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TUBERCULOSIS
RECENT ADVANCES
PRESENTATION BY
Dr . M. Vijay Kumar
INTRODUCTION :
• TB can affect any place in the body .
• Extrapulmonary TB - Worldwide 10 to 25% .
• Especially common in people living with HIV and in
children .
• Abdominal TB is a(3rd) very common type of EPTB.
• Gastrointestinal TB- 2nd most common type of
abdominal TB. (1643- autopsy on Louis XIII )
• The most common site of involvement is the ileocaecal
region (approximately 90%), possibly because of the
a. increased physiological stasis,
b. increased rate of fluid and electrolyte absorption,
c. minimal digestive activity,
d. an abundance of lymphoid tissue at this site
e. bacteria contact time with mucosa is more
f. liquid content in the region.
• Intestinal TB is prevalent in developing countries like
India due to low living standards and poor literacy.
• In 2010,there were about 2 million cases reported
from India.
• Most cases of intestinal tuberculosis is caused by
mycobacterium tuberculosis.
• Mycobacterium Bovis has become rare.
• M. Avium is a major pathogen in HIV positive patients.
The 4 routes of infection in intestinal TB are :
(1) Hematogenous from primary pulmonary focus.
(2) Swallowing of infected bacilli from active pulmonary
TB.
(3) Local spread from adjacent viscera.
(4) Ingested milk.
• Hypersegmentation of
small intestine
(chicken intestine)
Multiple strictures with
enormous dilatation of Straightening of ileocaecal junction
with ‘goose neck’ deformity.
proximal ileum (mega ileum)
• In patients with esophageal tuberculosis, the common
radiological features include ulceration, stricture,
pseudosinus tract formation and traction
diverticulum.
• In duodenal tuberculosis, barium study may reveal
segmental narrowing. The widening of ‘C’ loop of
duodenum may occur due to tubercular
lymphadenitis.
• Ultrasound :
• Beneficial in extraintestinal (peritoneal, lymph nodes)
tuberculosis.
• The USG of abdomen may show a mass of matted
loops of small bowel with thickened walls (hypoechoic
halo measuring >5 mm), rolled up or diseased
omentum, and loculated ascites.
• Interloop ascites due to localized collection of fluid
between radially-oriented bowel loops - Club
sandwich or Sliced bread sign.
• Bowel loop radiates from its mesenteric root—
stellate sign.
• Mesenteric thickness more than 15 mm.
• Pulled up caecum presenting with a mass in
subhepatic region and also sonologically visible-
“pseudokidney sign”.
TB Findings Differential diagnois
Tubercular ascites Fine septae (due to high fibrin Malignant ascites
content ), echogenic debris
( fine strands)
Peritoneal Peritoneal thickening and Mesothelioma, peritoneal
tuberculosis nodularity, carcinomatosis, and
Omental cakes sometimes septic
peritonitis and
hemoperitoneum
Tubercular conglomerate mass and/or as Metastatic
lymphadenitis scattered enlarged nodes with lymphadenopathy,
(mesenteric, peri- hypoechoic center because of Lymphoma(lower aortic
pancreatic, periportal necrosis . nodes)
and para-aortic)
• Lastly ultrasound is also helpful for guiding procedures
like
1.ascitic fluid aspiration or
2.fine needle aspiration cytology or biopsy from the
enlarged lymph nodes or hypertrophic lesions.
Computed Tomography (CT) : Abdominal CT scan is
better than ultrasound for detecting
• high density ascites,
• lymphadenopathy with caseation, (commonest
manifestation of tuberculosis on CT).
• bowel wall thickening and
• irregular soft tissue densities in the omental area.
• Loculated fluid collections
• transperitoneal reaction, i.e. septal, and mesenteric
(macronodules >5 mm in diameter)
• Contrast enhanced CT (CECT)
is better than plain CT,
though not pathognomic, the
pattern of peripheral rim
enhancement could be
highly suggestive of
tuberculosis.
• A similar pattern is seen in
metastatic
lymphadenopathy.
• High density ascites due to high protein and cellular
contents of fluid though common in tuberculosis, but
can also be seen on CT in mesothelioma and
peritoneal carcinomatosis.
• Differentiation:
Tuberculosis - smooth peritoneum with minimal
thickening and marked enhancement.
Peritoneal malignancy - nodular and irregular
thickening of peritoneum.
• The most common CT finding of bowel wall
involvement is a mural thickening affecting the
ileocaecal region either limited to terminal ileum,
caecum or both the regions.
• The tuberculosis of the pancreas may produce
multiple well defined hypoechoic areas on USG and as
hypodense necrotic regions on CT.
• Tuberculosis of the liver and spleen may appear as tiny
low density foci on CT widely distributed throughout
the organ.
• There is a hepatosplenomegaly with areas of
calcification within them. 1-3 cm round lesions or
simple tumor like masses. These lesions may show
peripheral enhancement on CECT.
Microscopy :
Light emitting diodes (LED) have been developed to
offer benefits of fluorescent microscopy without the
associated costs. Sensitivity of 78%,specificity of 92%
for pulmonary lesions.34%,88% for extrapulmonary
lesions.
• The mean time per smear examination 1.41 minute for
LED microscopy as compared with 2.48 minute for ZN
stain.
Culture :
• BACTEC MGIT 960 is fluorescent signalling system for
early detection of growth.
• It provides an early recovery of mycobacterium with in
10days compared to 24 to 28 days by conventional
culture methods.
• Drug susceptibility can be checked in shorter time
span.
• But high cost and limited availability.
MODS (microscopic observation drug susceptibility):
• Rapid and accurate detection of mycobacterium and simultaneous
drug susceptibility testing.
3 Principles:
• Grows faster in liquid medium
• Characteristic cord formation can be visualized microscopically
• Incorporation of drugs permits repid and direct drug susceptibility
testing concomitantly with bacterial growth.
Advantage: Inverted light microscope
Disadvantage : bacterial contamination especially aerobic spore
bearers due to highly enriched medium.
Antigen detection test :
• Mostly used target antigen Lipoarabinomannan.
• Sensitivity and specificity pulmonary TB 2-100%, 33-
100%,extrapulmonary 0-100%,62-100%.
• Sensitivity of urine LAM is higher in HIV infected than
HIV uninfected individuals.
Serodiagnosis:
• Conventional histological and microbiological methods
are often inadequate for the diagnosis of abdominal
tuberculosis as it is a paucibacillary disease.
• A number of serological tests based on the detection
of antibody to a variety of mycobacterial antigens
developed but all of them have a low predictive value.
• Polymerase chain reaction (PCR) assay for detection of
M. tuberculosis in endoscopic biopsy specimens has
shown promising results.
• PCR can detect 1-2 organism or 8fg of mycobacterial
DNA.
• Positive PCR signifies infection but need not be active
disease.
• Various targets are used -38kDa, devR , IS6110,
MPB64.
Endoscopy :
• Endoscopy visualizes the tubercular lesion directly,
hence, is a useful tool in the diagnosis of colonic and
gastro-duodenal tuberculosis; and helps in the
confirmation of the diagnosis by obtaining
histopathological evidence of tuberculosis.
• Tuberculosis of the colon involves discrete segments
of the colon and produces mucosal nodules and ulcers
of varying sizes which are pathognomonic.
• Other colonoscopic findings include hyperemic friable
mucosa, pseudopolyps and cobblestone appearance of
the mucosa simulating Crohn’s disease and
malignancy.
• The findings on endoscopy of ileum include
submucosal granulomas in all cases from which biopsy
may be taken for confirmation of the diagnosis.
• Endoscopic biopsy specimen may be subjected to PCR
for detection of AFB.
Colonic tuberculosis.
Note the multiple colonic
ulcers and nodules on
colonoscopic view
Laparoscopy :
• Laparoscopy examination is an effective method of
diagnosing tubercular peritonitis because (i) it directly
visualizes the inflamed thickened peritoneum studded
with whitish-yellow miliary tubercles and (ii) biopsy of
the peritoneum confirms the diagnosis.
• Accurate diagnosis in 80-90% of patients.
• Laparoscopic biopsy specimens may reveal AFB in 75%
patients and caseating granulomas in 85-90% patients.
• The finding of adhesions or fibrotic strands within
turbid ascites is virtually diagnostic of tuberculosis.
• The liver, spleen and omentum also studded with
tubercles in hepatosplenic tuberculosis.
• Laparoscopy through open exposure of the
peritoneum may be employed in patients with
fibroadhesive peritoneal tuberculosis so as to avoid
chances of perforation.
Ascitic Tap (Paracentesis)
• The ascitic fluid in tuberculosis is exudative (protein >3
g%) with serum-ascites albumin gradient <1.1 g%.
• Ascitic fluid WBC count is 150-4000 cell/mm3 and
consists of predominant lymphocytes.
• Ascitic fluid reveals AFB only in <3% of the cases and
culture for M. tuberculosis is positive only in 20% of
patients.
• Adenosine deaminase (ADA) activity in ascitic fluid is a
sensitive and specific marker for tuberculosis.
• ADA is an enzyme present in T-lymphocytes and
macrophages.
• Sensitivity and specificity of 100 and 97% respectively
when the cut off value of 33U/L in ascitic fluid was
taken. (more than 42 IU/litre in serum is significant.)
• Ascitic fluid to serum ADA ratio >0.985 .
• Falsely low levels -in immunocompromised individuals.
• Interferon-γ (INF-γ) is an important immuneregulator,
is produced by T-lymphocytes .
• Capable of activating the macrophages, increasing their
bactericidal activity against M. tuberculosis.
• High levels of INF-γ have been found in ascites due to
tuberculosis than nontubercular.
• FDA approved Enzyme- Link ed Immunospot Assay
(ELISPOT)for measuring gamma.
• Quantiferon-TB gold (QFT-G) is a blood test that uses
an interferon gamma release assay that measures the
release of interferon gamma after stimulation in vitro
by M. tuberculosis antigens.
• IGRA (112 pg /mL for IFN-gamma) for the diagnosis of
ITB was sensitive 81%,specific 85%.
• Combining both ADA and INF-γ estimation in ascitic
fluid increase the sensitivity and specificity of the
diagnosis of tubercular ascites.
Nucleic Acid Amplification:
• Used to amplify the quantity of M. tuberculosis DNA in
diagnostic specimens.
• where organisms may be present in amounts too small to
be seen by routine staining techniques.
• Two NAA tests were approved by the United States Food
and Drug Administration as of 2012, but only for use with
sputum or respiratory secretions obtained by bronchoscopy.
• However in 2014 guidelines issued by the WHO the Gene
Xpert has been validated for the extra pulmonary TB too.
GeneXpert Assay :
• The Gene Xpert MTB RIF assay is an automated
nucleicacid amplification test that can simultaneously
identify M.tuberculosis and rifampin resistance.
• Standards for TB care in INDIA WHO 2014: For all EPTB,
appropriate specimens from the presumed sites of
involvement must be obtained for microscopy/ culture
and drug sensitivity testing (DST)/CB-NAAT/molecular
test/ histo-pathological examination.
MTBDR Plus :
• It is a molecular probe capable of detecting rifampicin and
isoniazid resistance mutations (rpoB gene for rifampicin
resistance; katG and inhA genes for isoniazid resistance).
• Since the assay does not depend on culture, it yielded
results even in specimens that were contaminated or had no
growth.
• Molecular testing was successful even when the AFB smear
was negative. Use of the assay can reduce time to initiation
of therapy for MDR-TB.
Soft Tissue Biopsy and Culture :
• Invasive diagnostic procedures are indicated with
suspected abdominal tuberculosis.
• In addition to specimens of involved sites (lymph
node, intestine, peritoneum, liver biopsy), bone
marrow aspiration for culture may be useful and have
a good diagnostic yield in disseminated (military)
tuberculosis particularly in HIV infected patients.
• Diagnostic Algorithm :
• Neither clinical signs, laboratory, radiological and
endoscopic methods nor bacteriological and
histopathological findings provide a gold standard by
themselves for the diagnosis of abdominal TB, hence,
an algorithmic approach is useful.
• Other supportive investigations are done based on the
clinical features and imaging.
• Flow chart 1: Algorithmic approach to diagnosis of abdominal tuberculosis
• Treatment
• The treatment of abdominal tuberculosis is on the
same lines as for pulmonary tuberculosis.
• Conventional antitubercular therapy for at least 6
months including initial 2 months of HREZ (e.g.
isoniazid, rifampicin, ethambutol and pyrazinamide)
followed by 4 month HR is recommended in all
patients with abdominal tuberculosis.
DRUGS MECHANISM of DOSE Hepatotoxicity,
action (mg/Kg ) S/E
ISONIAZID (H) Inhibits 5 O2 dependent pathway. Inhibits MAO-A. Yes. Peripheral
ketoenoylreductase Single most important drug. neuritis,cheese
(inh A). Metabolised by Acetylation. reaction,lupus like
Bactericidal and static Cross resistance with E (KatG). syndrome,anaemia,optic
atrophy,gynaecomastia.
RIFAMPICIN (R) Inhibits DNA 10 Enterohepatic circulation, only Yes. hyperbilirubinemia
dependent RNA bactericidal against dormant bacteria in without SGOT elevation.
polymerase. caseous lesion. Eliminated mainly in feces. Orange discolouration of
Most effective and fastest acting drug in urine and secretions. drug
Bactericidal leprosy. Inducer of drug metabolising interactions (OC pills, Anti
enzymes. coagulants,ART).
PYRAZINAMIDE Intracellular only. 25 Active in Acidic media – intracellular and Yes. Non gouty arthralgia.
(Z) inflammation sites Hyperuricemia,
Bactericidal porphyria,photosensitivity
ETHAMBUTOL Inhibits arabinosyl 15 Not cross BBB as streptomycin. NOT hepatotoxic.
(E) transferase. Contraindicated in children. Optic neuritis, dose
Bacteriostatic adjustment renal failure.
STREPTOMYCIN Extracellular only. 15 Not absorbed orally. I.M injection. NOT hepatotoxic.
(S) Bactericidal Contraindicated in pregnancy Ototoxic.
Second line drugs :
• Thiacetazone – static ,SJS - C/I in HIV, Bone marrow suppression.
• Para amino salicylic acid (PAS) – kidney, liver, thyroid disfunction.
• Ethionamide – used in leprosy. Hepatitis, optic neuritis,
hypothyroidism.
• Cycloserine – neuropsychiatric side effect.
• Kanamycin, amikacin – injectable aminoglycoside.
• Capreomycin – injectable polypeptide.
• Fluoroquinolones – Ofloxacin, Moxifloxacin ,Levofloxacin
• Newer Macrolides – Azithromycin,Clarithromycin….effective against
MAC.
• Linezolid
• RIFABUTIN :
• Less effective against TB
• More effective against MAC
• Longer acting (half life)
• Less potential to induce microsomal enzymes
• Donot reuire dose adjustment in liver disease
• Prefered in patients on anti-HIV drugs.
• GIT side effects, anterior uveitis, polymyalgia syndrome, pancytopenia, pseudo
jaundice.
• BEDAQUILINE:
• Inhibitor of mycobacterial ATP synthase.
• Indicated as a part of MDT. Causes QT prolongation.
• Corticosteroids have been employed to decrease
fibrosis during healing so as to prevent development of
obstruction but now-a-days, not preferred as they may
delay healing and predispose to perforation or further
obstruction.
• Studies have now shown that even obstructing
intestinal lesions can be successfully treated with
antitubercular drugs without the need for surgery and
complete resolution of radiological abnormalities may
occur.
Indications for surgery :
• Intestinal obstruction.
• Severe haemorrhage.
• Acute abdominal presentation like perforation.
• Intraabdominal abscess formation or fistula
formation.
• Uncertain diagnosis.
Strictures are managed by stricturoplasty or
resection of the involved segment of the bowel.
• The perforation is managed by resection and
anastomosis rather than by simple closure so as to
avoid fistula formation.
• Bypass surgery such as enteroenterostomy,
ileotransverse colostomy is not recommended for
obstructive lesions as they may cause formation of
blind loops leading to obstruction, fistulation,
malabsorption etc.
Treatment of HIV Co-existent Tuberculosis
• The key therapeutic principles :
1. ATT should precede HAART.
2. Already on HAART - appropriate modifications in
HAART and ATT.
3. Not receiving HAART – depend on CD4 count and
type of TB.
• In HIV-infected patients with TB, DOTS should be
initiated with isoniazid, rifampicin, ethambutol and
pyrazinamide (HREZ) for first two months followed by
isoniazid and rifampicin (HR) for subsequent 7 months.
• Principles of ATT in the setting of HIV positive TB are
identical to those for HIV-negative cases with two
exceptions.
• Since rifampicin resistance is common in HIV patients if
CD4 count is <100/mm3, therefore, first exception, is
that treatment regimen should be daily or thrice a
week instead of twice a week DOTS during the
continuation phase.
• Second exception is that the continuation phase
should be extended to 7 months, so as to make it a
regimen of 9 month duration for HIV-TB patients.
• Adverse reactions to both ATT and antiretroviral
therapy are common, need to be carefully monitored.
• Immune restoration syndrome or immune
reconstitution inflammatory syndromes (IRIS) have
been reported in 32- 36% of patients with HIV-TB
infection, within days to weeks after start of ART.
• Fever, lymphadenopathy, worsening pulmonary
infiltrates, serositis, skin lesions, new or expanding CNS
mass lesion, ARF and ARDS can occur as manifestations
of IRIS.