic lymphadenopathy (especially cervical)

CSF lymphocytic pleocytosis with elevated protein and low glucose

Differential diagnosis of Crohn’s disease and amebiasis

Exudative pleural effusion with lymphocyte predominance, negative

bacterial cultures, and pleural thickening

HIV infection

11

Clinical Clues to Prompt Suspicion of EPTB

Joint inflammation (monoarticular) with negative bacterial

cultures

Persistent sterile pyuria

Unexplained pericardial effusion, constrictive pericarditis, or

pericardial calcification

Vertebral osteomyelitis involving the thoracic spine

12

EPTB Symptoms

Can have the same symptoms as in pulmonary TB:

– fever, night sweats, fatigue, loss of appetite, wt loss.

Complaints specific to the body site infected with TB.

– Blood in the urine (TB of the kidney)

– Headache/confusion (TB meningitis)

– Back pain (TB of the spine)

– Hoarseness (TB of the larynx)

– Disseminated (miliary) TB may have no localizing signs,

may present with anemia, or low platelets

13

Lymph Node TB

Most common—35% of cases, king’s Evil or scrofula

Predisposing factors– age under 14 yrs, Female gender, Asian ethnicity,

HIV

Commonest presentation—cervical lymphadenopathy (scrofula)—post

cervical and supraclavicular

Other common sites– mediastinal, axillary, mesentric, perihepatic and

inguinal

Classical triad of multiplicity, matting and caseation, FNA– esp useful in

HIV patients, excision biopsy

Complications—fistulisation and rupture, compression of adjacent

structures, secondary bacterial infections and local extension of TB to

skin or other organs

14

15

Pleuritis and Pleural Effusion

2nd most common site of EPTB, can occur as sequel of

primary infection or as a manifestation of TB reactivation

Rupture of sub-pleural focus into the pleural space with

inflammatory response

Symptoms: pleuritic chest pain, SOB, fever

HIV-infected more likely to have +smear/culture and

+pleural biopsy

16

Pleural TB

Resolves spontaneously, however patient at high risk of

reactivation (40-65 %)

Complications– bronchopleural fistula, empyema and fibrothorax

17

Biomarkers

Adenosine deaminase (ADA) level

Several meta- analyses show sensitivity of ADA is around 91% and

specificity 89%

– Similar performance in HIV infected

ADA ≥ 70 IU/L is highly suggestive of TB pleuritis

≤ 40 IU/L virtually rules out TB

ADA 2 is predominant isoform in TB pleural fluid—90 % of ADA activity,

ADA 1: ADA 2 ratio less than 0.45 is highly suggestive of TB

Interferon gamma—produced by CD4 T lymphocytes, high levels≥ 200 pG/L suggestive of TB

Lysozyme—Higher levels in TB than in other causes of exudative pleural

effusion

18

CNS Tuberculosis

TBM—commonest and most severe form of TB in terms of

morbidity and mortality, represents a medical emergency

Cranial nerve palsies, focal neurological deficits, impairment of

consciousness and seizures

Hydrocephalus, cerebral vasculitis and infarctions, inflammatory

encasement of nerves and direct damage to cerebral parenchyma

Crucial to suspect the disease on a clinical basis and to promptly

introduce ATT with steroids

Intracranial Tuberculomas, Spinal Tuberculous Arachnoiditis

19

Coronal T1-weighted gadolinium-enhanced magnetic resonance image demonstrates characteristic abnormal leptomeningeal enhancement (short, thick, white arrow), with intensely enhancing walls of both lateral ventricles (black arrows). High signal within the left frontal lobe represents an enhancing tuberculoma (thin white arrow). Entrapment of the left temporal horn (long, thick, white arrow) and midline shift to the right are due to the ventricular mass lesion.

20

Pericardial Tuberculosis May result in acute pericarditis, chronic pericardial effusion, cardiac

temponade or pericardial constriction

Accounts for 2/3 rd of cases of constrictive pericarditis in India

Results from direct extension from mediastinal lymph nodes or

lymphohematogenous route from a focus elsewhere

Stages– dry, effusive, absortive and constrictive

May present with fever with no localisation

Cardiomegaly on CXR PA view may be the only clue

Low voltage and shifting axis on ECG

Echocardiography

21

22

Characteristic Findings in Body Fluids in various forms

of EPTB Variable Pleural Fluid Pericardial Fluid CSF

Appearance Straw colored Straw colored or

serosanguinous

Clear early, turbid with

chronicity

pH 7.3-7.4, never more than 7.4 Not well described Not well described

Cell count

Total Count

Differential

1000-5000

50-90% lymphocytes, few

mesothelial cells

Not well described

Leucocyte count increased,

PMN preponderance early,

later mononuclear cells

predominate

100-500

PMN preponderance

early,Laterupto 95%

mononuclear

Protein Usually high

More than 2.5 g/dL

Usually high Ususally high(100-500

mg/dL), can be very high

with blockage or chronicity

Glucose Less than serum conc Low 50% of bld glucose

23

Miliary TB

Miliary TB occurs when tubercle bacilli enter the bloodstream and are

carried to all parts of the body

Wide range of presentations

May include on one extreme ARDS and on the other extreme failure

to thrive without fever

Symptoms may be dominated by whatever organ system is primarily

involved

Typical patient has a febrile wasting syndrome of 2-4 months

duration

Fulminant disease esp in primary form—septic shock, ARDS and MOF

24

25

Miliary Tuberculosis

Sputum smear is positive in about 25% of cases in both

HIV and non-HIV patients

In sputum smear negative miliary TB, bronchoscopy led to

an immediate diagnosis in 65% and this increased to 79%

with culture

26

Bone TB

Pott’s spine-commonest site- thoracic spine and thoracolumbar junction

Occurs as a result of hematogenous transmission

Local pain, swelling and limitation of joint movement may precede

radiological changes by 4-8 wks

Structural damage to the skeleton may produce deformities and

compression of nerve roots and spinal cord

Affected bone may fracture and may produce spinal cord compression

Untreated TB may involve adjacent soft tissues and epidural space

Vertebral abscess may travel along psoas muscle- Psoas abscess

Extraspinal tuberculous osteomyelitis, Poncet’s

27

28

Genitourinary Tuberculosis MTB reach kidneys, epidydimis or female genital organs via

hematogenous spread

Peak incidence in females of age 20-40 yrs

Risk factors– male gender, HIV infection, hemodialysis and ESRD,

recipients of renal transplant

Kidneys- most common site of GU TB

Renal TB—Symptoms—urinary frequency, urgency, dysuria and nocturia

Urine– classical triad of hematuria, proteinuria and sterile pyuria

29

Urogenital Tuberculosis

Male genital tract TB—acute epidydymitis or

epidydmoorchitis-may cause caseation and fistula,

chronic prostatitis and extensive scarring of

epidydmus, ejaculatory ducts and seminal vesicles

leading to male infertility

30

Female GU TB

May present with infertility, menstrual irregularities and chronic pelvic or

lower abdominal pain

Fallopian tubes—most commonly affected, followed by endometrium,

ovaries and cervix

Tubo-ovarian abscesses and adnexal masses mimicking ovarian cancer

mostly in presence of peritoneal involvement and when serum levels of

CA-25 marker are raised

Requires a high index of suspicion

31

A 75-year-old woman with ureteric tuberculosis. (A) Retrograde pyelogram image demonstrates irregularity of the ureter and absence of contrast in the strictured distal portion (arrow). (B, C) Contrast-enhanced computed tomography image in the portal venous phase of the same patient demonstrates rightsided hydronephrosis (arrow, B) caused by stricturing and thickening of the distal ureter (arrow, C).

32

A 30-year-old woman who presented with fever of unknown origin,later found to have tuberculous peritonitis and salpingitis. Contrast-enhanced computed tomography image in the portal venous phase demonstrates massive ascites (23 HU), diffuse peritoneal enhancement (black arrow), omental caking (thin white arrow), and nodular soft-tissue thickening (thick white arrow).

33

34

Gastrointestinal TB

20-40 years age group

Slight female preponderance

Pain abdomen, abdominal distension, wt loss, diarrhea

constipation, bleeding P/R

Signs- anemia, malnutrition, abdominal

tenderness,ascitis,mass in right iliac fossa, intestinal

obstruction

Classic doughy abdomen– 5-10 %

35

Peritoneal TB

Results often from the re-activation of latent peritoneal TB foci

Classical risk factors --HIV infection, cirrhosis and CAPD; diabetes

mellitus, underlying malignancy and therapy with anti-TNF agents

Ascitic fluid is exudative, with a SAAG ≤ 1.1 g/dl and leukocyte count

variable from 150 to 4000/mm3 with a lymphocytic predominance,

although neutrophyllic pleocytosis can be seen in cases undergoing

peritoneal dialysis

36

investigations

Abdominal lymphadenopathy-retroperitoneal, peripancreatic, porta

hepatic and mesentric-on CT

Caseous lymph nodes appear as low attenuating necrotic centres with

thick enhancing inflammatory rim

Preferential thickening of medial caecal wall with exophytic mass

engulfing terminal ileum associated with massive lymphadenopathy—typical of TB

Short segments of mural thickening with normal intervening bowel

associated with ileo-caecal involvement

37

Investigations

Colonoscopy- edematous, deformed ileocaecal valve

with both sides diseased, ulceration, girdle strictures

FNAC, Biopsy

Laproscopy—multiple yellowish white miliary nodules

over peritoneum, erythematous, thickened, hypremic

peritoneum

38

TB of Adrenal Glands

5th most common site of EP TB, after the liver, spleen, kidneys, and bones

In 6% of patients with active TB and is nearly always b/L, The gland

becomes enlarged and demonstrates rim enhancement and central low

attenuation consistent with caseous necrosis.

Patients may present with an Addisonian-type clinical picture.

A 60-year-old woman with adrenal tuberculosis. Contrast enhanced computed tomography image in the portal venous phase demonstrates right adrenal enlargement, rim enhancement and central low attenuation

consistent with caseous necrosis (arrow).

39

Cutaneous Tuberculosis

Lupus vulgaris

Scrofuloderma

Tuberculous verrucosa cutis

Tuberculids- erythema nodosum,

erythema induratum

Prosector’s warts

40

Ocular Tuberculosis

41

TNF alpha Inhibitor Associated Tuberculosis

Seen in patients with RA or Crohn’s disease after t/t

with TNF alpha inhibitors, especially infliximab

EPTB in 52-57 %

Patients should be screened for latent tuberculosis

infection or active disease before initiation of therapy with

a TNF-alpha inhibitor.

42

Microscopy

Direct visualization of AFB-- the first microbiological test to be performed

ZN staining/ Kinyoun staining, low sensitivity

Light emitting diode (LED) technology --cheaper and viable alternative to

Ziehl–Neelsen microscopy and to fluorescence microscopy based on

mercury vapor or halogen lamps, 10%more sensitive, 1/4th time

In some cases, concentration of large volumes of sampled fluid(CSF,

ascites, etc.) and repeated analyses can increase the diagnostic yield

Microscopy, as well as culture, may be affected by the rapid mycobacterial

killing operated by some antibiotic agents like fluoroquinolones, resulting

in false-negative results

43

IGRAs

based on the assessment of the IFN-g released after stimulation of

sensitized T-cells by highly MTB-specific antigens, including ESAT 6 and

CFP10,

two commercially available IGRAs: QuantiFERON-TBGold In Tube assay

(QIAGEN corp., Hilden, Germany), which utilizes an ELISA technique to

measure the amount of IFN-g secreted, and the T.SPOT-TB (Oxford

Immunotec, Abingdon,UK), which uses an ELI Spot assay to quantify the

number of IFN-g-producing cells

cannot distinguish between latent infection and active TB; therefore, they

are not suited to diagnose active TB.

Next generation tests--Dual cytokines-Interferon gamma and IL 2

44

Culture

Most sensitive diagnostic test, with a lower limit of detection of 10 bacilli/mL of

sputum

Liquid culture --mainstay for the diagnosis of EPTB., BACTEC MGIT 960 based

on modified Middlebrook 7H9 Broth with an oxygen-sensitive fluorescent

detection technology , Capilia TB—rapid speciation strip test-MPB 64 antigen,

15 min

Solid cultures on the egg-based Lo¨wenstein–Jensen medium

advantages of liquid culture --sensitivity, identification of Mycobacterium

species and to perform phenotypic DSTs as well as genotyping

Main drawback is the time needed for mycobacteria to grow

Samples from biopsy or FNA may be submitted for analyses in incorrect

media (e.g., formalin) or insufficient volume,

45

Immunohistochemistry & Immunocytochemistry

Can detect degraded AFB

Can detect different mycobacterial antigens in formalin

fixed paraffin embedded tissue, tissue aspirate and body

fluids e.g. BCG, MPT64, Antigen 5 (38kDa), LAM, ESAT6,

HspX, Tb8.4, and the phospholipase C encoding A (PlcA)

protein

Can be applied to extrapulmonary specimens

High sensitivity (70-100%) & high specificity (65-100%)

Performs equally well in HIV co-infected patient

Results within 1 day, insensitive to contamination

Disadv—invasive tissue sample collection and preparation

46

Nucleic Acid Amplification Tests

The Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay is the first

automated and standardised NAAT assay

results within two hours and performs a RT PCR in a platform that is polyvalent

Xpert had 88% sensitivity against all cases of tuberculosis, ranging from 98%

in smear-positive to 68% in smear-negative culture-positive cases and 98%

specificity

The sensitivity in people with HIV was 80% identifying 30% more cases than

smear microscopy

WHO reviewed about 20 relevant studies concerning the use of the Xpert

MTB/RIF system for the diagnosis of EPTB-- for lymph nodes sensitivity was

84.9% and specificity 92.5%, for gastric fluid 83.8 and 98.1% respectively, for

tissue 81.2 and 98.1%, respectively, and for CSF 79.5 and 98.6%, respectively.

47

Gene Expert MTB/RF RIF-positive assays need to be confirmed by another

method.

Requires stable electricity, a backup system and space for

storage of cartridges at temp below 28°C

Initial diagnostic test in individuals suspected of having

MDR-TB infection, in HIV-associated TB and as a follow-up

test in patients with negative smear-microscopy in

settings where MDR-TB and HIV are infrequent

GeneXpert Omni—smaller, lighter,less expensive, 4 hr

battery

Xpert Ultra—next generation cartridge, will replace culture

48

MODS Assay

High sensitivity -- 92% to 97.5%

An inverted microscope with automated reader software

is used to see cording

faster results (7-10 days)and is considerably cheaper than

liquid culture

49

loop-mediated isothermal amplification (LAMP) assay

Results available within two hours, and sensitivity and specificity is said to

range from 88% to 100% and 94% to 99%, respectively

A multipurpose platform, the NATeasy, is being developed in China and

integrates NAAT in disposable, contamination-proof devices .

A joint initiative of the Indian government, academia and industry is

developing TrueLab, which is a multipurpose platform for real-time PCR. The

platform is hand-held and battery-operated and combines a simplified sample

preparation device

50

Line Probe Assays

LPAs use multiplex PCR amplification and reverse

hybridisation to identify M. tuberculosis complex and

mutations to genes associated with rifampicin and

isoniazid resistance.

In culture isolates, LPAs can attain high sensitivity and

specificity to detect rifampicin (≥ 97% and ≥ 99%) and isoniazid resistance (≥90% and ≥99%) and provide results

in one to two days

MTBDR and Genotype MTBDR plus

NTM+MDRTB Detection Kit 2 (Nipro Corporation,

Japan) and GenoType® MTBDRplus V2 assay

51

Serological Tests

very poor sensitivity or specificity, and that they have no

clinical value.

Indian Govt has banned them.

52

Lipoarabinomannan-Based Assays

(LAM) is a cell envelope glycolipid released from metabolically active

mycobacteria that can be detected and quantified in urine

LAM is excreted more readily in patients with advanced HIV infection, and that

the assay could be a rule-in test for adults with disseminated tuberculosis

WHO recommends to use it for diagnosis in people with HIV with low CD 4

counts and those who are seriously ill, not to be used for screening

Determine TB LAM 20 minutes to perform

53

GBD TB REaD™ POC (Enzymatic detection M.

tuberculosis β-lactamase reporter assay)

54

Pipeline of molecular diagnostics for tuberculosis, by level of deployment (ie, reference, intermediate, and peripheral microscopy laboratories).

Madhukar Pai, and Marco Schito J Infect Dis. 2015;211:S21-S28

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

55

Take Home Points

EPTB-Not uncommon, especially in HIV-infected persons

High index of suspicion, always include in D/D

Difficult to diagnose as it can mimic many diseases, is paucibacillary

and limited diagnostics in some countries

Respiratory isolation key until PTB ruled out

Treat it like you would pulmonary TB, except:

– Steroids in meningeal and pericardial disease

– Longer treatment in bone/joint TB, TB meningitis, disseminated TB

56