Escolar Documentos
Profissional Documentos
Cultura Documentos
During the year long Centenary Celebrations of the IJMR (from July 2012 to July 2013) 13 top articles
published during the last five decades in the IJMR and ranked 1-13 on the basis of number of citations received,
will be reproduced one in each issue under the Section Most Cited Articles.
This issue carries an article ranked 8 and was published in 2004, and received 80 citations.
[Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res. 2004 Oct;120(4):316-53]
Review Article
Extrapulmonary tuberculosis
S.K. Sharma & A. Mohan*
Department of Medicine, All India Institute of Medical Sciences, New Delhi & *Department of Emergency
Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India
Received September 25, 2003
Extrapulmonary involvement can occur in isolation or along with a pulmonary focus as in the
case of patients with disseminated tuberculosis (TB). The recent human immunodeficiency virus
(HIV) and acquired immunodeficiency syndrome (AIDS) pandemic has resulted in changing
epidemiology and has once again brought extrapulmonary tuberculosis (EPTB) into focus.
EPTB constitutes about 15 to 20 per cent of all cases of tuberculosis in immunocompetent patients
and accounts for more than 50 per cent of the cases in HIV-positive individuals. Lymph nodes
are the most common site of involvement followed by pleural effusion and virtually every site
of the body can be affected. Since the clinical presentation of EPTB is atypical, tissue samples
for the confirmation of diagnostic can sometimes be difficult to procure, and the conventional
diagnostic methods have a poor yield, the diagnosis is often delayed. Availabiity of computerised
tomographic scan, magnetic resosnance imaging laparoscopy, endoscopy have tremendously
helped in anatomical localisation of EPTB. The disease usually responds to standard
antituberculosis drug treatment. Biopsy and/or surgery is required to procure tissue samples for
diagnosis and for managing complications. Further research is required for evolving the most
suitable treatment regimens, optimal duration of treatment and safety when used with highly
active antiretroviral treatmenrt (HAART).
Key words Abdominal tuberculosis - bone and joint tuberculosis - disseminated tuberculosis - extrapulmonary tuberculosis genitourinary tuberculosis - laryngeal tuberculosis - lymph node tuberculosis - miliary tuberculosis - neurological tuberculosis pericardial tuberculosis - tuberculosis in otorhinolaryngology - tuberculosis meningitis - tuberculosis pleural effusion
Epidemiology
In the era before the human immunodeficiency
virus (HIV) pandemic, and in studies involving
immunocompetent adults, it has been observed that
EPTB constituted about 15 to 20 per cent of all cases
of TB (Fig.1a)1,5-13. In HIV-positive patients, EPTB
accounts for more than 50 per cent of all cases of
TB (Fig.1b)14-22. The diagnosis of EPTB, especially
316
317
318
Fig.1a. Distribution of tuberculosis cases by anatomical site in HIV-negative patients. Data derived from references 3,5,6,10,11.
PTB, pulmonary tuberculosis; EPTB, extrapulmonary tuberculosis; GUTB, genitourinary tuberculosis; MTB, miliary tuberculosis;
TBM, tuberculosis meningitis; ABD, abdominal tuberculosis; LNTB, lymph node tuberculosis.
Fig.1b. Distribution of tuberculosis cases by anatomical site in HIV-positive patients data derived from references 14-22.
PTB, pulmonary tuberculosis; EPTB, extrapulmonary tuberculosis; LNTB, lymph node tuberculosis.
319
320
Fig.2. Contrast enhanced computerized tomographic (CECT) scan of the chest of a young woman who presented with low grade
fever for 3 months, cough and dysphagia showing subcarinal (a) and right hilar (b) lymph nodes. Arrows points to hypodensity
which indicates necrosis in the lymph node. CECT scan of the abdomen of the same patient showing bilateral psoas abscesses
(c) (arrows). Coronal reconstruction of the CECT scan of the abdomen of the same patient showing bilateral psoas abscesses
(d) (arrows). CT guided fine needle aspirate from the psoas abscess revealed numerous acid-fast bacilli.
321
322
323
Fig.3a and 3b. Chest radiograph (postero-anterior view) of a patient with tuberculosis pericardial effusion showing a globular
heart shadow (a) before treatment. Chest radiograph taken 9 months after antituberculosis treatment (b) reveals considerable
resolution of the pericardial effusion.
324
Fig.3c, 3d and 3e. Contrast enhanced CT scan of the chest of a patient with constrictive pericarditis showing thickened pericardium
(black arrow) and dilated right atrium (white arrow) (c). Right and left ventricular pressure tracings (paper speed 100 mm/sec and
100 mm Hg gain) of the same patient showing markedly elevated and equal diastolic pressures with mild elevation of right ventricular
systolic pressure (45 mm Hg) (d). Operative photograph showing thickened pericardium (e).
325
Fig.4. Magnetic resonance imaging (MRI) scan of the dorsolumbar spine, (sagittal view, T1 weighted image) showing central
hypointense lesion (arrow) with reduced vertical height of the vertebra (a). MRI scan of the dorsolumbar spine (sagittal view, T2
weighted image) showing destruction of D10 and D11 vertebrae (arrow), reduction in the intervening disc (inset, arrow) with
anterior granulation tissue and cord compression (b).
326
Genitourinary tuberculosis
327
328
329
330
Histopathological, cytopathological
and
microbiologial examination of tissue specimens
and body fluids
74-98
Pleural effusion
73-93
75,180,182-184
58-100
Pericardial 115,190
75-100
Cutaneous tuberculosis
133
DTB/MTB 156,166,169,180,191
Numbers in superscript indicate reference numbers
DTB, diseminated tuberculosis
MTB, miliary tuberculosis
67
21-62
331
Sharma
et al160
Prout and
Benatar 191
Biehl 169
Kim et al165
Cumulative
yield (%)
Sputum
29/75
10/88
31/39
13/26
25/33
41.4
Bronchoscopy
38/95
2/37
3/3
ND
12/19
35.7
Gastric lavage
7/11
ND
ND
20/35
6/8
61.1
CSF
14/44
ND
1/31
15/45
0/26
20.5
Urine
5/28
ND
3/17
7/29
18/27
32.0
Bone marrow
18/22
3/11
20/21
ND
9/22
58.1
Liver biopsy
11/11
6/9
12/13
ND
11/12
88.9
9/9
16/19
ND
3/3
ND
90.3
Variable
*Data are shown as number positive/number tested. Criteria for subjecting the patients to these tests not clearly defined in any of
thestudies. Often, more than one test have been performed for confirming the diagnosis. For histopathological diagnosis, presence of
granulomas, caseation and demonstration of acid-fast bacilli have been variously used to define a positive test
yield from smear and culture
includes yield from bronchoscopic aspirate, washings, brushings, bronchoalveolar lavage and transbronchial lung biopsy
yield from aspiration and/or trephine biopsy
CSF, cerebrospinal fluid; ND, not described
Superscript numerals denote reference numbers
Table III. Characteristic body fluid findings in patients with various forms of extrapulmonary tuberculosis
Variable
Pleural fluid
Pericardial fluid
Cerebrospinal fluid
Appearance
Straw coloured
Straw coloured or
serosanguinous
Clear early;
Turbid with chronicity
pH
7.3-7.4
Rarely <7.3
Never >7.4
1000-5000
50-90% lymphocytes,
eosinophils <5%
Few mesothelial cells
100-500
Rarely >1000
PMN preponderant
early. Later, up to 95%
Mononuclear
Protein
Usually high
Glucose
Low
Cell count
Total count
Differential
count
Cytology
332
Table IV. Yield of various tissues and body fluid specimens by the conventional smear and culture methods in patients with
extrapulmonary tuberculosis
Variable
Pleural fluid
Pericardial fluid
Cerebrospinal fluid
Smear microscopy
< 10%
< 1%
5-37%
Mycobacterial culture
12-70%
25-60%
40-80%
Fig.6. Chest radiograph (postero-anterior view) showing left sided encysted pleural effusion (a) Contrast enhanced CT scan of the
chest of the same patient (b) showing left sided loculated empyema surrounded by thick enhancing pleura (arrow).
333
Fig.7. Chest radiograph (postero-anterior view) showing classical miliary pattern (a). Contrast enhanced CT scan of the chest (b)
showing classical miliary pattern. Branching nodular (2 to 3 mm) and linear opacities resulting in a tree-in-bud appearance can
also be discerned. These nodules resemble millet seeds (c).
Fig.8. Intravenous pyelogram showing calyceal cut-off sign black arrow and ureteral narrowing (white arrow) (a) thimble bladder
(black arrows) (b). Percutaenous nephrogram showing irregularity, narowing and stricture of ureter (white arrow) (c).
334
335
336
Fig.14. Contrast enhanced MRI of the brain (sagittal view, T1 weighted image) showing intramedullary enhancing ring lesion
(arrow) opposite C6 vertebral body (a) before treatment. The lesion resolved completely following nine months of antituberculosis
treatment (b).
337
338
Table V. Sensitivity and specificity of immunodiagnostic and molecular methods applied to the pleural fluid and
cerebrospinal fluid
Diagnostic method
Pleural fluid
Cerebrospinal fluid
ELISA:
Detection of antibody in the fluid
Sensitivity
Specificity
Detection of antigen in the fluid
Sensitivity
Specificity
0.22 - 0.68a
0.90 -1.00a
0.60 - 0.90b
0.58 - 1.00b
0.48 - 1.00c
0.98 - 1.00c
0.61 - 0.79d
1.00 d
Molecular methods :
Polymerase chain reaction
Sensitivity
Specificity
0.22 - 0.81e
0.77-1.00 e
0.50 - 0.90f
1.00 f
Data
Data
c
Data
d
Data
e
Data
f
Data
a
derived
derived
derived
derived
derived
derived
from
from
from
from
from
from
references
references
references
references
references
references
203-207
208-210
205,211-213
214-216
217-220
221-223
Table VI. Sensitivity and specificity of some commonly used non-conventional diagnostic tests in the diagnosis of extrapulmonary
tuberculosis
Test
Pleural fluid
Pericardial fluid
Cutoff
Sensitivity
Specificity
Cutoff
0.88
0.8
0.83
0.40
0.89
1.00
0.91
-
0.86
0.81
0.67
1.00
0.92
0.97
0.81
-
Perez-Rodriguez et al 227
Ocana et al 228
Burgess et al229
Dogan 230
Burgess et al231
Aggeli et al232
Gambhir et al233
Mishra et al234
45.5
48
35
100
40
45
50
-
50
30
72
-
1.00
0.94
1.00
-
IFN-
Villegas et al224
Wongtim et al 235
Sharma et al180
Burgess et al231
6*
240
134
-
0.86
0.95
0.89
-
0.97
0.96
0.97
-
200
ADA (IU/l)
Villegas et al224
Reechaipichitkul et al 225
Sharma et al226
* U/ml
pg/ml
ADA, adenosine deaminase; IFN-, interferon-
Sensitivity
Cerebrospinal fluid
Specificity
Cutoff
Sensitivity
Specificity
0.83
0.68
0.94
-
8
5
0.44
0.89
0.75
0.92
1.00
1.00
339
5-44
30-50
20-28
32
Pericardial 113
Intensive phase
(daily or three times a week)
Continuation phase
2HRZE (2HRZS)
6HE
(category I)
2H 3R3Z3E3 (2H3R3Z3S3)
4HR
4H 3R 3
2HRZ
6HE
2H 3R3Z 3
4HR
4H 3R 3
Immunodiagnostic methods
340
Table IX. Summary of recent randomised controlled trials of additional corticosteroid treatment in patients with extrapulmonary
tuberculosis
Study
Patients
Comments
Prednisone (n=30)
Placebo (n=36)
Galarza et al (1995)252
Prednisone (n=57)
Placebo (n=60)
Lee et al (1988)253
Prednisolone (n=21)
Placebo (n=19)
Corticosteroids, in conjunction
with ATT will resolve
the clinical symptoms more
quickly and hasten the
absorption of pleural effusion
Dexamethasone (n=75)
Placebo (n=85)
Standardised ATT
Adults: dexamethasone
12 mg/day;
children: 8 mg/day tapered
over 6 wk
Dexamethasone (n=24)
Placebo (n=23)
Standardised ATT
Oral dexamethasone 16mg/day
for 7 days; then 8mg/day
for 21 days
Rifampicin, isoniazid,
pyrazinamide, and ethambutol
for 2 months, followed by
rifampicin and isoniazid for a
further 4 months in standard
doses Prednisolone (60 mg/day)
tapered by 10 mg/week until
completion at the end of the
sixth week
Pleural effusion:
Wyser et al (1996)251
Tuberculosis meningitis:
Girgis et al (1991)254
Kumaravelu et al
(1994) 255
Pericardial tuberculosis:
Strang et al (1987) 107
Prednisolone (n=53)
Placebo (n=61)
Hakim et al (2000)256
Prednisolone (n=29)
Placebo (n=29)
341
342
343
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Surgery
Surgery is often required to procure specimens for
diagnostic testing and to ameliorate complications
such as intestinal perforation and hydrocephalus
where it may be life saving. Details regarding surgical
management of EPTB is beyond the scope of this
review.
Complications
Complications commonly seen in patients with
EPTB are listed in Table X. High index of clincal
suspicion and early institution of specific
antituberculosis treatment can help in reducing the
occurrence of these complications
In conclusion, high index of clinical suspicion,
timely judicious use of invasive diagnostic methods
344
13.
24.
14.
25.
15.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
16.
17.
18.
19.
20.
21.
22.
23.
51.
52.
53.
54.
55.
36.
37.
38.
39.
40.
345
41.
42.
43.
56.
44.
57.
45.
58.
46.
59.
47.
60.
48.
61.
49.
62.
346
78.
63.
79.
64.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
65.
Lee JH, Shin DH, Kang KW, Park SS, Lee DH. The
medical treatment of a tuberculous tracheo-oesophageal
fistula. Tuber Lung Dis 1992; 73 : 177-9.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
347
93.
94.
95.
96.
97.
98.
99.
348
131. Pandhi RK, Bedi TR, Kanwar AJ, Bhutani LK. Cutaneous
tuberculosis: a clinical and investigative study. Indian J
Dermatol 1977; 22 : 99-107.
349
350
178. Kim JY, Park YB, Kim YS, Kang SB, Shin JW, Park IW,
et al. Miliary tuberculosis and acute respiratory distress
syndrome. Int J Tuberc Lung Dis 2003; 7 : 359-64.
351
209. Park SC, Lee BI, Cho SN, Kim WJ, Lee BC,
Kim SM, et al. Diagnosis of tuberculous meningitis by
detection of immunoglobulin G antibodies to purified
protein derivative and lipoarabinomannan antigen in
cerebrospinal fluid. Tuber Lung Dis 1993; 74 : 317-22.
352
353
253. Lee CH, Wang WJ, Lan RS, Tsai YH, Chiang YC.
Corticosteroids in the treatment of tuberculous pleurisy.
A double-blind, placebo-controlled, randomized study.
Chest 1988; 94 : 1256-9.
Reprint requests: Dr S.K. Sharma, Professor & Head, Department of Medicine and Chief, Division of Pulmonary and
Critical Care Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
e-mail: sksharma@aiims.ac.in